Molecular analysis of the short arm of chromosome 3 in small-cell and non-small-cell carcinoma of the lung

Previous studies have suggested that the loss of DNA sequences on the short arm of chromosome 3 (3p) is associated with small-cell lung carcinoma. We therefore looked for loss of 3p alleles in tumor tissue from 42 patients with either small-cell or non-small-cell lung carcinoma. All 13 patients with small-cell lung carcinoma who were heterozygous for one or more alleles at 3p in normal tissue had the loss of at least one codominant allele in the tumor tissue. Cell lines of small-cell lung carcinoma from an additional eight patients were homozygous for 3p alleles; this result was significantly different from the predicted frequency of homozygosity. The tumor tissue studied included cell lines of small-cell lung carcinoma obtained from biopsy specimens, an autopsy sample, and an excised lymph node containing tumor cells. Loss of alleles at 3p was observed in tumor samples obtained before and after chemotherapy. Four of 15 evaluable patients with non-small-cell carcinoma of the lung had loss of 3p alleles. We conclude that loss of alleles at 3p is a change found consistently in small-cell lung carcinoma and occasionally in non-small-cell lung carcinoma.     

Structural genomic variation in childhood epilepsies with complex phenotypes

A genetic contribution to a broad range of epilepsies has been postulated, and particularly copy number variations (CNVs) have emerged as significant genetic risk factors. However, the role of CNVs in patients with epilepsies with complex phenotypes is not known. Therefore, we investigated the role of CNVs in patients with unclassified epilepsies and complex phenotypes. A total of 222 patients from three European countries, including patients with structural lesions on magnetic resonance imaging (MRI), dysmorphic features, and multiple congenital anomalies, were clinically evaluated and screened for CNVs. MRI findings including acquired or developmental lesions and patient characteristics were subdivided and analyzed in subgroups. MRI data were available for 88.3% of patients, of whom 41.6% had abnormal MRI findings. Eighty-eight rare CNVs were discovered in 71 out of 222 patients (31.9%). Segregation of all identified variants could be assessed in 42 patients, 11 of which were de novo. The frequency of all structural variants and de novo variants was not statistically different between patients with or without MRI abnormalities or MRI subcategories. Patients with dysmorphic features were more likely to carry a rare CNV. Genome-wide screening methods for rare CNVs may provide clues for the genetic etiology in patients with a broader range of epilepsies than previously anticipated, including in patients with various brain anomalies detectable by MRI. Performing genome-wide screens for rare CNVs can be a valuable contribution to the routine diagnostic workup in patients with a broad range of childhood epilepsies.     

Prediction of tamoxifen outcome by genetic variation of CYP2D6 in post-menopausal women with early breast cancer

The question of whether genetic polymorphisms of CYP2D6 can affect treatment outcome in patients with early post-menopausal oestrogen receptor (ER)-positive breast cancer has been a matter of debate over the past few years. In this article we revisit the hypothesis of CYP2D6 being a potential tamoxifen outcome predictor and provide detailed insight into the ongoing controversy that prevented the CYP2D6 marker from being accepted by the scientific and clinical community. We summarize the available pharmacokinetic, pharmacodynamic and pharmacogenetic evidence and resolve the controversy based on the recognized methodological and statistical issues. The cumulative evidence suggests that genotyping for CYP2D6 is clinically relevant in post-menopausal women. This is important, because the clarification of this issue has the potential to resolve a clinical management question that is relevant to hundreds of thousands of women diagnosed with ER-positive breast cancer each year, who should not be denied effective endocrine therapy.     

Prevalence of thrombophilia and catheter-related thrombosis in cystic fibrosis

Venous thrombosis in children and young adults is frequently associated with predisposing conditions and with an indwelling catheter or totally implantable venous access device (TIVAD). These systems are commonly used for the delivery of antibiotic therapy in patients with cystic fibrosis (CF). We reviewed our CF center's history of catheter-related events over 13 years and prospectively investigated the presence of risk factors for thrombosis in 66 children and adults with CF (age, 3-38 years; 32 females). Five thrombotic events had occurred in 4 patients, 2 of whom carried the factor V Leiden mutation. Five asymptomatic patients were diagnosed with heterozygous mutations of the factor V or prothrombin gene. Functional activity of protein C was decreased in 13 subjects, with a correlation to impaired liver function. Protein S activity was abnormal in 20 patients and was related to CF genotype. Anti-phospholipid antibodies (APA) were present in 6 asymptomatic patients. A reinvestigation after 3 years confirmed protein S deficiency in 12 of 14 patients, while most abnormalities for protein C or APA were inconsistent. In conclusion, a thrombophilic state was detected in 53% of patients, and 2 out of 4 subjects with TIVAD-related thrombosis carried a genetic defect. It may thus be helpful to include a hemostatic evaluation in the clinical decision process for or against TIVAD insertion in eligible CF patients.     

Metabolic responses of the heart in acute myocardial infarction in man

Acute myocardial infarction evokes a characteristic neurohumoral response: Catecholamine release is increased, plasma contents of free fatty acids and glucose are elevated and glucose tolerance is diminished. To what degree the myocardium participates in this stress response was evaluated by sampling coronary sinus and arterial blood in 50 patients with acute transmural infarction. Studies were initiated an average of 8 hours after the clinical onset of infarction and were continued for up to 60 hours. A total of 173 separate metabolic studies were analyzed. Forty-one percent exhibited a pattern of predominant myocardial free fatty acid uptake (mean extraction ratio 24 percent) in the presence of elevated plasma free fatty acid and glucose contents (respective means 1,181 μmol/liter and 210 mg/100 ml). Myocardial extraction ratios for glucose, lactate and pyruvate were low (respective means 1.1, 4 and 11 percent). Twenty-one percent of the studies revealed normal myocardial metabolism and 18 percent showed enhanced carbohydrate uptake, as evidenced by increased myocardial extractions of lactate and pyruvate (respective means 42 percent) and of glucose (mean 5 percent). Plasma contents of glucose and free fatty acids were lower than in the predominant free fatty acid group (respective means 156 mg/100 ml and 743 μmol/liter). The remaining 20 percent of studies showed high plasma substrate contents and low myocardial substrate uptake suggesting metabolic breakdown. The free fatty acid metabolic pattern was observed in more than 50 percent of the studies performed at the time of or close to the occurrence of important clinical complications. Propranolol, 0.1 mg/kg intravenously, shifted myocardial substrate utilization from free fatty acids toward carbohydrates. The myocardial respiratory quotient increased from an average of 0.79 to 0.88 (P < 0.01).The study demonstrates that the metabolic patterns of the myocardium are influenced by the systemic response to stress. Beta adrenergic blockade changed substrate utilization of the myocardium, supporting the hypothesis that adrenergic activation plays an important role in these metabolic responses.     

Modulatory effects of melatonin on behavior, hemolymph metabolites, and neurotransmitter release in crayfish

Melatonin affects a variety of circadian processes such as behavior and neurotransmitter release in vertebrates. Crayfish melatonin production occurs in the eyestalks, and the cycle of production may change seasonally. To date, however, melatonin's roles and mechanisms of action in crustacean physiology are unclear. We injected melatonin or saline into crayfish in scotophase and monitored activity and hemolymph glucose/lactate over 24 h in early spring. Crayfish were significantly more active in photophase versus the expected scotophase, and had concurrent glucose/lactate peaks. Melatonin reversed the activity pattern, causing a scotophase activity peak, but not the glucose/lactate patterns. This study was repeated in late summer, during which control activity and glucose/lactate levels were elevated in scotophase. Melatonin decreased the amplitude of scotophase activity and glucose/lactate, eliminating activity and glucose cycles. We also injected melatonin or saline at various times of day in early summer and monitored locomotor activity for 1 h. Controls had high activity at 1200 (mid-photophase) and 2100 h (early scotophase), and melatonin increased activity at 1200 h but decreased it at 2100 h. Melatonin also increased activity at 1500 h but not 1800 h (late photophase). Next, we examined the influence of melatonin on crayfish neurophysiology. Melatonin (10 microM) enhanced synaptic transmission at the neuromuscular junction (NMJ). The presynaptic action resulted in more vesicles being released during evoked stimulation. Our study indicates that melatonin may have a phylogenetically conserved role in the transduction of circadian information in invertebrates as in vertebrates. Behavioral and physiological effects may be mediated by modulation of central pathways, enhanced at the peripheral level via neuromodulation of the NMJ.