Exceptional aggressiveness of cerebral cavernous malformation disease associated with PDCD10 mutations.

PurposeThe phenotypic manifestations of cerebral cavernous malformation disease caused by rare PDCD10 mutations have not been systematically examined, and a mechanistic link to Rho kinase-mediated hyperpermeability, a potential therapeutic target, has not been established.MethodsWe analyzed PDCD10 small interfering RNA-treated endothelial cells for stress fibers, Rho kinase activity, and permeability. Rho kinase activity was assessed in cerebral cavernous malformation lesions. Brain permeability and cerebral cavernous malformation lesion burden were quantified, and clinical manifestations were assessed in prospectively enrolled subjects with PDCD10 mutations.ResultsWe determined that PDCD10 protein suppresses endothelial stress fibers, Rho kinase activity, and permeability in vitro. Pdcd10 heterozygous mice have greater lesion burden than other Ccm genotypes. We demonstrated robust Rho kinase activity in murine and human cerebral cavernous malformation vasculature and increased brain vascular permeability in humans with PDCD10 mutation. Clinical phenotype is exceptionally aggressive compared with the more common KRIT1 and CCM2 familial and sporadic cerebral cavernous malformation, with greater lesion burden and more frequent hemorrhages earlier in life. We first report other phenotypic features, including scoliosis, cognitive disability, and skin lesions, unrelated to lesion burden or bleeding.ConclusionThese findings define a unique cerebral cavernous malformation disease with exceptional aggressiveness, and they inform preclinical therapeutic testing, clinical counseling, and the design of trials.Genet Med 17 3, 188-196

Peer-Led Diabetes Self-Management Program for Patients With Glycated Hemoglobin Values Greater Than 7%

INTRODUCTION: Type II diabetes mellitus is the 7th leading cause of death in Kalamazoo County. Glycated hemoglobin (HbA1c) is a biomarker used to evaluate blood glucose control spanning a 3-month period; a value \u3e7% indicates poorly controlled diabetes over the past 3 months. PURPOSE: To determine the effectiveness of a free diabetes self-management program when implemented in Kalamazoo County. METHODS: Nineteen individuals (5 males, 14 females, average age 58 years, range 39 to 82 years) with type II diabetes mellitus and a self-reported HbA1c \u3e7% enrolled in the study. These individuals began a 6-week diabetes self-management program, during which participants met in small groups for 2.5 hours each week. The focus of this program was for participants to build skills that enabled them to better manage their chronic disease by improving problem solving, nutrition, blood glucose monitoring, and working with healthcare providers. HbA1c values were obtained via medical records prior to program completion (baseline) and 3-months post-program. Surveys that evaluated subjective information were also obtained at baseline and 3-months post-program. RESULTS: Nearly 950 members of the Kalamazoo community with type II diabetes mellitus were contacted to participate in this free self-management program. Recruitment was a challenge as only 99 verbally agreed they would attend the program, of which 48 attended the first session and 19 of those enrolled in the study. Five participants were excluded due to medical-record-documented HbA1c values \u3c7%, 6 did not complete the program, and 1 was lost to follow-up. Of the 7 participants who completed their 3-month follow-up, most variables exhibited desirable trends from baseline to 3-months post-program, and those that remained unchanged were already within a desirable range at baseline. The variables closest to significance were an increase in median self-efficacy score (49 to 78 using a 0-80 scale, p = 0.062) and a decrease in median HbA1c (10.2% to 8.5%, p = 0.31). DISCUSSION: Despite limited statistical power due to small sample size, this program provided valuable education to many community members who may be considered underserved and have HbA1c values as high as 14%. Future work is needed to analyze the healthcare barriers these individuals endure and how they may be overcome. Facilitation of healthcare provider referral to the program may be an option that encourages both participant adherence and expansion of this low-cost diabetes education model throughout the community

Cytochrome P450 and Matrix Metalloproteinase Genetic Modifiers of Disease Severity in Cerebral Cavernous Malformation type 1

11sinonenoneChoquet, Hélène; Trapani, Eliana; Goitre, Luca; Trabalzini, Lorenza; Akers, Amy; Fontanella, Marco; Hart, Blaine L.; Morrison, Leslie A.; Pawlikowska, Ludmila; Kim, Helen; Retta, Saverio FrancescoChoquet, Hélène; Trapani, Eliana; Goitre, Luca; Trabalzini, Lorenza; Akers, Amy; Fontanella, Marco; Hart, Blaine L.; Morrison, Leslie A.; Pawlikowska, Ludmila; Kim, Helen; Retta, Saverio Francesc

Alcohol Use in Emerging Adulthood: Can Moffitt's Developmental Theory Help Us Understand Binge Drinking Among College Students?

It is well-known that college students are at an increased risk for alcohol use and binge drinking compared to their same-age peers who are not in college. We use Moffitt\u27s developmental taxonomy, specifically, her discussion of adolescence-limited offending, to contextualize this finding regarding this minor form of deviance. We also incorporate Arnett\u27s notion of emerging adulthood to argue that the maturity gap, as described by Moffitt, can extend beyond adolescence. The current research used data from Wave III of the National Longitudinal Study of Adolescent Health (N = 4,264). We examined differences in sample characteristics between respondents who were currently enrolled in college full-time and those who were not. We also estimated several logistic regression models to determine how full-time college status and two measures of maturity were correlated with weekly binge drinking. We found that respondents who were full-time college students had an increased risk for binge drinking and were also less mature than their peers. Further analyses indicated that full-time college students were at an increased risk for binge drinking because they lacked maturity and the lack of adult roles that characterize the college years gives students more freedom to binge drink. These results supported both Moffitt\u27s explanation of adolescence-limited offending and Arnett\u27s notion of emerging adults

A novel mouse model of cerebral cavernous malformations based on the two-hit mutation hypothesis recapitulates the human disease

Cerebral cavernous malformations (CCMs) are vascular lesions of the central nervous system appearing as multicavernous, blood-filled capillaries, leading to headache, seizure and hemorrhagic stroke. CCM occurs either sporadically or as an autosomal dominant disorder caused by germline mutation of one of the three genes: CCM1/KRIT1, CCM2/MGC4607 and CCM3/PDCD10. Surgically resected human CCM lesions have provided molecular and immunohistochemical evidence for a two-hit (germline plus somatic) mutation mechanism. In contrast to the equivalent human genotype, mice heterozygous for a Ccm1- or Ccm2-null allele do not develop CCM lesions. Based on the two-hit hypothesis, we attempted to improve the penetrance of the model by crossing Ccm1 and Ccm2 heterozygotes into a mismatch repair-deficient Msh2−/− background. Ccm1+/−Msh2−/− mice exhibit CCM lesions with high penetrance as shown by magnetic resonance imaging and histology. Significantly, the CCM lesions range in size from early-stage, isolated caverns to large, multicavernous lesions. A subset of endothelial cells within the CCM lesions revealed somatic loss of CCM protein staining, supporting the two-hit mutation mechanism. The late-stage CCM lesions displayed many of the characteristics of human CCM lesions, including hemosiderin deposits, immune cell infiltration, increased endothelial cell proliferation and increased Rho-kinase activity. Some of these characteristics were also seen, but to a lesser extent, in early-stage lesions. Tight junctions were maintained between CCM lesion endothelial cells, but gaps were evident between endothelial cells and basement membrane was defective. In contrast, the Ccm2+/−Msh2−/− mice lacked cerebrovascular lesions. The CCM1 mouse model provides an in vivo tool to investigate CCM pathogenesis and new therapies

Brain Vascular Malformation Consortium: Overview, Progress and Future Directions.

Brain vascular malformations are resource-intensive to manage effectively, are associated with serious neurological morbidity, lack specific medical therapies, and have no validated biomarkers for disease severity and progression. Investigators have tended to work in "research silos" with suboptimal cross-communication. We present here a paradigm for interdisciplinary collaboration to facilitate rare disease research. The Brain Vascular Malformation Consortium (BVMC) is a multidisciplinary, inter-institutional group of investigators, one of 17 consortia in the Office of Rare Disease Research Rare Disease Clinical Research Network (RDCRN). The diseases under study are: familial Cerebral Cavernous Malformations type 1, common Hispanic mutation (CCM1-CHM); Sturge-Weber Syndrome (SWS); and brain arteriovenous malformation in hereditary hemorrhagic telangiectasia (HHT). Each project is developing biomarkers for disease progression and severity, and has established scalable, relational databases for observational and longitudinal studies that are stored centrally by the RDCRN Data Management and Coordinating Center. Patient Support Organizations (PSOs) are a key RDCRN component in the recruitment and support of participants. The BVMC PSOs include Angioma Alliance, Sturge Weber Foundation, and HHT Foundation International. Our networks of clinical centers of excellence in SWS and HHT, as well as our PSOs, have enhanced BVMC patient recruitment. The BVMC provides unique and valuable resources to the clinical neurovascular community, and recently reported findings are reviewed. Future planned studies will apply successful approaches and insights across the three projects to leverage the combined resources of the BVMC and RDCRN in advancing new biomarkers and treatment strategies for patients with vascular malformations

Intracranial Hemorrhage Rate and Lesion Burden in Patients With Familial Cerebral Cavernous Malformation

Background Familial cerebral cavernous alformation (CCM) is an autosomal dominant disease caused by mutations in KRIT1, CCM2, or PDCD10. Cases typically present with multiple lesions, strong family history, and neurological symptoms, including seizures, headaches, or other deficits. Intracranial hemorrhage (ICH) is a severe manifestation of CCM, which can lead to death or long‐term neurological deficits. Few studies have reported ICH rates and risk factors in familial CCM. We report ICH rates and assess whether CCM lesion burden, a disease severity marker, is associated with risk of symptomatic ICH during follow‐up in a well‐characterized cohort of familial CCM cases. Methods and Results We studied 386 patients with familial CCM with follow‐up data enrolled in the Brain Vascular Malformation Consortium CCM Project. We estimated symptomatic ICH rates overall and stratified by history of ICH before enrollment. CCM lesion burden (total lesion count and large lesion size) assessed at baseline enrollment was tested for association with increased risk of subsequent ICH during follow‐up using Cox regression models adjusted for history of ICH before enrollment, age, sex, and family structure and stratified on recruitment site. The symptomatic ICH rate for familial CCM cases was 2.8 per 100 patient‐years (95% CI, 1.9–4.1). Those with ICH before enrollment had a follow‐up ICH rate of 4.5 per 100 patient‐years (95% CI, 2.6–8.1) compared with 2.0 per 100 patient‐years (95% CI, 1.3–3.5) in those without (P=0.042). Total lesion count was associated with increased risk of ICH during follow‐up (hazard ratio [HR], 1.37 per doubling of total lesion count [95% CI, 1.10–1.71], P=0.006). The symptomatic ICH rate for familial CCM cases was 2.8 per 100 patient‐years (95% CI, 1.9–4.1). Those with ICH before enrollment had a follow‐up ICH rate of 4.5 per 100 patient‐years (95% CI, 2.6–8.1) compared with 2.0 per 100 patient‐years (95% CI, 1.3–3.5) in those without (P=0.042). Total lesion count was associated with increased risk of ICH during follow‐up (hazard ratio [HR], 1.37 per doubling of total lesion count [95% CI, 1.10–1.71], P=0.006). Conclusions Patients with familial CCM with prior history of an ICH event are at higher risk for rehemorrhage during follow‐up. In addition, total CCM lesion burden is significantly associated with increased risk of subsequent symptomatic ICH; hence lesion burden may be an important predictor of patient outcome and aid patient risk stratification