Electronic Medical Record Cancer Incidence over Six Years Comparing New Users of Glargine with New Users of NPH Insulin

Background: Recent studies suggested that insulin glargine use could be associated with increased risk of cancer. We compared the incidence of cancer in new users of glargine versus new users of NPH in a longitudinal clinical cohort with diabetes for up to 6 years. Methods and Findings: From all patients who had been regularly followed at Massachusetts General Hospital from 1/01/2005 to 12/31/2010, 3,680 patients who had a medication record for glargine or NPH usage were obtained from the electronic medical record (EMR). From those we selected 539 new glargine users (age: 60.1±13.6 years, BMI: 32.7±7.5 kg/m2) and 343 new NPH users (61.5±14.1 years, 32.7±8.3 kg/m2) who had no prevalent cancer during 19 months prior to glargine or NPH initiation. All incident cancer cases were ascertained from the EMR requiring at least 2 ICD-9 codes within a 2 month period. Insulin exposure time and cumulative dose were validated. The statistical analysis compared the rates of cancer in new glargine vs. new NPH users while on treatment, adjusted for the propensity to receive one or the other insulin. There were 26 and 28 new cancer cases in new glargine and new NPH users for 1559 and 1126 person-years follow-up, respectively. There were no differences in the propensity-adjusted clinical characteristics between groups. The adjusted hazard ratio for the cancer incidence comparing glargine vs. NPH use was 0.65 (95% CI: 0.36–1.19). Conclusions: Insulin glargine is not associated with development of cancers when compared with NPH in this longitudinal and carefully retrieved EMR data

Cystamine Preparations Exhibit Anticoagulant Activity

Transglutaminases are a superfamily of isoenzymes found in cells and plasma. These enzymes catalyze the formation of ε-N-(γ-glutamyl)-lysyl crosslinks between proteins. Cystamine blocks transglutaminase activity and is used in vitro in human samples and in vivo in mice and rats in studies of coagulation, immune dysfunction, and inflammatory disease. These studies have suggested cystamine blocks fibrin crosslinking and has anti-inflammatory effects, implicating transglutaminase activity in the pathogenesis of several diseases. We measured the effects of cystamine on fibrin crosslinking, tissue factor-triggered plasma clot formation and thrombin generation, and coagulation factor enzymatic activity. At concentrations that blocked fibrin crosslinking, cystamine also inhibited plasma clot formation and reduced thrombin generation. Cystamine inhibited the amidolytic activity of coagulation factor XI and thrombin towards chromogenic substrates. These findings demonstrate that cystamine exhibits anticoagulant activity during coagulation. Given the close relationship between coagulation and inflammation, these findings suggest prior studies that used cystamine to implicate transglutaminase activity in disease pathogenesis warrant re-examination

Personalized Genetic Risk Counseling to Motivate Diabetes Prevention: A randomized trial

OBJECTIVE To examine whether diabetes genetic risk testing and counseling can improve diabetes prevention behaviors. RESEARCH DESIGN AND METHODS We conducted a randomized trial of diabetes genetic risk counseling among overweight patients at increased phenotypic risk for type 2 diabetes. Participants were randomly allocated to genetic testing versus no testing. Genetic risk was calculated by summing 36 single nucleotide polymorphisms associated with type 2 diabetes. Participants in the top and bottom score quartiles received individual genetic counseling before being enrolled with untested control participants in a 12-week, validated, diabetes prevention program. Middle-risk quartile participants were not studied further. We examined the effect of this genetic counseling intervention on patient self-reported attitudes, program attendance, and weight loss, separately comparing higher-risk and lower-risk result recipients with control participants. RESULTS The 108 participants enrolled in the diabetes prevention program included 42 participants at higher diabetes genetic risk, 32 at lower diabetes genetic risk, and 34 untested control subjects. Mean age was 57.9 ± 10.6 years, 61% were men, and average BMI was 34.8 kg/m2, with no differences among randomization groups. Participants attended 6.8 ± 4.3 group sessions and lost 8.5 ± 10.1 pounds, with 33 of 108 (30.6%) losing ≥5% body weight. There were few statistically significant differences in self-reported motivation, program attendance, or mean weight loss when higher-risk recipients and lower-risk recipients were compared with control subjects (P > 0.05 for all but one comparison). CONCLUSIONS Diabetes genetic risk counseling with currently available variants does not significantly alter self-reported motivation or prevention program adherence for overweight individuals at risk for diabetes

Behavioral deficits, early gliosis, dysmyelination and synaptic dysfunction in a mouse model of mucolipidosis IV

Mucolipidosis IV (MLIV) is caused by mutations in the gene MCOLN1. Patients with MLIV have severe neurologic deficits and very little is known about the brain pathology in this lysosomal disease. Using an accurate mouse model of mucolipidosis IV, we observed early behavioral deficits which were accompanied by activation of microglia and astrocytes. The glial activation that persisted during the course of disease was not accompanied by neuronal loss even at the late stage. In vivo [Ca2+]-imaging revealed no changes in resting [Ca2+] levels in Mcoln1−/− cortical neurons, implying their physiological health. Despite the absence of neuron loss, we observed alterations in synaptic plasticity, as indicated by elevated paired-pulse facilitation and enhanced long-term potentiation. Myelination deficits and severely dysmorphic corpus callosum were present early and resembled white matter pathology in mucolipidosis IV patients. These results indicate the early involvement of glia, and challenge the traditional view of mucolipidosis IV as an overtly neurodegenerative condition. Electronic supplementary material The online version of this article (doi:10.1186/s40478-014-0133-7) contains supplementary material, which is available to authorized users

Cystamine inhibits plasma clot formation.

<p>Plasma clot formation was triggered by re-calcification and addition of lipidated tissue factor, in the presence of cystamine. Clot formation was monitored by turbidity. The data are representative of four experiments.</p

Cystamine inhibits fibrin crosslinking.

<p>Representative western blots and densitometry analysis showing the effects of cystamine (A, B) and T101 (C, D) on fibrin formation and crosslinking. Plasma was clotted by re-calcification and addition of lipidated tissue factor in the presence of cystamine or T101. Samples were reduced, boiled and separated by SDS-PAGE and identified by western blotting with anti-fibrinogen polyclonal antibody. MWM, molecular weight marker. NPP, un-clotted normal-pooled plasma. The upper high MW band (indicated by asterisk on the blot) was used for densitometry analysis of this species.</p

Clot formation and thrombin generation parameters.

<p>Mean ± standard deviation</p><p>*<i>P</i><0.05 vs 0 mM cystamine (untreated plasma)</p><p>Clot formation and thrombin generation parameters.</p

Cystamine inhibits the amidolytic activity of coagulation enzymes.

<p>Factors IXa (circles), Xa (squares), VIIa (diamonds), XIa (triangles), and thrombin (inverted triangles) amidolytic activity were assayed by incubating enzymes with cystamine (A) or T101 (B) and measuring the cleavage rate of chromogenic substrates. The data show means of 2–3 experiments per enzyme.</p

Cancer free survival curves in new glargine and NPH insulin users.

<p>Cancer free survival curves in new glargine and NPH insulin users.</p

Comparison of cancer incidence between new glargine and NPH users (Intent-to-Treat Analysis).

<p>CI, confidence interval; HR, hazard ratio. Note: Unadjusted HR and 95% CI were obtained from a Cox proportional hazards model adjusting for treatment only. Adjusted HR and 95% CI were obtained from a Cox proportional hazards model that adjusted for all variables listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0109433#pone-0109433-t001" target="_blank">table 1</a> using inverse probability of treatment weights. Patients were followed until the first occurrence of one of the following events: the patient developed cancer, death, the study ended, or one year after the patient’s last visit in the database.</p><p>Comparison of cancer incidence between new glargine and NPH users (Intent-to-Treat Analysis).</p