Factors influencing the effectiveness of glucagon for preventing hypoglycemia

Background

Administration of small, intermittent doses of glucagon during closed-loop insulin delivery markedly reduces the frequency of hypoglycemia. However, in some cases, hypoglycemia occurs despite administration of glucagon in this setting.

Methods

Fourteen adult subjects with type 1 diabetes participated in 22 closed-loop studies, duration 21.5 ± 2.0 h. The majority of subjects completed two studies, one with insulin + glucagon, given subcutaneously by algorithm during impending hypoglycemia, and one with insulin + placebo. The more accurate of two subcutaneous glucose sensors was used as the controller input. To better understand reasons for success or failure of glucagon to prevent hypoglycemia, each response to a glucagon dose over 0.5 µg/kg was analyzed (n = 19 episodes).

Results

Hypoglycemia occurred in the hour after glucagon delivery in 37% of these episodes. In the failures, estimated insulin on board was significantly higher versus successes (5.8 ± 0.5 versus 2.9 ± 0.5 U, p < .001). Glucose at the time of glucagon delivery was significantly lower in failures versus successes (86 ± 3 versus 95 ± 3 mg/dl, p = .04). Sensor bias (glucose overestimation) was highly correlated with starting glucose (r = 0.65, p = .002). Prior cumulative glucagon dose was not associated with success or failure.

Conclusion

Glucagon may fail to prevent hypoglycemia when insulin on board is high or when glucagon delivery is delayed due to overestimation of glucose by the sensor. Improvements in sensor accuracy and delivery of larger or earlier glucagon doses when insulin on board is high may further reduce the frequency of hypoglycemia.     

GM-CSF differentially regulates eosinophil and neutrophil adhesive interactions with vascular endothelium in vivo

Allergic airway inflammation is characterized by elaboration of cytokines and chemokines leading to recruitment of inflammatory leukocytes, predominantly eosinophils, to the airways. Granulocyte macrophage colony stimulating factor (GM-CSF) is generated in the lungs of human subjects with asthma in response to allergen challenge and is necessary for the development of allergen-induced bronchial eosinophilia in mice. The effect of GM-CSF on human eosinophil and neutrophil interactions with the vascular endothelium under conditions of blood flow was investigated in post-capillary venules of the rabbit mesentery by intravital microscopy.While GM-CSF significantly reduced the rolling fraction of neutrophils in vivo and induced consistent shedding of neutrophil L-selectin in vitro, its effect on eosinophil rolling was variable. Eosinophils from 57% of the donors demonstrated inhibition of rolling, while eosinophils from the remaining 43% of donors demonstrated no inhibition or increased rolling. The variable effect of GM-CSF on inhibition of eosinophil rolling was associated with variable shedding of L-selectin in vitro. In contrast to the differential effect of GM-CSF on neutrophils versus eosinophils, stimulation with phorbol myristate acetate demonstrated a similar degree of inhibition of rolling and L-selectin shedding by neutrophils and eosinophils suggesting that there was no defect in L-selectin shedding in the eosinophil donors who did not respond to GM-CSF. Overall, these studies demonstrate that GM-CSF consistently inhibits interaction of neutrophils with endothelium in vivo, whereas its effect on eosinophil-endothelial interactions is variable. GM-CSF may thus be one factor accounting for the varying percentage of eosinophils and neutrophils recruited to sites of allergic inflammation in different individuals.     

Avoidance behaviors and negative psychological responses in the general population in the initial stage of the H1N1 pandemic in Hong Kong

Background  

During the SARS pandemic in Hong Kong, panic and worry were prevalent in the community and the general public avoided staying in public areas. Such avoidance behaviors could greatly impact daily routines of the community and the local economy. This study examined the prevalence of the avoidance behaviors (i.e. avoiding going out, visiting crowded places and visiting hospitals) and negative psychological responses of the general population in Hong Kong at the initial stage of the H1N1 epidemic.     

Potential and limitations of lamivudine monotherapy in chronic hepatitis B: evidence from genotyping

Background: Current oral therapy for hepatitis B virus (HBV) is limited by the presence of resistance leading to resumption of higher levels of HBV replication. Therefore, there is a need for a better definition of the potential role and limitations of lamivudine or similar therapies, used alone. Aims: To examine the viability of lamivudine and similar monotherapies as a treatment strategy in chronic HBV in the face of the worldwide burden of disease. Methods: We have reviewed the role of lamivudine monotherapy in the treatment of chronic HBV in a single tertiary referral liver centre over a 9‐year period. We analysed the outcome in 90 patients where lamivudine has apparently conferred long‐term viral suppression and investigated the development of genotypic resistance in the absence of ostensible phenotypic resistance. Patients were subdivided into hepatitis B e antigen (HBeAg)‐positive and anti‐HBe‐positive groups. Results: Virtually all HBeAg‐positive patients who failed to seroconvert have progressed to combination antiviral therapy. Only 19%(7/36) of HBeAg‐negative patients have continued suppression without detectable genotypic change after 4 years of therapy. Conclusions: These data demonstrate that despite a relatively low level of viraemia in HBeAg‐negative patients, we could detect resistance mutations by direct sequencing in all patients with amplifiable HBV DNA. Our results suggest that for patients with ongoing replication at ‘amplifiable’ levels of HBV DNA, but <10⁵ copies/ml, genotypic selection is readily detectable. Lamivudine monotherapy has not sufficed for the overwhelming majority of patients.     

Noninvasive blood glucose monitoring with optical coherence tomography: a pilot study in human subjects

OBJECTIVE: To study the feasibility of noninvasive blood glucose monitoring using optical coherence tomography (OCT) technique in healthy volunteers. RESEARCH DESIGN AND METHODS: An OCT system with the wavelength of 1,300 nm was used in 15 healthy subjects in 18 clinical experiments. Standard oral glucose tolerance tests were performed to induce changes in blood glucose concentration. Blood samples were taken from the right arm vein every 5 or 15 min. OCT images were taken every 10-20 s from the left forearm over a total period of 3 h. The slope of the signals was calculated at the depth of 200-600 micro m from the skin surface. RESULTS: A total of 426 blood samples and 8,437 OCT images and signals were collected and analyzed in these experiments. There was a good correlation between changes in the slope of noninvasively measured OCT signals and blood glucose concentrations throughout the duration of the experiments. The slope of OCT signals changed significantly (up to 2.8% per 10 mg/dl) with variation of plasma glucose values. The good correlation obtained between the OCT signal slope and blood glucose concentration is due to the coherent detection of backscattered photons, which allows measurements of OCT signal from a specific tissue layer without unwanted signal from other tissue layers. CONCLUSIONS: This pilot study demonstrated the capability of the OCT technique to monitor blood glucose concentration noninvasively in human subjects. Further studies with a larger number of subjects including diabetic subjects are planned to validate these preliminary results.     

Sodium current and potassium transient outward current genes in Brugada syndrome: screening and bioinformatics

Background

Brugada syndrome (BrS) is a primary arrhythmia syndrome characterized by the occurrence of malignant ventricular arrhythmias. Previously, the genes SCN1B, SCN3B, MOG1, and KCND3 have been associated with BrS. Recent data from exome screening efforts permit better discrimination between low-frequency genetic variants and true monogenetic disease-causing variants. We aimed to screen the genes SCN1B through SCN4B, MOG1, CAV3, and KCND3 for variations in a population of SCN5A negative Danish and Iranian BrS patients, as well as research prior associations using newly released exome data.

Methods

Screening of all exons and splice sites was performed using Sanger sequencing. Bioinformatic searches were performed in the Single-nucleotide polymorphism database (build 132) and in the National Heart, Lung, and Blood Institute Grand Opportunity Exome Sequencing Project (ESP) for both previously published variant-BrS associations and newly uncovered variations within the noted genes.

Results

A total of 42 BrS patients were screened, and 2 different nonsynonymous mutations in SCN1Bb (H162P and R214Q) were found in 2 different Danish patients. The variants were not found in 216 Danish controls, but R214Q was present in ESP data (5 of 841 alleles). No other mutations were found. Previously BrS-associated mutations in KNCD3 and SCN3B were also present in ESP data. This was not the case for MOG1, but a nonsense polymorphism was present in 0.5% of alleles.

Conclusions

Our study supports the association of SCN1Bb with BrS. However, recently released exome data make some of the prior associations of BrS with genes SCN3B, MOG1, and KCND3 less likely.     

ACR Appropriateness Criteria® Acute Onset Flank Pain-Suspicion of Stone Disease

ABSTRACT: Low dose (<3 mSv) noncontrast CT (NCCT) is the imaging study of choice for accurate evaluation of patients with acute onset of flank pain and suspicion of stone disease (sensitivity 97%, specificity 95%). NCCT can reliably characterize the location and size of an offending ureteral calculus, identify complications, and diagnose alternative etiologies of abdominal pain such as appendicitis. By comparison, the sensitivity of radiographs (59%) and ultrasound (24-57%) for the detection of renal and ureteral calculi is relatively poor. Ultrasound can accurately diagnose pelvicaliectasis and ureterectasis, but it may take several hours for these findings to develop. In the pregnant patient, however, ultrasound is a first line test as it does not expose the fetus to ionizing radiation. MR is an accurate test for the diagnosis of pelvicaliectasis and ureterectasis, but is less sensitive than CT for the diagnosis of renal and ureteral calculi. For patients with known stone disease whose stones are visible on radiographs, radiographs are a good tool for post-treatment follow-up.The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every two years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.     

Dual institution experience of extranodal marginal zone lymphoma reveals excellent long‐term outcomes

Extranodal marginal zone lymphoma (EMZL) is a B‐cell lymphoma arising from mucosa‐associated lymphoid tissue (MALT). The disease characteristics, clinical course and treatment vary considerably based on site of involvement. Because long‐term outcome data for EMZL are limited, we sought to describe the clinical details of a large number of patients with EMZL evaluated at the Case Comprehensive Cancer Center over a 12‐year period to identify prognostic markers including the impact of site of involvement. We identified 211 cases of EMZL involving the stomach (30%), ocular adnexa (19%), lungs (16%) and intestines (9%). Initial treatment included antibiotics (18%), radiation (21%), rituximab (20%), chemotherapy (3%), rituximab + chemotherapy (7%), surgery (17%) or observation (8%). After a median follow‐up of 44·3 months (range 2·2–214·9), median progression‐free survival (PFS) was 68·2 months (95% confidence interval [CI] 54·5–111·3) and median overall survival (OS) has not been reached. Age >60 years, elevated lactate dehydrogenase level (LDH), ≥4 lymph node groups involvement, and high follicular lymphoma international prognostic index (FLIPI) were associated with inferior PFS/OS. In summary, patients with EMZL have excellent prognosis with median OS in excess of 10 years. Age, elevated LDH, advanced disease, and high FLIPI score are associated with worse outcomes.     

Association of the Phe206Leu allele of the L-selectin gene with coronary artery disease

BACKGROUND AND AIMS: The aim of this study was to assess the association between the L-selectin Phe206Leu polymorphism and coronary artery disease. METHODS: A total of 322 patients (221 men and 101 women) with coronary artery disease in one or more vessels documented by angiography were studied; 157 subjects (85 men and 72 women) without atherosclerosis were included as controls. All subjects were genotyped for the L-selectin Phe206Leu gene polymorphism using polymerase chain reaction with sequence-specific primer (PCR-SSP). To assess disease severity, all patients were classified by numbers of coronary arteries with 50% stenosis. RESULTS: A significantly increased frequency of the 206Leu mutant allele was observed in patients with coronary artery disease compared to the controls. The 206Leu allele frequency occurred in 42% of the patients with coronary artery disease compared to 30% of the controls (p<0.009). No association was found between the severity of coronary artery disease and the L-selectin Phe206Leu polymorphism. CONCLUSION: Our findings suggest that carriage of L-selectin 206Leu mutant allele could contribute to susceptibility of Iranian individuals to contracting coronary artery disease.     

The effect of a six-month exercise program on very low-density lipoprotein apolipoprotein B secretion in type 2 diabetes

The dyslipidemia and insulin resistance of type 2 diabetes can be improved by aerobic exercise. The effect of 6 months supervised exercise on very low-density lipoprotein (VLDL) apolipoprotein B metabolism was investigated in patients with type 2 diabetes. Moderately obese patients (n = 18) were randomized into supervised (n = 9) and unsupervised (n = 9) exercise groups. All patients were given a training session and a personal exercise program and asked to exercise four times per week at 70% maximal oxygen uptake for 6 months. Patients in the supervised group had a weekly session with an exercise trainer. VLDL apolipoprotein (apo)B metabolism was measured with an infusion of 1-(13)C leucine before and after 6 months of the exercise program. Supervised exercise for 6 months resulted in a significant within-group decrease in percent hemoglobin A1c (P < 0.001), body fat (P < 0.004), nonesterified fatty acid (P < 0.04), and triglycerides (P < 0.05) and an increase in insulin sensitivity (P < 0.01). There was a decrease in VLDL apoB pool size (160.8 +/- 42.6 to 84.9 +/- 23.2 mg, P < 0.01) and VLDL apoB secretion rate (11.3 +/- 2.6 to 5.5 +/- 2.0 mg/kg.d, P < 0.05) with no change in fractional catabolic rate. In a between-group comparison, the decrease in VLDL apoB secretion rate in the supervised group did not achieve significance. This study demonstrates that in type 2 diabetes, a supervised exercise program reduces VLDL apoB pool size, which may be due to a decrease in VLDL apoB secretion rate.