Bone marrow transplantation alters the tremor phenotype in the murine model of globoid-cell leukodystrophy

Tremor is a prominent phenotype of the twitcher mouse, an authentic genetic model of Globoid-Cell Leukodystrophy (GLD, Krabbe’s disease). In the current study, the tremor was quantified using a force-plate actometer designed to accommodate low-weight mice. The actometer records the force oscillations caused by a mouse’s movements, and the rhythmic structure of the force variations can be revealed. Results showed that twitcher mice had significantly increased power across a broad band of higher frequencies compared to wildtype mice. Bone marrow transplantation (BMT), the only available therapy for GLD, worsened the tremor in the twitcher mice and induced a measureable alteration of movement phenotype in the wildtype mice. These data highlight the damaging effects of conditioning radiation and BMT in the neonatal period. The behavioral methodology used herein provides a quantitative approach for assessing the efficacy of potential therapeutic interventions for Krabbe’s disease

Challenging the “jolly fat” hypothesis among older adults: High body mass index predicts increases in depressive symptoms over a 5-year period

Several investigators have observed lowered risk of depression among obese older adults, coining the “jolly fat” hypothesis. We examined this hypothesis using baseline and a 5-year follow-up body mass index, depressive symptoms, and covariates from 638 community-based older adults. High objectively measured body mass index and functional limitations predicted increased future depressive symptoms. However, symptoms did not predict future body mass index. Self-reported body mass index showed similar associations despite underestimating obesity prevalence. Results did not differ on the basis of gender. Results for this study, the first longitudinal reciprocal risk analysis between objectively measured body mass index and depressive symptoms among older adults, do not support the “jolly fat” hypothesis

Habitual chocolate intake and type 2 diabetes mellitus in the Maine-Syracuse Longitudinal Study: (1975-2010): Prospective observations

Compounds in cocoa and chocolate have established cardiovascular benefits, including beneficial effects on insulin resistance, a risk factor for type 2 diabetes mellitus. The aims of this study was to investigate relations between habitual chocolate intakes and diabetes mellitus. Cross-sectional and prospective analyses were undertaken on 953 community-dwelling participants (mean age 62 years, 59% women) from the Maine-Syracuse Longitudinal Study (MSLS). Habitual chocolate intakes, measured using a food frequency questionnaire, were related to prevalence of diabetes mellitus (cross-sectionally) and with risk of diabetes measured approximately five years later (prospectively). We also examined the relation between diabetes (the predictor) and chocolate consumption (the outcome) up to 30 years later. Chocolate intake was inversely associated with type 2 diabetes. Compared to participants who consumed chocolate more than once per week, those who never or rarely ate chocolate exhibited a significantly higher odds of having type 2 diabetes 5 years later (OR: 1.91, 95% CI: 1.03, 3.55, p ¼ 0.04), after adjustment for cardiovascular, lifestyle and dietary factors including other polyphenol-rich beverages. However, individuals diagnosed with diabetes prior to the nutritional assessment consumed lower amounts of chocolate at the time of the dietary assessment. Our findings suggest that relations between chocolate and type 2 diabetes may be bi-directional

Expression of nampt in hippocampal and cortical excitatory neurons is critical for cognitive function

Nicotinamide adenine dinucleotide (NAD(+)) is an enzyme cofactor or cosubstrate in many essential biological pathways. To date, the primary source of neuronal NAD(+) has been unclear. NAD(+) can be synthesized from several different precursors, among which nicotinamide is the substrate predominantly used in mammals. The rate-limiting step in the NAD(+) biosynthetic pathway from nicotinamide is performed by nicotinamide phosphoribosyltransferase (Nampt). Here, we tested the hypothesis that neurons use intracellular Nampt-mediated NAD(+) biosynthesis by generating and evaluating mice lacking Nampt in forebrain excitatory neurons (CaMKIIαNampt(−/−) mice). CaMKIIαNampt(−/−) mice showed hippocampal and cortical atrophy, astrogliosis, microgliosis, and abnormal CA1 dendritic morphology by 2–3 months of age. Importantly, these histological changes occurred with altered intrahippocampal connectivity and abnormal behavior; including hyperactivity, some defects in motor skills, memory impairment, and reduced anxiety, but in the absence of impaired sensory processes or long-term potentiation of the Schaffer collateral pathway. These results clearly demonstrate that forebrain excitatory neurons mainly use intracellular Nampt-mediated NAD(+) biosynthesis to mediate their survival and function. Studying this particular NAD(+) biosynthetic pathway in these neurons provides critical insight into their vulnerability to pathophysiological stimuli and the development of therapeutic and preventive interventions for their preservation

Bone Marrow Transplantation Alters the Tremor Phenotype in the Murine Model of Globoid-Cell Leukodystrophy

This is the publisher's version, also available electronically from "http://www.mdpi.com".Tremor is a prominent phenotype of the twitcher mouse, an authentic genetic model of Globoid-Cell Leukodystrophy (GLD, Krabbe’s disease). In the current study, the tremor was quantified using a force-plate actometer designed to accommodate low-weight mice. The actometer records the force oscillations caused by a mouse’s movements, and the rhythmic structure of the force variations can be revealed. Results showed that twitcher mice had significantly increased power across a broad band of higher frequencies compared to wildtype mice. Bone marrow transplantation (BMT), the only available therapy for GLD, worsened the tremor in the twitcher mice and induced a measureable alteration of movement phenotype in the wildtype mice. These data highlight the damaging effects of conditioning radiation and BMT in the neonatal period. The behavioral methodology used herein provides a quantitative approach for assessing the efficacy of potential therapeutic interventions for Krabbe’s disease

Comprehensive functional characterization of murine infantile Batten disease including Parkinson-like behavior and dopaminergic markers

Infantile neuronal ceroid lipofuscinosis (INCL, Infantile Batten disease) is a neurodegenerative lysosomal storage disease caused by a deficiency in palmitoyl protein thioesterase-1 (PPT1). The PPT1-deficient mouse (Cln1−/−) is a useful phenocopy of human INCL. Cln1−/− mice display retinal dysfunction, seizures, motor deficits, and die at ~8 months of age. However, little is known about the cognitive and behavioral functions of Cln1−/− mice during disease progression. In the present study, younger (~1–2 months of age) Cln1−/− mice showed minor deficits in motor/sensorimotor functions while older (~5–6 months of age) Cln1−/− mice exhibited more severe impairments, including decreased locomotor activity, inferior cued water maze performance, decreased running wheel ability, and altered auditory cue conditioning. Unexpectedly, certain cognitive functions such as some learning and memory capabilities seemed intact in older Cln1−/− mice. Younger and older Cln1−/− mice presented with walking initiation defects, gait abnormalities, and slowed movements, which are analogous to some symptoms reported in INCL and parkinsonism. However, there was no evidence of alterations in dopaminergic markers in Cln1−/− mice. Results from this study demonstrate quantifiable changes in behavioral functions during progression of murine INCL and suggest that Parkinson-like motor/sensorimotor deficits in Cln1−/− mice are not mediated by dopamine deficiency

Red giant bound on the axion-electron coupling reexamined

If axions or other low-mass pseudoscalars couple to electrons (``fine structure constant'' $\alpha_a$) they are emitted from red giant stars by the Compton process $\gamma+e\to e+a$ and by bremsstrahlung $e+(Z,A)\to (Z,A)+e+a$. We construct a simple analytic expression for the energy-loss rate for all conditions relevant for a red giant and include axion losses in evolutionary calculations from the main sequence to the helium flash. We find that \alpha_a\lapprox0.5\mn(-26) or m_a\lapprox 9\,\meV/\cos^2\beta lest the red giant core at helium ignition exceed its standard mass by more than 0.025\,\MM_\odot, in conflict with observational evidence. Our bound is the most restrictive limit on $\alpha_a$, but it does not exclude the possibility that axion emission contributes significantly to the cooling of ZZ~Ceti stars such as G117--B15A for which the period decrease was recently measured.Comment: 11 pages, uuencoded and compressed postscript fil

Cool bottom processes on the thermally-pulsing AGB and the isotopic composition of circumstellar dust grains

(Abridged) We examine the effects of cool bottom processing (CBP) on several isotopic ratios in the convective envelope during the TP-AGB phase of evolution in a 1.5 M_sun initial-mass star of solar initial composition. We use a parametric model which treats extra mixing by introducing mass flow between the convective envelope and the underlying radiative zone. The parameters of this model are the mass circulation rate (Mdot) and the maximum temperature (T_P) experienced by the circulating material. The effects of nuclear reactions in the flowing matter were calculated using a set of structures of the radiative zone selected from a complete stellar evolution calculation. The compositions of the flowing material were obtained and the resulting changes in the envelope determined. Abundant ^26Al was produced by CBP for log T_P > 7.65. While ^26Al/^27Al depends on T_P, the isotopic ratios in CNO elements depend dominantly on the circulation rate. The correspondence is shown between models of CBP as parameterized by a diffusion formalism within the stellar evolution model and those using the mass-flow formalism employed here. The isotopic ratios are compared with the data on circumstellar dust grains. It is found that the ratios ^{18}O/^{16}O, ^{17}O/^{16}O, and ^26Al/^27Al observed for oxide grains formed at C/O < 1 are reasonably well-understood. However, the ^15N/^14N, ^12C/^13C, and ^26Al/^27Al in carbide grains (C/O > 1) require many stellar sources with ^14N/^15N at least a factor of 4 below solar. The rare grains with ^12C/^13C < 10 cannot be produced by any red-giant or AGB source.Comment: 35 pages, plus 18 included figures. Scheduled for January 10, 2003 issue of Ap