Daytime Glycemic Variability and Frailty in Older Patients with Diabetes: a Pilot Study Using Continuous Glucose Monitoring.

We investigated the relationship between glucose variability and frailty. Forty-eight type 2 diabetic patients aged ≥ 65 years were enrolled. The FRAIL scale was used for frailty assessment, and participants were classified into 'healthy & pre-frail' (n = 24) and 'frail' (n = 24) groups. A continuous glucose monitoring (CGM) system was used for a mean of 6.9 days and standardized CGM metrics were analyzed: mean glucose, glucose management indicator (GMI), coefficient of variation, and time in range, time above range (TAR), and time below range. The demographics did not differ between groups. However, among the CGM metrics, mean glucose, GMI, and TAR in the postprandial periods were higher in the frail group (all P < 0.05). After multivariate adjustments, the post-lunch TAR (OR = 1.12, P = 0.019) affected the prevalence of frailty. Higher glucose variability with marked daytime postprandial hyperglycemia is significantly associated with frailty in older patients with diabetes.

The effect of distance between holes on the structural stability of subchondral bone in microfracture surgery: a finite element model study.

BACKGROUND: Microfracture is a surgical technique that involves creating multiple holes of 3-4 mm depth in the subchondral bone to recruit stem cells in the bone marrow to the lesion, inducing fibrocartilage repair and knee cartilage regeneration. Recently, it has been reported that increasing the exposed area of the lower cartilaginous bone (drilling a lot of holes) increases the outflow of stem cells, which is expected to affect the physical properties of the subchondral bone when the exposed area is large. The purpose of this study was to analyse the effect of the distance between the holes in the microfracture procedure on the structural stability of the osteochondral bone using a finite element method. METHODS: In this study, lateral aspects of the femoral knee, which were removed during total knee arthroplasty were photographed using microtomography. The model was implemented using a solitary walks program, which is a three-dimensional simplified geometric representation based on the basic microtomography data. A microfracture model was created by drilling 4 mm-deep holes at 1, 1.5, 2, 2.5, 3, 4, and 5 mm intervals in a simplified three-dimensional (3D) geometric femoral model. The structural stability of these models was analysed with the ABAQUS program. We compared the finite element model (FEM) based on the microtomography image and the simplified geometric finite element model. RESULTS: Von Mises stress of the subchondral bone plate barely increased, even when the distance between holes was set to 1 mm. Altering the distance between the holes had little impact on the structural stability of the subchondral bone plate. Safety factors were all below 1. CONCLUSIONS: Although we did not confirm an optimal distance between holes, this study does provide reference data and an epidemiological basis for determining the optimal distance between the holes used in the microfracture procedure.

Risk of osteoporosis after gastrectomy in long-term gastric cancer survivors.

INTRODUCTION: Although early detection and successful gastrectomy have improved the survival of patients with gastric cancer, long-term health problems remain troubling. We evaluated the prevalence of osteoporosis and its risk factors in long-term survivors of gastric cancer after gastrectomy. METHODS: We reviewed the medical records of a tertiary hospital between 2007 and 2014 to identify survivors of gastric cancer who had visited our center at around 5 years after gastrectomy. We evaluated their health status, including bone mineral density (BMD). Dual-energy X-ray absorptiometry was used to measure the BMD of the lumbar spine and femur (total and neck area). The prevalence of osteoporosis, defined by a BMD T score <-2.5, was investigated, and clinical variables associated with the presence of osteoporosis were identified. RESULTS: A total of 250 survivors were included. The mean age was 54.6 years old, and the median follow-up was 6.0 years. The prevalence of osteoporosis was 34.0% (27.4% for men and 43.6% for women). Older age [odds ratio (OR) 5.50, 95% CI 2.33-13.00], higher alkaline phosphatase levels before gastrectomy (OR 5.67, 95% CI 1.36-23.64), and marked weight loss (≥20%) after gastrectomy (OR 3.59, 95% CI 1.32-9.77) were independently associated with the presence of osteoporosis. CONCLUSIONS: In our cohort, osteoporosis was commonly observed in long-term survivors of gastric cancer, and several risk factors for it were identified. To reduce the risk of osteoporosis after gastrectomy, maintaining adequate body weight may be necessary.

Comparison of clinical outcomes and second-look arthroscopic findings after ACL reconstruction using a hamstring autograft or a tibialis allograft.

PURPOSE: The purpose of this prospective randomized clinical study was to compare the clinical and radiological outcomes, including tibial tunnel widening and the progression of osteoarthritis after ACL reconstruction using a hamstring autograft or a tibialis allograft. In addition, we compared the graft tear and synovial coverage of grafts in patients that underwent the second-look arthroscopy. METHODS: Among 184 patients with an ACL injury who underwent ACL reconstruction, 68 patients of autograft group and 64 patients of tibialis allograft group were included for this study after minimum of 2-year follow-up. The Lachman and pivot-shift tests, Tegner activity score, Lysholm knee score, and IKDC score were compared between the two groups. The quadriceps and hamstring isokinetic strengths using dynamometer were also compared. Degree of OA was determined using the Kellgren-Lawrence grading system on the weight-bearing radiographs. In total, 51 patients (26 patients in autograft group and 25 in the tibialis allograft group) underwent the second-look arthroscopy, in which we compared the apparent tear of graft and synovial coverage of grafts. RESULTS: At the final follow-up, there were no statistical significances in the two groups in Lachman and pivot-shift tests (n.s.). The Tegner activity, Lysholm knee score, and IKDC scores were similar in the two groups. Moreover, no significant differences were observed in the muscle power (n.s.). Some patients showed the progression of OA (five in autograft and four in allograft groups) without intergroup difference (n.s.). Regarding the findings of second-look arthroscopy, although there was no significant difference in graft tear, synovial coverage was better in autograft group than in allograft group. CONCLUSION: Even though hamstring autografts and tibialis allografts provided good functional outcomes without significant differences, the second-look arthroscopy revealed that hamstring autografts produced better synovial coverage than tibialis allograft. LEVEL OF EVIDENCE: I.

Assessing the accuracy of patient-specific guides for total knee arthroplasty.

PURPOSE: Patient-specific guides have been introduced recently as a means of making accurate bone cuts through custom cutting blocks constructed based on pre-operative three-dimensional imaging. However, the controversy concerning the improved results of patient-specific guides have not been resolved yet; in addition, there have been no studies to investigate the causes of variable with inconsistent results and solutions for the causes. METHODS: Thirty eight patients (38 knees) underwent total knee arthroplasty with patient-specific guides. The mean age of the patients was 68 years (SD ± 6.3), and all patients had a minimum 2-year follow-up. An intra-operative alignment using navigation and the causes of outliers were evaluated. RESULTS: An average coronal alignment of PSI jigs was 0.5° (SD ± 0.9°) in femur and 0.1° (SD ± 0.8°) in tibia, and the number of outliers was two and three cases, respectively. An average sagittal alignment was 0.6° (SD ± 0.9°) in femur and 5.5° (SD ± 1.1°) in tibia, and the number of outliers was three and five cases, respectively. All outliers resulted from large osteophytes near the contact point of patient-specific guides which disturb sitting of the guide. CONCLUSION: It was suggested that patient-specific guides were an effective and safe method to achieve accurate alignments, with no additional intra-operative complication. It is important to note that surgeons need to be precautious using the patient-specific instrumentation in patients with severe varus deformity. In addition, existing osteophytes which disturb sitting of the guides should be carefully evaluated pre-operatively and intra-operatively. LEVEL OF EVIDENCE: IV.

Polarization characteristics of semipolar (112̄2) InGaN/GaN quantum well structures grown on relaxed InGaN buffer layers and comparison with experiment.

Partial strain relaxation effects on polarization ratio of semipolar (112̄2) InxGa1−xN/GaN quantum well (QW) structures grown on relaxed InGaN buffers were investigated using the multiband effective-mass theory. The absolute value of the polarization ratio gradually decreases with increasing In composition in InGaN buffer layer when the strain relaxation ratio (ε0y'y'−εy'y')/ε0y'y' along y'-axis is assumed to be linearly proportional to the difference of lattice constants between the well and the buffer layer. Also, it changes its sign for the QW structure grown on InGaN buffer layer with a relatively larger In composition (x > 0.07). These results are in good agreement with the experiment. This can be explained by the fact that, with increasing In composition in the InGaN subsrate, the spontaneous emission rate for the y'-polarization gradually increases while that for x'-polarization decreases due to the decrease in a matrix element at the band-edge (k‖ = 0).

Asia-Pacific Perspectives on the Role of Continuous Glucose Monitoring in Optimizing Diabetes Management.

Diabetes is prevalent, and it imposes a substantial public health burden globally and in the Asia-Pacific (APAC) region. The cornerstone for optimizing diabetes management and treatment outcomes is glucose monitoring, the techniques of which have evolved from self-monitoring of blood glucose (SMBG) to glycated hemoglobin (HbA1c), and to continuous glucose monitoring (CGM). Contextual differences with Western populations and limited regionally generated clinical evidence warrant regional standards of diabetes care, including glucose monitoring in APAC. Hence, the APAC Diabetes Care Advisory Board convened to gather insights into clinician-reported CGM utilization for optimized glucose monitoring and diabetes management in the region. We discuss the findings from a pre-meeting survey and an expert panel meeting regarding glucose monitoring patterns and influencing factors, patient profiles for CGM initiation and continuation, CGM benefits, and CGM optimization challenges and potential solutions in APAC. While CGM is becoming the new standard of care and a useful adjunct to HbA1c and SMBG globally, glucose monitoring type, timing, and frequency should be individualized according to local and patient-specific contexts. The results of this APAC survey guide methods for the formulation of future APAC-specific consensus guidelines for the application of CGM in people living with diabetes.

Asia-Pacific consensus recommendations for application of continuous glucose monitoring in diabetes management.

Glucose monitoring has evolved from self-monitoring of blood glucose to glycated hemoglobin, and the latest continuous glucose monitoring (CGM). A key challenge to adoption of CGM for management of diabetes in Asia is the lack of regional CGM recommendations. Hence, thirteen diabetes-specialists from eight Asia-Pacific (APAC) countries/regions convened to formulate evidence-based, APAC-specific CGM recommendations for individuals with diabetes. We defined CGM metrics/targets and developed 13 guiding-statements on use of CGM in: (1) people with diabetes on intensive insulin therapy, and (2) people with type 2 diabetes on basal insulin with/without glucose lowering drugs. Continual use of CGM is recommended in individuals with diabetes on intensive insulin therapy and suboptimal glycemic control, or at high risk of problematic hypoglycemia. Continual/intermittent CGM may also be considered in individuals with type 2 diabetes on basal insulin regimen and with suboptimal glycemic control. In this paper, we provided guidance for optimizing CGM in special populations/situations, including elderly, pregnancy, Ramadan-fasting, newly diagnosed type 1 diabetes, and comorbid renal disease. Statements on remote CGM, and stepwise interpretation of CGM data were also developed. Two Delphi surveys were conducted to rate the agreement on statements. The current APAC-specific CGM recommendations provide useful guidance for optimizing use of CGM in the region.

Global dynamic conformational changes in the suppressor domain of IP3 receptor by stepwise binding of the two lobes of calmodulin.

The roles of calmodulin (CaM) have been key points of controversy in the regulation of inositol-1,4,5-trisphosphate receptor (IP(3)R). To address the issue, we studied the interaction between CaM and the suppressor domain of IP(3)R, a key allosteric regulatory domain. First, by means of a pulldown and a fluorescence titration experiment, we confirmed the interaction. Through subsequent NMR binding experiments, we observed dramatic peak disappearances of the suppressor domain on interaction with apo-CaM. The data indicated that apo-CaM induces large-scale dynamic conformational changes in the suppressor domain, involving partial unfolding and subdomain rearrangement. Analysis of the NMR data of CaM surprisingly revealed that its C lobe alone can cause such changes. Further binding experiments showed that calcium allows the free N lobe to bind to the suppressor domain, which induces extra conformational changes in both of the proteins. These results were also confirmed with CaM deletion mutants with either the N or C lobe. On the basis of this novel binding mechanism, we propose a model in which the partial unfolding of the suppressor domain by apo-CaM and the stepwise binding of the N lobe of CaM to the suppressor domain are important elements of calcium/CaM inhibition of IP(3)R. We believe that our working model encompasses previous regulation mechanisms of IP(3)R by calcium/CaM and provides new insights into the CaM-target interaction.

A wafer-level vacuum package using glass-reflowed silicon through-wafer interconnection for nano/micro devices.

We propose a vacuum wafer-level packaging (WLP) process using glass-reflowed silicon via for nano/micro devices (NMDs). A through-wafer interconnection (TWIn) substrate with silicon vias and reflowed glass is introduced to accomplish a vertical feed-through of device. NMDs are fabricated in the single crystal silicon (SCS) layer which is formed on the TWIn substrate by Au eutectic bonding including Cr adhesion layer. The WLPof the devices is achieved with the capping glass wafer anodically bonded to the SCS layer. In order to demonstrate the successful hermetic packaging, we fabricated the micro-Pirani gauge in the SCS layer, and packaged it in the wafer-level. The vacuum level inside the packaging was measured to be 3.1 Torr with +/- 0.12 Torr uncertainty, and the packaging leakage was not detected during 24 hour after the packaging.

Transcription factor AP-2ß regulates the neurotransmitter phenotype and maturation of chromaffin cells.

During development, sympathetic neurons and chromaffin cells originate from bipotential sympathoadrenal (SA) progenitors arising from neural crests (NC) in the trunk regions. Recently, we showed that AP-2ß, a member of the AP2 family, plays a critical role in the development of sympathetic neurons and locus coeruleus and their norepinephrine (NE) neurotransmitter phenotype. In the present study, we investigated the potential role of AP-2ß in the development of NC-derived neuroendocrine chromaffin cells of the adrenal medulla and the epinephrine (EPI) phenotype determination. In support of its role in chromaffin cell development, AP-2ß is prominently expressed in both embryonic and adult adrenal medulla. In adrenal chromaffin cells of the AP-2ß(-/-) mouse, the expression levels of catecholamine biosynthesizing enzymes, dopamine ß-hydroxylase (DBH) and phenylethanolamine-N-methyl-transferase (PNMT), as well as the SA-specific transcription factor, Phox2b, are significantly reduced compared to wild type. In addition, ultrastructural analysis demonstrated that the formation of large secretory vesicles, a hallmark of differentiated chromaffin cells, is defective in AP-2ß(-/-) mice. Furthermore, the level of EPI content is largely diminished (>80%) in the adrenal gland of AP-2ß(-/-) mice. Chromatin immunoprecipitation (ChIP) assays of rat adrenal gland showed that AP-2ß binds to the upstream promoter of the PNMT gene in vivo; strongly suggesting that it is a direct target gene. Overall, our data suggest that AP-2ß plays critical roles in the epinephrine phenotype and maturation of adrenal chromaffin cells.

Secretory granules in inositol 1,4,5-trisphosphate-dependent Ca2+ signaling in the cytoplasm of neuroendocrine cells.

Of all the intracellular organelles, secretory granules contain by far the highest calcium concentration; secretory granules of typical neuroendocrine chromaffin cells contain approximately 40 mM Ca(2+) and occupy approximately 20% cell volume, accounting for >60% of total cellular calcium. They also contain the majority of cellular inositol 1,4,5-trisphosphate receptors (IP(3)Rs) in addition to the presence of >2 mM of chromogranins A and B that function as high-capacity, low-affinity Ca(2+) storage proteins. Chromogranins A and B also interact with the IP(3)Rs and activate the IP(3)R/Ca(2+) channels. In experiments with both neuroendocrine PC12 and nonneuroendocrine NIH3T3 cells, in which the number of secretory granules present was changed by either suppression or induction of secretory granule formation, secretory granules were demonstrated to account for >70% of the IP(3)-induced Ca(2+) releases in the cytoplasm. Moreover, the IP(3) sensitivity of secretory granule IP(3)R/Ca(2+) channels is at least approximately 6- to 7-fold more sensitive than those of the endoplasmic reticulum, thus enabling secretory granules to release Ca(2+) ahead of the endoplasmic reticulum. Further, there is a direct correlation between the number of secretory granules and the IP(3) sensitivity of cytoplasmic IP(3)R/Ca(2+) channels and the increased ratio of IP(3)-induced cytoplasmic Ca(2+) release, highlighting the importance of secretory granules in the IP(3)-dependent Ca(2+) signaling. Given that secretory granules are present in all secretory cells, these results presage critical roles of secretory granules in the control of cytoplasmic Ca(2+) concentrations in other secretory cells.-Yoo, S. H. Secretory granules in inositol 1,4,5-trisphosphate-dependent Ca(2+) signaling in the cytoplasm of neuroendocrine cells.

Modulation of Inflammatory Pathways and Adipogenesis by the Action of Gentisic Acid in RAW 264.7 and 3T3-L1 Cell Lines.

Gentisic acid (GA), a benzoic acid derivative present in various food ingredients, has been shown to have diverse pharmaceutical activities such as anti-carcinogenic, antioxidant, and hepatoprotective effects. In this study, we used a co-culture system to investigate the mechanisms of the anti-inflammatory and anti-adipogenic effects of GA on macrophages and adipocytes, respectively, as well as its effect on obesity-related chronic inflammation. We found that GA effectively suppressed lipopolysaccharide-stimulated inflammatory responses by controlling the production of nitric oxide and pro-inflammatory cytokines and modulating inflammation-related protein pathways. GA treatment also inhibited lipid accumulation in adipocytes by modulating the expression of major adipogenic transcription factors and their upstream protein pathways. Furthermore, in the macrophage-adipocyte co-culture system, GA decreased the production of obesity-related cytokines. These results indicate that GA possesses effective anti-inflammatory and anti-adipogenic activities and may be used in developing treatments for the management of obesity-related chronic inflammatory diseases.

Inositol 1,4,5-trisphosphate receptor in chromaffin secretory granules and its relation to chromogranins.

The inositol 1,4,5-trisphosphate (IP(3))-mediated intracellular Ca(2+) releases in secretory cells play vital roles in controlling not only the intracellular Ca(2+) concentrations but also the Ca(2+)-dependent exocytotic processes. Of intracellular organelles that release Ca(2+) in response to IP(3), secretory granules stand out as the most prominent organelle and are responsible for the majority of IP(3)-dependent Ca(2+) releases in the cytoplasm of chromaffin cells. Bovine chromaffin granules were the first granules that demonstrated the IP(3)-mediated Ca(2+) release as well as the presence of the IP(3) receptor (IP(3)R) in granule membranes. Secretory granules contain all three (type 1, 2, and 3) IP(3)R isoforms, and 58-69% of total cellular IP(3)R isoforms are expressed in bovine chromaffin granules. Moreover, secretory granules contain large amounts (2-4 mM) of chromogranins and secretogranins; chromogranins A and B, and secretogranin II being the major species. Chromogranins A and B, and secretogranin II are high-capacity, low-affinity Ca(2+) binding proteins, binding 30-93 mol of Ca(2+)/mol of protein with dissociation constants of 1.5-4.0 mM. Due to this high Ca(2+) storage properties of chromogranins secretory granules contain ~40 mM Ca(2+). Furthermore, chromogranins A and B directly interact with the IP(3)Rs and modulate the IP(3)R/Ca(2+) channels, i.e., increasing the open probability and the mean open time of the channels 8- to 16-fold and 9- to 42-fold, respectively. Coupled chromogranins change the IP(3)R/Ca(2+) channels to a more ordered, release-ready state, whereby making the IP(3)R/Ca(2+) channels significantly more sensitive to IP(3).

Junctional membrane inositol 1,4,5-trisphosphate receptor complex coordinates sensitization of the silent EGF-induced Ca2+ signaling.

Ca(2+) is a highly versatile intracellular signal that regulates many different cellular processes, and cells have developed mechanisms to have exquisite control over Ca(2+) signaling. Epidermal growth factor (EGF), which fails to mobilize intracellular Ca(2+) when administrated alone, becomes capable of evoking [Ca(2+)](i) increase and exocytosis after bradykinin (BK) stimulation in chromaffin cells. Here, we provide evidence that this sensitization process is coordinated by a macromolecular signaling complex comprised of inositol 1,4,5-trisphosphate receptor type I (IP(3)R1), cAMP-dependent protein kinase (PKA), EGF receptor (EGFR), and an A-kinase anchoring protein, yotiao. The IP(3)R complex functions as a focal point to promote Ca(2+) release in two ways: (1) it facilitates PKA-dependent phosphorylation of IP(3)R1 in response to BK-induced elevation of cAMP, and (2) it couples the plasmalemmal EGFR with IP(3)R1 at the Ca(2+) store located juxtaposed to the plasma membrane. Our study illustrates how the junctional membrane IP(3)R complex connects different signaling pathways to define the fidelity and specificity of Ca(2+) signaling.

Effect of Voluntary Participation on Mobile Health Care in Diabetes Management: Randomized Controlled Open-Label Trial.

BACKGROUND: The role of mobile health care (mHealth) in glycemic control has been investigated, but its impact on self-management skills and its psychological aspects have not been studied. OBJECTIVE: We evaluated the efficacy of mHealth-based diabetes self-management education and the effect of voluntary participation on its effects. METHODS: This study was a randomized controlled open-label trial conducted for 6 months at Kangbuk Samsung Hospital. Participants in the control group (n=31) maintained their previous diabetes management strategies. Participants in the intervention group (n=41) additionally received mHealth-based diabetes self-management education through a mobile app and regular individualized feedback from health care professionals. The primary outcome was change in glycated hemoglobin (HbA1c) level over 6 months between the 2 groups (intervention versus control) and within each group (at 6 months versus baseline). The secondary outcomes were changes in body mass index, blood pressure, lipid profile, and questionnaire scores (the Korean version of the Summary of Diabetes Self-Care Activities Questionnaire, an Audit of Diabetes Dependent Quality of Life, the Appraisal of Diabetes Scale, and Problem Areas in Diabetes) over 6 months between groups and within each group. RESULTS: A total of 66 participants completed this study. HbA1c (P=.04), total cholesterol level (P=.04), and Problem Areas in Diabetes scores (P=.02) significantly decreased; total diet (P=.03) and self-monitoring of blood glucose level scores (P=.01), based on the Summary of Diabetes Self-Care Activities Questionnaire, markedly increased within the intervention group. These significant changes were observed in self-motivated participants who were recruited voluntarily via advertisements. CONCLUSIONS: mHealth-based diabetes self-management education was effective at improving glycemic control and diabetes self-management skills and lowering diabetes-related distress in voluntary participants. TRIAL REGISTRATION: ClinicalTrials.gov NCT03468283; http://clinicaltrials.gov/ct2/show/NCT03468283.

Neuroendocrine Targeting of Tissue Plasminogen Activator (t-PA).

t-PA has a widespread neuroendocrine distribution including prominent expression in chromaffin cells of the sympathoadrenal system. Chromaffin cell t-PA is sorted into catecholamine storage vesicles and co-released with catecholamines in response to sympathoadrenal activation, suggesting that catecholamine storage vesicles may serve as a reservoir for the rapid release of t-PA. Chromogranin A (CgA), a major core protein in secretory vesicles throughout the neuroendocrine system, may play a crucial role in targeting proteins into the regulated secretory pathway, by forming aggregated "granin" complexes to which other proteins destined for the regulated secretory vesicle bind and become separated from constitutively secreted proteins in the trans-Golgi network (TGN). Formation of such complexes is facilitated by conditions of the TGN (low pH, high Ca+2). We tested the hypothesis that t-PA interacts specifically with CgA and that this interaction is enhanced under conditions of the TGN. Immobilized t-PA was incubated with 125I-CgA. t-PA interacted specifically and saturably with CgA and the interaction was domain-specific, mediated by the EGF/finger and kringle 1 domains of t-PA and by a specific internal hydrophilic domain within CgA (KERTHQQKKHSSYEDELSEVL) as assessed by antibody and peptide competition studies. The interaction of t-PA with aggregated CgA complexes may play a role in the targeting of t-PA and its release from neurosecretory cells. These results may have broad implications for the regulation of local neurosecretory cell plasminogen activation under both normal physiological conditions and pathological conditions including cerebral ischemia.

Identification of residues participating in the interaction between an intraluminal loop of inositol 1,4,5-trisphosphate receptor and a conserved N-terminal region of chromogranin B.

The inositol 1,4,5-trisphosphate receptor (IP3R) is a membrane channel that conducts calcium ions from the intracellular calcium stores. Despite a wealth of information on the cytoplasmic regulation of the IP3R, little is known about its regulation on the luminal side of the calcium stores. Here, we report studies on the IP3R intraluminal loop L3-2 and a conserved N-terminal region of chromogranin B. The IP3R loop is an important part of the channel's pore-forming region, and the chromogranin peptide has been shown to competitively inhibit calcium signaling by IP3R. Using the NMR titration approach, we showed that a part of the L3-2 is involved in a specific interaction with the chromogranin B peptide. Further NMR resonance assignments revealed that the 14th-20th residues of L3-2 are the keys to the binding to the chromogranin B peptide. Through detailed analysis of the data, we suggest a mechanism of IP3R regulation by chromogranin B involving conformational exchanges of the L3-2 region. Our report presents the findings of the first study on the interaction between the luminal loop of the IP3 receptor and its regulator at residue-resolution. The approaches described here should help to guide further studies on the interactions between the IP3R and other luminal side regulators.

Early imatinib-mesylate-induced hepatotoxicity in chronic myelogenous leukaemia.

Imatinib mesylate is the first molecule of targeted therapy in chronic myelogenous leukaemia inhibiting constitutively activated BCR-ABL kinase. There are no long-term follow-up studies of large sample sizes to assess the toxicity of the use of imatinib mesylate over 10 years. Several cases of hepatotoxicity, including fatal liver failure, have been associated with the long-term use of imatinib mesylate. We report here on a patient who experienced immediate dominant cholestatic damage of the liver and mild hepatocyte damage during imatinib mesylate therapy. This differs from most reports showing dominantly acute hepatitis with necrosis associated with the use of imatinib mesylate.

Impact of initial active engagement in self-monitoring with a telemonitoring device on glycemic control among patients with type 2 diabetes.

This study aimed to investigate the effect of patient engagement in self-monitoring with a telemonitoring device on glycemic control among patients with type 2 diabetes. We conducted a subanalysis of the telemonitoring device study in Kaiser Permanente Northern California members. We divided the telemonitoring group into 53 frequent and 54 infrequent users based on self-monitoring of blood glucose (SMBG) frequency of the first 6 weeks. The frequency of SMBG transmitted from the telemonitoring device was examined over 24 weeks. Clinic and laboratory tests were collected at baseline, 6 weeks and 6 months. There was no significant difference in baseline HbA1c level between the two groups. After 6 months, change in HbA1c was -2.4 ± 1.6% among frequent users and -1.5 ± 1.5% among infrequent users (p = 0.003). The proportion of patients achieving target HbA1C level at 6 months was significantly higher among frequent users than among infrequent users. An increased frequency of SMBG was significantly correlated with a reduction in HbA1c at 6 months. In conclusion, initial active engagement in self-monitoring with a telemonitoring device could provide incremental improvement of glycemic control over 6 months.