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.     

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.     

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.     

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.     

The role of MSX1 in tooth agenesis in Iranians

INTRODUCTION: MSX1 gene has a critical role in craniofacial development, the aim of this case-control study is to test the hypothesis that MSX1 mutation contributes to congenital tooth agenesis in Iranians. MATERIALS AND METHODS: The study group consisted of 20 affected individuals with tooth agenesis of lower second premolars or upper lateral incisors with mean age of 24.6. The control group consisted of 20 unaffected individuals. DNA was extracted from all 40 individuals; the polymerase chain reaction (PCR) for MSX1 was carried out with Phenol: Chloroform: Isoamylalchol (PCI) extraction method. Ban II restriction digest and agarose gel electrophoresis of the 20 affected individuals verified the presence of mutation in all 20 affected individuals. The unaffected controls did not show any mutation. Statistical analysis performed by the chi-squared method. RESULTS: Ban II did not digest PCR product (DNA) in the control group (195 bp band on electrophoresis gel) but digested the affected allele (106 bp and 89 bp bands). There is a statistically significant correlation between tooth agenesis and MSX1 mutation (P < 0.001). CONCLUSION: The results indicated that MSX1 gene mutation contributes to tooth agenesis in Iranian individuals. As the timing of tooth calcification can vary, radiographic finding of congenital tooth agenesis can be confirmed by this molecular method during different dental ages to achieve certainty.     

Subarachnoid hemorrhage following spontaneous intracranial carotid artery dissection

Summary Subarachnoid hemorrhage due to spontaneous dissection of intracranial vessels is uncommon. Most such cases are confined to the posterior circulation. Dissection of an intracranial carotid artery producing subarachnoid hemorrhage without a focal ischemic event is rarely documented. We report a case and review the subject.     

Intravascular ultrasound of normal left main arteries: Insights for stent optimization and standardization

• Left main (LM) lumen diameters >4 mm are the norm and diameter >4.5 mm is present in almost 50% of patients by intravascular ultrasound (IVUS).
• Normal LM minimum lumen area averages 14.1 mm² for women and 16.2 mm² for men, requiring an area stenosis of 57–63% for LM lesion to be hemodynamically significant using the prevailing criterion of 6 mm² as a cut‐off for revascularization.
• Incomplete LM visualization with IVUS is common (68%) without dedicated and specific LM IVUS techniques.