Rasagiline: neurodegeneration, neuroprotection, and mitochondrial permeability transition

Mitochondria are involved directly in cell survival and death. The assumption has been made that drugs that protect mitochondrial viability and prevent apoptotic cascade-induced mitochondrial permeability transition pore (MPTp) opening will be cytoprotective. Rasagiline (N-propargyl-1R-aminoindan) is a novel, highly potent irreversible monoamine oxidase (MAO) B inhibitor anti-Parkinson drug. Unlike selegiline, it is not derived from amphetamine, and is not metabolized to neurotoxic L-methamphetamine derivative. In addition, it does not have sympathomimetic activity. Rasagiline is effective as monotherapy or adjunct to levodopa for patients with early and late Parkinson's disease (PD) and adverse events do not occur with greater frequency in subjects receiving rasagiline than in those on placebo. Phase III controlled studies indicate that it might have a disease-modifying effect in PD that may be related to its neuroprotective activity. Its S isomer, TVP1022, is more than 1,000 times less potent as an MAO inhibitor. Both drugs, however, have neuroprotective activity in neuronal cell cultures in response to various neurotoxins, and in vivo in response to global ischemia, neurotrauma, head injury, anoxia, etc., indicating that MAO inhibition is not a prerequisite for neuroprotection. Their neuroprotective effect has been demonstrated to be associated directly with the propargylamine moiety, which protects mitochondrial viability and MTPp by activating Bcl-2 and protein kinase C (PKC) and by downregulating the proapoptotic FAS and Bax protein families. Rasagiline and its derivatives also process amyloid precursor protein (APP) to the neuroprotective, neurotrophic, soluble APP alpha (sAPPalpha) by PKC- and MAP kinase-dependent activation of alpha-secretase. The identification of the propargylamine moiety as the neuroprotective component of rasagiline has led us to development of novel bifunctional anti-Alzheimer drugs (ladostigil) possessing cholinesterase and brain-selective MAO inhibitory activity and a similar neuroprotective mechanism of action.     

Myocardial bridging: noninvasive diagnosis with multidetector CT

An epicardial segment of a coronary artery that courses through the myocardium is termed "myocardial bridging". Generally, this is a benign condition but it may lead to angina, ischemia or infarction. The current diagnostic standard of reference is coronary catheter angiography. Intravascular ultrasound (IVUS) and intracoronary Doppler (ICD) have been recently introduced as well. These are all invasive imaging modalities. We describe the utilization of gated multidetector CT (MDCT) as a non-invasive alternative for diagnosis of this anomaly. Information regarding the tunneled coronary artery including its length, depth, precise location and surrounding myocardium is easily obtainable.     

Tolerability and immunogenicity of an eleven valent mixed carrier Streptococcus pneumoniae capsular polysaccharide-diphtheria toxoid or tetanus protein conjugate vaccine in Finnish and Israeli infants

BACKGROUND: To have wide global coverage of pneumococcal serotypes, the number of serotypes covered by the current 7-valent pneumococcal conjugate vaccine must be increased. We have studied the safety and immunogenicity of an 11-valent mixed carrier vaccine (PncDT11) in infants. METHODS: The study vaccine contained polysaccharide antigens of serotypes 1, 4, 5, 7F, 9V, 19F and 23F conjugated to tetanus protein and serotypes 3, 6B, 14 and 18C conjugated to diphtheria toxoid. The vaccine was administered to Finnish (n = 117) and Israeli (n = 135) infants at ages 2, 4, 6 and 12 months concomitantly with other vaccines used in national vaccination programs. IgG antibodies to polysaccharides were determined by enzyme immunoassay from serum samples taken at ages 2, 7, 12 and 13 months. After each injection the infants were followed for 30 min to detect any immediate adverse reactions, and parents were given a diary card to report any adverse events during the next 5 days. RESULTS: No severe adverse reactions occurred, and immediate adverse reactions were rare. After each dose approximately 30% of the vaccinees experienced local reactions of which pain was the most common. Fever of >38 degrees C was reported in 33 to 53% of the vaccinees and high fever (>40 degrees C) was reported 6 times. The PncDT11 vaccine was immunogenic. The antibody concentrations after primary immunization series were higher in Israeli than in Finnish infants, but the differences were not significant for most serotypes. The difference was most marked at 13 months, a time point at which the difference was significant in 10 of 11 serotypes. CONCLUSION: PncDT11 is safe and immunogenic in infants. The use of 11-valent pneumococcal vaccine would increase the serotype coverage beyond the currently available 7-valent vaccine.     

Deletion of 5q31 and 7q31 in patients with stable melphalan treated multiple myeloma

Multiple myeloma represents a malignant proliferation of plasma cells derived from a single clone. It is well known that alkylating agents are capable of inducing myelodysplastic syndromes (MDS) and acute myelocytic leukemias (AML). This risk of both diseases in patients with multiple myeloma has been estimated to be 10-20% after 10 years. We aimed to evaluate the time course and the type of genetic abnormalities in melphalan-treated patients in the chronic stage of the disease. We applied fluorescence in situ hybridization methods with probes to 5q31 and 7q31 to mononuclear peripheral blood leukocytes of 18 melphalan-treated patients and compared the results to those of 8 untreated myeloma patients. We found three patients (17%) with a 5q31 deletion in their peripheral white blood cells, but no 7q31 deletion. These findings suggest that 5q- occurs before the overt development of MDS/AML and raise important concerns regarding long-term treatment of myeloma patients with alkylating agents. Also, the performance of cytogenetic evaluation should be considered before autologous transplantation. The clinical and biological implications of these findings should be evaluated in larger clinical and laboratory studies.     

Are inequalities in height narrowing? Comparing effects of social class on height in two generations

Objective: To determine whether social inequalities in height change across generations. Methods: The target population was from the 1958 British birth cohort, all born 3rd–9th March 1958, followed to 1991, and the offspring of one third of this population. Main outcomes were height measured at 7, 11, 16, and 33 years (cohort members) and once at 4–18 years (offspring). Multilevel models applied to associations of social class of origin with (a) child-to-adult growth trajectory (cohort members), (b) height (offspring), and (c) generational height increment. Results: Height inequalities were observed among cohort members, with differences >2.0 cm at all ages between classes I and II, and IV and V. By adulthood, the difference in mean height had declined significantly in boys and slightly in girls. A secular trend was seen between the two generations. While male offspring had a similar mean height to their fathers in classes I and II, boys in classes IV and V gained 2.1 cm (p<0.001). Height gains of female offspring were evident in all classes, with a greater gain in classes IV and V (non-significant). The social class effect on height was weaker among offspring, with a difference between classes I and II, and IV and V of less than 1 cm. Conclusions: Social inequalities in height observed among the cohort weakened substantially in the next generation due to a greater height gain among offspring from manual classes. Inequalities in childhood height have narrowed between the two generations in this study.     

New supplements to infant formulas

Foods, which, in addition to their nutritional attributes, contain also elements that are considered to be health-promoting, have been termed "functional foods". In this regard, human milk has gained recognition as being the ultimate functional food for infants - by its biological compatibility, nutritional value and the undisputed added value of its health promoting qualities. Intensive research activity has recently evolved in a quest to identify and define the components of human milk that might confer disease-preventing and health-enhancing properties and to determine the instances and clinical conditions in which these factors become particularly important. The outcome of such research would also provide a rationale for advocating the supplementation of commercial infant formulas with such substances. In effect, the body of data accumulated from scientific and clinical studies on nucleotides, probiotics, prebiotics and long-chain polyunsaturated fatty acids in human milk and as additives to infant formula, has become regarded as convincing enough by the infant formula industry so as to launch into the market formulas supplemented with one or more of these factors - in an effort to emulate human milk and its beneficial effects. The following review is intended for the reader to obtain a general idea of the new supplements that have been introduced to infant formulas. We summarize the pertinent experimental and clinical observations concerning each of the supplements, pointing out their potential specific benefits, their possible disadvantages and the issues that still remain unresolved.     

Changing social gradients in cigarette smoking and cessation over two decades of adult follow-up in a British birth cohort

BACKGROUND: We aimed to establish whether socioeconomic gradients in smoking among men and women increase with age as a result of differential uptake, quitting and smoking persistence over time. METHODS: A prospective British birth cohort (all births 3-9 March 1958) was followed to 41 years. Analyses of smoking at 41 years by socioeconomic position of origin include 10,521 participants and for socioeconomic position at 23 years n = 9240. RESULTS: By 41 years half of the cohort had smoked regularly (> or = 1 cigarette/day). Smoking prevalence peaked at 23 years (40 per cent) and subsequently declined; quitting increased between 23 years (10 per cent) and 41 years (29 per cent). Individuals from manual backgrounds were more likely to smoke and less likely to quit than those from non-manual groups, and these differences increased over the two decades during which the cohort was followed up. For social position of origin, the odds ratio for current smoking at 23 years among women was 1.28 (95 per cent confidence interval (CI) 1.21, 1.35), i.e. a 28 per cent greater risk of smoking per unit increment on a four-point scale from professional/managerial to unskilled manual. The odds ratio increased to 1.45 (95 per cent CI 1.36, 1.56) at 41 years, trend over time p = 0.01. For men, equivalent results are 1.18 (1.11, 1.24) at 23 years and 1.33 (1.24, 1.42) at 41 years, trend p = 0.01. The social gradients in current smoking also increase over time for men and women using social position at 23 years. CONCLUSION: Conclusions Social gradients in smoking have become more marked across the lifecourse of this birth cohort. This implies continued socioeconomic inequalities in future health outcomes in a contemporary adult population.