Pathological changes in mesostriatal neurons in a PKC-gamma mutant rat

The AS/AGU rat originated as a recessive mutation (agu) in a closed colony of Albino Swiss (AS) rats. The mutation is in the gene coding for the gamma isoform of protein kinase C. It is characterized by movement impairments and progressive dysfunction of the nigrostriatal dopaminergic (DA) and raphe striatal serotonergic (5-HT) systems. The movement impairments including rigidity of the hind limbs, a staggering gait, a tendency to fall over every few steps, a slight whole body tremor and difficulty in initiating movements. The dysfunction in both systems is characterised by a failure to release DA or 5-HT within the striatum and cell loss within the substantia nigra pars compacta (dopaminergic cells) and the dorsal raphe nuclei (5-HT+ve cells). In this study, three experiments were carried out to examine the possible pathological responses of midbrain cell groups to the agu mutation in the gene coding for protein kinase C-gamma (PKC-γ). Experiment 1 was carried out to examine levels of two groups of molecules in the midbrain cell groups using quantitative immunofluorescence microscopy of cell bodies or their surrounding neuropil (a) those molecules giving information about the capacity of midbrain aminergic cell bodies to synthesis transmitters; tyrosine hydroxylase (TH) in the dopaminergic neurons and serotonin (5-HT) in the serotonergic neurons (b) those which have been found to occur in human neurodegenerative conditions such as Parkinson’s disease: ubiquitin, parkin and α-synuclein (Lewy body proteins). Immunofluorescence levels of tyrosine hydroxylase (in dopaminergic cells of the SNC) and serotonin (in 5HT+ve cells of the dorsal raphe nuclei) were both significantly increased in AS/AGU (mutant) compared to the AS (control) rats aged 6 months and older. TH and 5-HT immunofluorescence levels were both significantly decreased in the striatum in the AS/AGU (mutant) compared to the AS (control) rat aged 12 months. Ubiquitin immunofluorescence show a gradual increase with age in AS and AS/AGU rats and the increase was much greater in the mutant in every region except the oculomotor and pontine nuclei. Parkin immunofluorescence show increases in the mutant within the SNC and the dorsal raphe nucleus and this increase was significant at older ages. Alpha-synuclein does not occur in the cell bodies of the substantia nigra or VTA but outside in the neuropil. Alpha-synuclein immunofluorescence levels progressively increased with age in both strains in the SN and VTA and were higher in the mutant. The levels of those molecules (ubiquitin, parkin and alpha-synuclein) do not differ in the striatum of mutants compared to controls. Experiment 2 examined SNC cell bodies to look for possible strain differences in cell size or ultrastructure or any sign of cell death using light and transmission electron microscopy. The diameter (maximum and minimum) of the SNC cells and nuclei were measured in toluidine blue paraffin wax and immunoperoxidase DAB staining for TH sections. Cell diameter was reduced in the AS/AGU mutant compared to the AS control. No obvious ultrastructural differences were seen in nigrostriatal neurons of both strains. The volume fractions of mitochondria and rough endoplasmic reticulum were significantly higher in the mutant. No Lewy bodies were present. Experiment 3 examined TH+ve nigrostriatal dopaminergic terminals in the dorsal caudate-putamen to determine whether there are (a) differences in the percentages and numbers of TH+ve terminals and (b) differences in synaptic vesicles numbers. In 12-month AS/AGU mutant, there are reduction in TH+ve terminals (40%) together with a reduction in vesicle numbers (40%) in such terminals where in 3-month AS/AGU mutant, the reduction in TH+ve terminals was more (50%) and a reduction in vesicles numbers by three quarters. TH-ve terminals are also reduced in numbers in 12 months aged AS/AGU mutant rats. In 12-month AS/AGU rats, there were significantly reduced numbers of synaptic terminals in the striatum compared to AS controls. This applied to both dopaminergic terminals (which make up 15% of the total) and to non-dopaminergic terminals. In 3-month AS/AGU rats, there is a reduction in terminal numbers, but this is restricted to the dopaminergic terminals only: non-dopaminergic ones are unaffected

Peptide YY ablation in mice leads to the development of hyperinsulinaemia and obesity

Aims/hypothesis. Obese people exhibit reduced circulating peptide YY (PYY) levels, but it is unclear whether this is a consequence or cause of obesity. We therefore investigated the effect of Pyy ablation on energy homeostasis. Methods. Body composition, i.p. glucose tolerance, food intake and hypothalamic neuropeptide expression were determined in Pyy knock-out and wild-type mice on a normal or high-fat diet. Results. Pyy knock-out significantly increased bodyweight and increased fat mass by 50% in aged females on a normal diet. Male chow-fed Pyy −/− mice were resistant to obesity but became significantly fatter and glucose-intolerant compared with wild-types when fed a high-fat diet. Pyy knock-out animals exhibited significantly elevated fasting or glucose-stimulated serum insulin concentrations vs wild-types, with no increase in basal or fasting-induced food intake. Pyy knock-out decreased or had no effect on neuropeptide Y expression in the arcuate nucleus of the hypothalamus, and significantly increased proopiomelanocortin expression in this region. Male but not female knock-outs exhibited significantly increased growth hormone-releasing hormone expression in the ventromedial hypothalamus and significantly elevated serum IGF-I and testosterone levels. This sex difference in activation of the hypothalamo–pituitary somatotrophic axis by Pyy ablation may contribute to the resistance of chow-fed male knock-outs to late-onset obesity. Conclusions/interpretation. PYY signalling is important in the regulation of energy balance and glucose homeostasis, possibly via regulation of insulin release. Therefore reduced PYY levels may predispose to the development of obesity, particularly with ageing or under conditions of high-fat feeding

Does diet affect breast cancer risk?

The role of specific dietary factors in breast cancer causation is not completely resolved. Results from prospective studies do not support the concept that fat intake in middle life has a major relation to breast cancer risk. However, weight gain in middle life contributes substantially to breast cancer risk. Alcohol is the best established dietary risk factor, probably by increasing endogenous estrogen levels. Hypotheses relating diet during youth to risk decades later will be difficult to test. Nevertheless, available evidence is strong that breast cancer risk can be reduced by avoiding weight gain during adult years, and by limiting alcohol consumption

Health enhancing strength training in nonagenarians (STRONG): rationale, design and methods

<p>Abstract</p> <p>Background</p> <p>The Health Enhancing Strength Training in Nonagenarians (STRONG) is a randomised control trial to assess the effectiveness of an aerobic and strength training program for improving muscle strength, functional capacity and quality of life in nonagenarians.</p> <p>Methods</p> <p>Sixty (51 women) nonagenarians (age range: 90–102 years) who live in a geriatric nursing home will be randomly assigned to either a usual care (control) group (n = 30) or an intervention (training) group (n = 30). Participants allocated in the usual care group will receive general physical activity guidelines and participants allocated in the intervention group will also enrol in three weekly non-consecutive individualized training sessions (~45–50 min each) during 8 weeks. The exercise program will consist of muscular strength [with a special focus on leg press at 30% (start of the program) to 70% 1 repetition maximum (end)] and aerobic exercises (cycle-ergometry during 3–5 to 15 minutes at 12–14 points in the rate of perceived exertion scale).</p> <p>Results</p> <p>Results from STRONG will help to better understand the potential of regular physical activity for improving the well-being of the oldest population groups.</p> <p>Conclusion</p> <p>The increase in life expectancy together with the dramatic decrease in birth rates in industrialized countries calls the attention to health care systems and public health policymakers to focus attention on promoting healthy lifestyle in the highest sector of the population pyramid. Our study attempts to improve functional capacity and QOL of nonagenarians by implementing an individualised aerobic and strength training program in a geriatric residential care. Results from STRONG will help to better understand the potential of regular physical activity for improving the well being even in persons aged 90 years or over.</p> <p>Trail Registration</p> <p>ClinicalTrials.gov ID: NCT00848978</p