Patient-Related and Angiographic Predictors of Restenosis After Excimer Laser Coronary Angioplasty

Excimer laser coronary angioplasty (ELCA) is a useful technique for the treatment of selected complex coronary lesions. However, this technology has been limited by significant restenosis and, to date, predictors of restenosis after use of this device are not clearly defined. In order to determine predictors of restenosis after ELCA, 43 lesions presenting with restenosis (> 50% diameter stenosis) at angiographic follow-up were compared to 46 lesions without restenosis, based on patient-related, qualitative and quantitative angiographic parameters. Univariate analysis revealed 9 variables with at least a borderline (p < 0.15) significant relation to restenosis: (1) age (p = 0.0759), (2) proximal left anterior descending site (p = 0.074), (3) presence of a restenotic lesion (p = 0.104), (4) lesion length (p = 0.0034), (5) reference diameter of the treated vessel (p = 0.0076), (6) post laser minimal luminal diameter (MLD) (p = 0.1160), (7) post-procedural MLD (p = 0.0001), (8) post-procedural stenosis (p = 0.0250) and (9) total procedural gain (p = 0.0051). After entering stepwise logistic regression analysis, only 3 variables emerged as independent predictors of restenosis: treatment of a restenotic lesion (p = 0.0255), lesion length (p = 0.0291) and post-procedural MLD (p = 0.0007). Based on these data, we conclude that post-procedural MLD is the most important predictor of restenosis after ELCA. Lesion length and the treatment of restenotic lesions are also independently associated with an increased risk of restenosis after ELCA. Therefore, achieving the best possible luminal result at the time of the first intervention should be the goal of the procedure, especially when treating high restenosis risk lesions.     

Consensus-based clinical guidelines for ambulatory electromyography and contingent electrical stimulation in sleep bruxism

As yet, there are still no evidence-based clinical diagnostic and management guidelines for ambulatory single-channel EMG devices, like the BUTLER^® GrindCare^® (GrindCare), that are used in patients with sleep bruxism. Therefore, a consensus meeting was organised with GrindCare developers, researchers, and academic and non-academic clinicians experienced with the use of ambulatory EMG devices. The aim of the meeting was to discuss and develop recommendations for clinical guidelines for GrindCare usage, based on the existing clinical and research experience of the consensus meeting's participants. As an important outcome of the consensus meeting, clinical guidelines were proposed in which an initial 2-week baseline phase with the device in its inactive (non-stimulus) mode for habituation and assessment of the number of jaw-muscle activities is followed by a 4-week active phase with contingent electrical stimuli suppressing the jaw-muscle activities. As to avoid the commonly reported reduction in sensitivity to the stimuli, a 2-week inactive phase is subsequently installed, followed by a repetition of active and inactive phases until a lasting reduction in the number of jaw-muscle activities and/or associated complaints has been achieved. This proposal has the characteristics of a single-patient clinical trial. From a research point of view, adoption of this approach by large numbers of GrindCare users creates a great opportunity to recruit relatively large numbers of study participants that follow the same protocol.     

The common 'thermolabile' variant of methylene tetrahydrofolate reductase is a major determinant of mild hyperhomocysteinaemia

Mild hyperhomocysteinaemia is a major risk factor for vascular disease and neural tube defects (NTDs), conferring an approximately three-fold relative risk for each condition. It has several possible causes: heterozygosity for rare loss of function mutations in the genes for 5,10-methylene tetrahydrofolate reductase (MTHFR) or cystathionine-&bgr;-synthase (CBS); dietary insufficiency of vitamin co-factors B6, B12 or folates; or homozygosity for a common 'thermolabile' mutation in the MTHFR gene which has also been associated with vascular disease and NTDs. We quantified the contribution of the thermolabile mutation to the hyperhomocysteinaemic phenotype in a working male population (625 individuals). Serum folate and vitamin B12 concentrations were also measured and their relationship with homocysteine status and MTHFR genotype assessed. The homozygous thermolabile genotype occurred in 48.4, 35.5, and 23.4% for the top 5, 10 and 20% of individuals repectively) ranked by plasma homocysteine levels, compared with a frequency of 11.5% in the study population as a whole establishing that the mutation is a major determinant of homocystein levels at the upper end of the range. Serum folate concentrations also varied with genotype, being lowest in thermolabile homozygotes. The MTHFR thermolabile genotype should be considered when population studies are designed to determine the effective homocysteine-lowering dose of dietary folate supplements, and when prophylactic doses of folate are recommended for individuals.      

Insights into primary ovarian insufficiency through genetically engineered mouse models

Primary ovarian insufficiency (POI), also known as premature ovarian failure, is a form of hypergonadotropic hypogonadism that causes infertility in ~1% of women <40 years of age. POI has important health consequences for affected patients; however, the mechanisms that cause ovarian dysfunction are poorly understood. Elucidating these mechanisms is paramount to developing better testing and treatment strategies for affected girls and women. For obvious reasons, studies looking directly at the human ovary are extremely limited. Recently, numerous genetically engineered mouse models have been developed to investigate the molecular mechanisms that may be involved in the pathogenesis of POI. Two potential mechanisms may be involved in the development of POI: (1) abnormalities in primordial follicle activation and (2) increased rates of apoptosis of oocytes. Each of these mechanisms may lead to early depletion of ovarian follicular reserve, and thus be a contributing factor in POI. This review addresses current knowledge of molecular mechanisms controlling primordial follicle activation and oocyte apoptosis, as evidenced from various genetic mouse models. Translation of these data into clinically effective treatments or even prevention strategies may improve fertility and quality of life for women with this form of reproductive dysfunction.     

Differential roles of telomere attrition in type I and II endometrial carcinogenesis

Endometrial cancer has been generally categorized into two broad groups of tumors, type I (TI) and type II (TII), with distinct epidemiological/clinical features and genetic alterations. Because telomere attrition appears to trigger genomic instability in certain cancers, we explored the role of telomere dysfunction in endometrial cancer by analyzing telomeres and other markers of telomere status in both tumor types. We describe a new method, telomere chromogenic in situ hybridization, which permitted us to detect cells with short telomeres relative to control (stromal) cells within the same tissue section. Using this method, we found that both types of tumor cells had short telomeres. However, only TII tumors were significantly associated with critical telomere shortening in adjacent, morphologically normal epithelium, suggesting that telomere shortening contributes to the initiation of TII but not TI tumors. To explore this hypothesis, we analyzed mice with critically short telomeres and documented distinctive endometrial lesions that histologically resembled the in situ precursor of TII serous carcinomas; these lesions have not been observed previously in TI mouse models of endometrial cancer. Based on this and previous studies, we propose a model in which telomere attrition contributes to the initiation of TII and progression of TI endometrial cancers.