Clinical impact of CCM mutation detection in familial cavernous angioma

Introduction and background A 3-year-old Bosnian girl with a large symptomatic brainstem and multiple supratentorial cavernous angiomas, who underwent neurosurgical treatment, is presented. As multiple cavernomas are more common in familial cases, genetic analyses and neuroradiological imaging were performed in the patient and her parents to see whether there was any evidence for inheritance. This information is important for genetic counseling and provision of medical care for at-risk relatives. Currently, no recommendation is available on how to manage these cases.Results Genetic analyses demonstrated a novel CCM1 frameshift mutation (c.1683_1684insA; p.V562SfsX6) in the child and the asymptomatic 27-year-old mother. Sensitive gradient-echo magnetic resonance imaging of the mother revealed multiple supratentorial lesions, whereas analogous imaging of the father showed no pathological findings.Conclusion This case exemplifies that seemingly sporadic cases with multiple lesions might well be hereditary and that presymptomatic genetic testing of family members may identify relatives for whom clinical and neuroradiological monitoring is indicated.     

颅内海绵状血管瘤 CCM1基因第12外显子及其5′端内含子新突变位点

目的　探讨 CCM1基因突变在中国人颅内海绵状血管瘤 ( intracranial cavernous angiomas,ICCA)发病中所起的作用。方法　收集我院神经外科 2 0 0 2年 6月～ 2 0 0 3年 2月收治并经手术病理证实的2 1例 ICCA患者及 15名正常健康对照者 ,从外周静脉血中提取 DNA,PCR法扩增 CCM1基因第 12外显子及其两侧部分内含子序列 ,应用 DNA直接测序技术对扩增产物进行检测。结果　 5例患者中检测出 3处 CCM1基因突变 ,均为首次发现。其中 ,5例患者中均存在 1172 C→ T的错义突变 ,使编码 KRIT1蛋白391位的氨基酸由丝氨酸变成苯丙氨酸。另有 1例患者存在 116 0 A→ C的错义突变 ,使编码 KRIT1蛋白387位氨基酸的谷氨酰胺变成脯氨酸。另一个突变发生在第 12外显子 5′端内含子区域 ,5例患者中有 4例第 4个碱基 C被 T取代。对照组检测结果无异常。结论　中国 ICCA患者存在 CCM1基因第 12外显子的突变 ,并与 ICCA的发病有关     

CCM2 expression during prenatal development and adult human neocortex

Cerebral cavernous malformation (CCM) is one of the most common types of vascular malformations of the central nervous system, affecting nearly one in 200 people. CCM lesions are characterized by grossly dilated vascular channels lined by a single layer of endothelium. Genetic linkage analyses have mapped three CCM loci to CCM1, CCM2 and CCM3. All three causative genes have now been identified allowing new insights into CCM pathophysiology. We focused on the CCM2 protein that might take place in blood vessel formation; we report here the expression patterns of CCM2 in prenatal development and adult human neocortex by means of immunohistochemistry and Western blot analysis. CCM2 was obviously detected in vascular endothelium and neuroglial precursor cells during development and also observed in arterial endothelium, neurons, some of the glial cells in adult neocortex. The expression patterns suggest that it could be one of the arterial markers whether this is a cause or a consequence of an altered vascular identity. CCM2 might play a role during vasculogenesis and angiogenesis during human brain development. Furthermore, with this study, CCM2 have been described for the first time in developing human neocortex.     

Current Ketamine Practice: Results of the 2016 American Society of Pain Management Nursing Survey on Ketamine

Background: Ketamine is increasingly utilized for a variety of pain management challenges. Audience comments from a ketamine presentation at the 2015 American Society of Pain Management Nursing (ASPMN) Conference reflected wide variation in ketamine practices as well as barriers to use. Aim: The goal was to gain a greater understanding of ASPMN member practice patterns and barriers related to ketamine as adjunctive therapy for pain management. Design: A questionnaire survey design was used. Settings: Respondents represented 35 states and 2 countries. Participants: The participants were 146 respondents from ASPMN membership (1,485 members). Methods: The survey was distributed by ASPMN on SurveyMonkey. Practice setting and ketamine administration practices were assessed with areas for comments. Results were reviewed using frequencies to describe responses and formatted into tables. Comments were individually reviewed and grouped into common themes. Results: Administration of ketamine as an analgesic was reported by 63% of respondents. Continuous intravenous ketamine infusions were the most common route of administration (65%); however, wide variability in dosing and length of therapy was reported. A wide variety of practices and challenges related to ketamine utilization were noted. Conclusions: Numerous studies have indicated the analgesic benefits of ketamine in pain management. The lack of practice standardization has created challenges to its consistent use and outcome measurement. Additionally, the off-label use of ketamine for pain management creates its own unique challenges. However, given the current national climate with intense focus on pain management, interdisciplinary practitioners have an ideal opportunity to evaluate ketamine's use in a comprehensive approach to pain management.     

Device interaction between cardiac contractility modulation (CCM) and subcutaneous defibrillator (S-ICD)

Combined implantation of cardiac contractility modulation (CCM) with subcutaneous implantable cardioverter-defibrillator (S-ICD) appears a suitable option to reduce the amount of intracardiac leads and complications for patients. Here we report on a patient with ischemic cardiomyopathy carrying an S-ICD in which a CCM device was implanted. During crosstalk testing post-CCM implantation, the S-ICD misannotated QRS complexes and T waves. The problem was solved through reprogramming the CCM, while preserving S-ICD functionality and improving heart failure symptoms. In conclusion, S-ICD combined with CCM seems to be a good and safe option for patients when device interference is being ruled out.     

Nerve function varies with hemoglobin A1c in controls and type 2 diabetes

Aims

To determine the cross-sectional threshold at which hemoglobin A1c (HbA1c) is associated with polyneuropathy in healthy controls, and the values associated with the most pronounced decline in nerve function in patients with diabetes.

Deep intronic KRIT1 mutation in a family with clinically silent multiple cerebral cavernous malformations

Loss‐of‐function mutations in CCM1/KRIT1, CCM2/MGC4607 and CCM3/PDCD10 genes are identified in the vast majority of familial cases with multiple cerebral cavernous malformations (CCMs). However, genomic DNA sequencing combined to large rearrangement screening fails to detect a mutation in 5% of those cases. We report a family in which CCM lesions were discovered fortuitously because of the investigation of a developmental delay in a boy. Three members of the family on three generations had typical multiple CCM lesions and no clinical signs related to CCM. No mutation was detected using genomic DNA sequencing and quantitative multiplex PCR of short fluorescent fragments (QMPSF). cDNA sequencing showed a 99‐nucleotide insertion between exons 5 and 6 of CCM1, resulting from a mutation located deep into intron 5 (c.262+132_262+133del) that activates a cryptic splice site. This pseudoexon leads to a premature stop codon. These data highly suggest that deep intronic mutations explain part of the incomplete mutation detection rate in CCM patients and underline the importance of analyzing the cDNA to provide comprehensive CCM diagnostic tests. This kind of mutation may be responsible for apparent sporadic presentations due to a reduced penetrance.     

Congruent validity and inter-day reliability of two breath by breath metabolic carts to measure resting metabolic rate in young adults

Background & aims

Achieving high inter-day reliability is a key factor to analyze the magnitude of change in RMR, for instance after an intervention. The aims of this study were: i) to determine the congruent validity of RMR and respiratory quotient (RQ) with two breath by breath commercially available metabolic carts [CCM Express (CCM) and Ultima CardiO2 (MGU)]; and ii) to analyze the inter-day reliability of RMR and RQ measurements.

Effects of cardiac contractility modulation by non-excitatory electrical stimulation on exercise capacity and quality of life: An individual patient's data meta-analysis of randomized controlled trials

Background

Although cardiac contractility modulation (CCM) has emerged as a promising device treatment for heart failure (HF), the effect of CCM on functional capacity and quality of life has not been the subject of an individual patient data meta-analysis to determine its effect on measures of functional capacity and life quality. This meta-analysis is aimed at systematically reviewing the latest available randomized evidence on the effectiveness of CCM on functional capacity and quality of life indexes in patients with HF.

Methods

The Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE were searched in May 2013 to identify eligible randomized controlled trials comparing CCM with sham treatment or usual care. Primary outcomes of interest were peak oxygen consumption, 6-minute walk test distance and quality of life measured by Minnesota Living With Heart Failure Questionnaire. There was no sufficient information to address safety. Mean difference and 95% confidence intervals (C.I.s) were calculated for continuous data using a fixed-effects model.

Results

Three studies enrolling 641 participants were identified and included. Pooled analysis showed that, compared to control, CCM significantly improved peak oxygen consumption (mean difference + 0.71, 95% C.I. 0.20 to 1.21 mL/kg/min, p = 0.006), 6-minute walk test distance (mean difference + 13.92, 95% C.I. − 0.08 to 27.91 m, p = 0.05) and quality of life measured by Minnesota Living With Heart Failure Questionnaire (mean difference − 7.17, 95% C.I. − 10.38 to − 3.96, p < 0.0001).

Conclusions

Meta-analysis of individual patient data from randomized trials suggests that CCM has significant if somewhat modest benefits in improving measures of functional capacity and quality of life.