Results of the Phase I Trial of RG7112, a Small-Molecule MDM2 Antagonist in Leukemia.

Purpose: RG7112 is a small-molecule MDM2 antagonist. MDM2 is a negative regulator of the tumor suppressor p53 and frequently overexpressed in leukemias. Thus, a phase I study of RG7112 in patients with hematologic malignancies was conducted.

Distress and psychosocial needs of a heterogeneous high risk familial cancer population.

In order to assess the levels of distress and psychosocial support needs of a high risk population, we undertook a study to look at both the objective and subjective levels of distress and the wants and needs of individuals from a high familial cancer risk population. Three hundred and eighteen individuals (160 affected, 158 unaffected) completed several distress and psychosocial needs questionnaires (including the Brief Symptom Inventory-18). Sixty key informants were also surveyed about their perspective on the support needs of this population.

Muenke syndrome with pigmentary disorder and probable hemimegalencephaly: An expansion of the phenotype.

We describe a 2-year-old boy born to healthy, consanguineous parents. He had craniofacial asymmetry with left frontal bossing, midface hypoplasia, proptosis, and low-set ears. In addition, he had curly, light hair, and oval hypomelanotic patches in the abdomen, lower limbs and back and one hyperpigmented patch in the groin without acanthosis nigricans.

Polymorphisms in multiple genes are associated with resting heart rate in a stepwise allele-dependent manner.

Objective: The purpose of this study was to use a candidate gene approach to identify common polymorphisms that are associated with resting sinus heart rate in a population without overt cardiovascular disease.

Background: Increased resting heart rate is significantly associated with susceptibility to development of myocardial infarction, sudden cardiac death, and overall cardiac mortality.

Methods: A longitudinal cohort of 1468 individuals (active and retired middle-aged Canadian firefighters) who were enrolled in the Firefighters and Their Endothelium (FATE) study was evaluated.

Comments on 'Flow dependence and repeatability of interrupter resistance in lower airways and nose'.

The authors (Eiser et al 2005 Physiol. Meas. 26 143-56) have undertaken a much needed investigation into the extent of the flow dependence of resistance, as measured by the interrupter technique (Rint).

Evaluation of BRCA1 and BRCA2 mutation prevalence, risk prediction models and a multistep testing approach in French-Canadian families with high risk of breast and ovarian cancer.

Background And Objective: In clinical settings with fixed resources allocated to predictive genetic testing for high-risk cancer predisposition genes, optimal strategies for mutation screening programmes are critically important. These depend on the mutation spectrum found in the population under consideration and the frequency of mutations detected as a function of the personal and family history of cancer, which are both affected by the presence of founder mutations and demographic characteristics of the underlying population. The results of multistep genetic testing for mutations in BRCA1 or BRCA2 in a large series of families with breast cancer in the French-Canadian population of Quebec, Canada are reported.

The effect of iron status on vascular health.

The effect of increased iron stores on the progression of atherosclerosis and endothelial health remains inconclusive. This study was designed to evaluate the relationship between hemochromatosis genotypes, serum ferritin levels and presymptomatic vascular abnormalities in a cohort of healthy subjects. Carotid intima-media thickness (CIMT) and brachial flow-mediated vasodilation (FMD) were assessed by high-resolution ultrasound in 907 male (47 +/- 10 years) participants enrolled in the Firefighters and their Endothelium (FATE) study.

No Evidence of BRCA1/2 genomic rearrangements in high-risk French-Canadian breast/ovarian cancer families.

The discovery of deleterious mutations in the breast and ovarian cancer susceptibility genes, BRCA1 and BRCA2, has facilitated the identification of individuals at particularly high risk of these diseases. There is a wide variation between populations in the prevalence and related risks of various types of BRCA1/2 mutations, so estimates cannot be extrapolated to Canadians, especially not founder populations such as French- Canadians. Polymerase chain reaction (PCR)-based methods were used to detect the majority of these mutations.

Partnering in oncogenetic research--the INHERIT BRCAs experience: opportunities and challenges.

Today it is common to conduct research in collaboration with colleagues from different disciplines and institutions. The INterdisciplinary HEalth Research International Team on BReast CAncer susceptibility (INHERIT BRCAs), involves Canadian and international experts from diverse fields working with health service providers, patients and collaborators from the World Health Organization and other European networks. Evidence-based information and knowledge transfer drive our efforts to advance genomic research to understand the genetic basis of cancer susceptibility and treatment response.

Adult onset spinocerebellar ataxia in a Canadian movement disorders clinic.

Background: The spinocerebellar ataxias (SCAs) are a genetically and clinically heterogeneous group of neurodegenerative disorders. Relative frequencies vary within different ethnic groups and geographical locations.

Objectives: 1) To determine the frequencies of hereditary and sporadic adult onset SCAs in the Movement Disorders population; 2) to assess if the fragile X mental retardation gene 1 (FMR1) premutation is found in this population.

No evidence of false reassurance among women with an inconclusive BRCA1/2 genetic test result.

Background: Little is known about how women who receive an inconclusive result from BRCA1/2 testing interpret their result. Clinical observations suggest that some of them may be falsely reassured and, consequently, may not adhere to recommended surveillance. The purpose of this study is to evaluate whether women with inconclusive BRCA1/2 test results are falsely reassured.

A new alternative splice variant of BRCA1 containing an additional in-frame exon.

The breast/ovarian cancer susceptibility gene BRCA1 interact with multiple protein complexes involved in cellular mechanisms, such as DNA repair, transcription, homologous recombination and cell cycle regulation. Extensive analyses over the past decade led to the detection of several BRCA1 alternative splice variants. Here, we identify the first BRCA1 alternative splice variant containing an additional in-frame exon.

Pressure oscillation amplitude after interruption of tidal breathing as an index of change in airway mechanics in preschool children.

Bronchodilator reversibility testing using change in airway resistance during interruption (Rint) is feasible in preschool children. Analysis of postocclusion oscillations of the mouth pressure-time transient (Pmo(t)), recorded during airflow interruption, may offer an alternative index of change in airway mechanics. We analyzed Pmo(t) oscillation amplitude in three different ways: 1) difference between the first relative maximum and minimum (AMxMn); 2) detection of the dominant frequency using Fourier analysis (AFS); and 3) curve-fitting based on a mathematical model (ACurv).

Molecular and genealogical characterization of the R1443X BRCA1 mutation in high-risk French-Canadian breast/ovarian cancer families.

The Quebec population contains about six-million French Canadians, descended from the French settlers who colonized "Nouvelle-France" between 1608 and 1765. Although the relative genetic contribution of each of these founders is highly variable, altogether they account for the major part of the contemporary French-Canadian gene pool. This study was designed to analyze the role of this founder effect in the introduction and diffusion of the BRCA1 recurrent R1443X mutant allele.

An open-label pilot study of methylphenidate in the treatment of cocaine dependent patients with adult attention deficit/hyperactivity disorder.

A multi-site, open-label study of methylphenidate for treating patients with comorbid diagnoses of attention deficit/hyperactivity disorder and cocaine dependence was performed. Forty-one participants, who met DSM-IV criteria for adult attention deficit/hyperactivity disorder and cocaine dependence, were enrolled into this ten week outpatient study. The targeted total daily dose of methylphenidate was 60 mg (20 mg TID).

Cortical gray matter volumes are associated with subjective responses to cocaine infusion.

We analyzed the relationship between cocaine-induced euphoria and measures of frontal and temporal gray matter volumes in eleven cocaine-dependent (CD) patients who underwent magnetic resonance imaging (MRI). Self-reported ratings of the intensity of euphoric response to cocaine infusion were obtained from the CD subjects at 3, 10, and 30 minutes after cocaine infusion. Significant positive correlation between frontal and temporal cortical gray matter volume and the intensity of euphoria was observed at 10 minutes after IV cocaine.

Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone.

Background: Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone has been proposed, but its efficacy and safety have not been well studied.

Methods: We conducted a multicenter, randomized, placebo-controlled trial involving 326 opiate-addicted persons who were assigned to office-based treatment with sublingual tablets consisting of buprenorphine (16 mg) in combination with naloxone (4 mg), buprenorphine alone (16 mg), or placebo given daily for four weeks. The primary outcome measures were the percentage of urine samples negative for opiates and the subjects' self-reported craving for opiates.

Safety and health policy considerations related to the use of buprenorphine/naloxone as an office-based treatment for opiate dependence.

Opiate dependence remains a fundamental challenge confronting health delivery systems and is often characterized as a social and moral issue. The impact of this disorder on healthcare policy is changing with the increased incidence of HIV, hepatitis C, and tuberculosis infections in opiate-dependent patients. These medical illnesses have substantial effect on escalating healthcare costs, and, therefore, also affect healthcare policy priorities, which are responsive to these costs.

Vitamin B12 decreases, but does not normalize, homocysteine and methylmalonic acid in end-stage renal disease: a link with glycine metabolism and possible explanation of hyperhomocysteinemia in end-stage renal disease.

The genetic and environmental factors influencing catabolism of homocysteine in end-stage renal disease (ESRD) patients remain poorly understood. This study investigated how genetic and nutritional influences affect the response to high-dose vitamin B(12) and folate treatment in ESRD patients with hyperhomocysteinemia. We studied 81 hemodialysis patients with hyperhomocysteinemia (> 16 micromol/L) on varied doses of a multivitamin containing 1 mg of folic acid per day.

The fate of endothelial function testing: rationale and design of the Firefighters And Their Endothelium (FATE) study.

Endothelial dysfunction plays a pivotal role in the development and progression of atherosclerotic vascular disease. The endothelium is strategically located between blood and vascular smooth muscle, making it both vulnerable to a variety of injurious stimuli but also available for interrogation as a marker of vascular health. Firefighters And Their Endothelium (FATE) is a prospective, longitudinal cohort study designed to assess the relationship between endothelial function, emerging cardiovascular risk factors and ultimately atherosclerotic vascular disease.

Handgrip-induced airway dilation in asthmatic patients with bronchoconstriction induced by MCh inhalation.

We investigated the effects of static and rhythmic handgrip on the time course of recovery of airway resistance measured with the interrupter technique (Rint) following bronchoconstriction induced by methacholine (MCh) inhalation in 17 asthmatic patients. On three separate occasions, a 100 +/- 5% increase in baseline Rint was induced by MCh inhalation. Subsequently, patients either rested [control trials (CTs)] or performed 3-min bouts of static or rhythmic handgrip.