Biomarkers of body iron stores and risk of developing type 2 diabetes

Aim:  Iron may contribute to the pathogenesis of type 2 diabetes mellitus (DM) by inducing oxidative stress and interfering with insulin secretion. Elevated ferritin levels are associated with increased DM risk among healthy individuals. However, it is yet unknown if ferritin predicts DM incidence among high-risk individuals with impaired glucose tolerance (IGT). Furthermore, the association between soluble transferrin receptors (sTfR), a novel marker of iron status, and DM risk has not yet been prospectively investigated in these individuals. We conducted this study to evaluate the association between baseline levels of ferritin and sTfR and the risk of developing DM among overweight and obese individuals at high risk of DM.
Methods:  This nested case–control study (280 cases and 280 matched controls) was conducted within the placebo arm of the Diabetes Prevention Program, is a clinical trial conducted among overweight/obese individuals with IGT. Ferritin and sTfR levels were measured by immunoturbidimetric assays. Incident DM was ascertained by annual 75-g oral glucose tolerance test and semi-annual fasting glucose.
Results:  Compared with controls, cases had higher sTfR levels (3.50 ± 0.07 vs. 3.30 ± 0.06 mg/l; p = 0.03), but ferritin levels were not statistically different. The multivariable odds ratios (OR) and 95% confidence intervals (95% CI) for DM incidence comparing highest with the lowest quartiles of sTfR was 2.26 (1.37–4.01) (p-trend: 0.008).
Conclusions:  Modestly elevated sTfR levels are associated with increased DM risk among overweight and obese individuals with IGT. Future studies should evaluate factors determining sTfR levels and examine if interventions that lower body iron stores reduce DM incidence.     

Nonlinear viscoelastic effects in oscillatory shear deformation of brain tissue.

Two nonlinear constitutive models were used to describe the dynamic viscoelastic behavior of brain tissue. Small disc-shaped samples of bovine brain tissue were tested in simple shear using forced vibrations (0.5 to 200 Hz) with finite amplitudes (up to 20% Lagrangian shear strain). The samples response to simple, double, and triple harmonic inputs was determined in order to characterize the nonlinearities up to the third-order. A quasilinear viscoelastic model was proposed to describe the spatial nonlinearity. A fully nonlinear viscoelastic model with product-form multiple hereditary integrals was proposed to describe the spatial as well as the temporal nonlinearities. The fully nonlinear model demonstrated superiority at high frequencies (above 44 Hz). Under finite strains, the linear complex modulus showed nonrecoverable asymptotic strain conditioning behavior. Discrepancies observed in previously published studies and the threshold of functional failure of the neural tissue were shown to be related to this strain conditioning effect.     

Targets of the nuclear factor I regulon involved in early and late development of postmitotic cerebellar granule neurons

Recent studies have shown that the nuclear factor I (NFI) family controls multiple stages of the postmitotic differentiation of cerebellar granule neurons (CGNs). Regulation of cell–cell signaling is an integral part of this NFI program, which involves expression of the cell adhesion molecules N cadherin and ephrin B1 throughout postmitotic CGN development. Here, we identify two additional downstream targets of NFI that are involved in extracellular CGN interactions. The cell adhesion molecule Tag‐1 is highly enriched in CGNs undergoing parallel fiber formation and is down‐regulated prior to onset of radial migration. We found that Tag‐1 expression was strongly reduced by NFI dominant repression in immature primary CGNs and in the cerebella of E18 Nfib‐null mice. Transient transfection and chromatin immunoprecipitation suggested that the Tag‐1 gene is directly regulated by NFI. Furthermore, functional, Nfi knockout and chromatin immunoprecipitation studies implicated Wnt7a as a direct target of NFI in maturing CGNs. Wnt7a is secreted by developing CGNs and is required for maturation of mossy fiber–CGN synaptic rosettes. Consistent with this, synapsin I was greatly reduced within the internal granule cell layer of P17 Nfia‐null mice. These findings indicated that NFI controls CGN postmitotic maturation through a combination of extracellular signaling molecules that operate either continuously to regulate multiple stages of development (N cadherin and ephrin B1) or primarily at early (Tag‐1) or late (Wnt7a) maturation steps. They also illustrate the importance of NFI as a critical link between cell‐intrinsic mechanisms and cell–cell interactions in the development of the mouse cerebellum. © 2009 Wiley‐Liss, Inc.     

Callosal axon guidance defects in p35(-/-) mice.

Mice lacking p35, an activator of cdk5 in the central nervous system (CNS), exhibit defects in a variety of CNS structures, most prominently characterized by a disruption in the laminar structure of the neocortex (Chae et al., 1997). In addition, alterations of certain axonal fiber tracts are found in the cortex of p35 mutant mice. Notably, the corpus callosum appears bundled at the midline, but dispersed lateral to the midline. Tracer injection experiments in adult p35 mutant mice reveal that projecting cortical axons fail to assimilate into the corpus callosum, and take oblique paths to the midline. After crossing the midline, cortical axons defasciculate prematurely from the corpus callosum and take similarly oblique paths through the cortex. This callosal phenotype is not detected in reeler mice, which also exhibit defects in cortical lamination, suggesting that the lack of fasciculation of callosal axons is not an inherent manifestation of a disruption of cortical lamination. The embryonic callosal axon tract is defasciculated before crossing the midline, suggesting that axon guidance may be affected during embryonic development of the corpus callosum. In addition, embryonic thalamocortical afferents also exhibit a defasciculated phenotype. These results suggest that defective axonal fasciculation and guidance may be primary responses to the loss of p35 in the cortex. Furthermore, this study postulates a role for the p35/cdk5 kinase in molecular signaling pathways necessary for proper guidance of selective axons during embryonic development.     

Prognostic significance of independent auras in temporal lobe seizures

We performed a retrospective study of auras that occurred independently of complex partial seizures in patients undergoing continuous EEG monitoring with stereotactically implanted depth electrodes placed in mesiotemporal structures. Forty of 54 patients had a history of independent auras, and 32 of these individuals had independent auras while being monitored. Two hundred ninety-two independent auras were recorded, and EEG characteristics and subjective symptoms were analyzed with regard to surgical outcome. Most patients had ictal EEG changes with all or some of their auras. Four patients had nonlocalized or multifocal complex partial seizures despite the presence of well-localized auras, indicating that if intracranial ictal recording is used as a gold standard for localization, complex partial seizures must be recorded. Presence or absence of EEG change with auras did not affect prognosis nor did variability of ictal EEG pattern, spatial extent of initial field potential, aura duration, or character of symptoms correlate with prognosis or postoperative persistence of auras.     

The Women's Health Initiative: A Landmark Resource for Skeletal Research Since 1992

The Women's Health Initiative (WHI) is a large longitudinal study designed to investigate strategies for the prevention and control of common chronic diseases in postmenopausal women, including cardiovascular disease, cancer, and osteoporotic fractures. The WHI consisted of three overlapping clinical trials of hormone therapy, diet modification to reduce total dietary fat, and calcium/vitamin D supplementation. Women who were ineligible for the hormone therapy or diet modification trials or not interested were invited to participate in the observational study. Women were recruited into WHI from 1993 to 1998 at 40 US clinical centers. WHI enrolled 26,046 underrepresented minority women and 135,762 white women. Women could participate in each trial if eligible. The final enrollment included 27,347 women in the hormone trial; 48,835 women in the diet modification trial; 36,282 women in the calcium/vitamin D trial, and 93,676 in the observational study. After the main study ended in 2005, women were invited to continue follow-up for exposures and outcomes through two extensions to 2020. Proposals were recently submitted to continue follow-up through 2027. Information was collected on an extensive number of risk factors for fractures at baseline and over the follow-up, including fall and fracture history, weight patterns, comorbidities, diet, reproductive history, medications, anthropometry, and biomarkers. Bone mineral density was measured at three WHI clinical centers (n = 11,020) chosen to maximize race/ethnic diversity. WHI encourages outside investigators to make use of the publicly available WHI data and to access the biobank of specimens ( www.whi.org ). © 2020 American Society for Bone and Mineral Research.     

Bone Mass and Strength in School‐Age Children Exhibit Sexual Dimorphism Related to Differences in Lean Mass: The Generation R Study

Bone strength, a key determinant of fracture risk, has been shown to display clear sexual dimorphism after puberty. We sought to determine whether sex differences in bone mass and hip bone geometry as an index of strength exist in school‐age prepubertal children and the degree to which the differences are independent of body size and lean mass. We studied 3514 children whose whole‐body and hip scans were measured using the same densitometer (GE‐Lunar iDXA) at a mean age of 6.2 years. Hip dual‐energy X‐ray absorptiometry (DXA) scans underwent hip structural analyses (HSA) with derivation of bone strength indices. Sex differences in these parameters were assessed by regression models adjusted for age, height, ethnicity, weight, and lean mass fraction (LMF). Whole‐body bone mineral density (BMD) and bone mineral content (BMC) levels were 1.3% and 4.3% higher in girls after adjustment by LMF. Independent of LMF, boys had 1.5% shorter femurs, 1.9% and 2.2% narrower shaft and femoral neck with 1.6% to 3.4% thicker cortices than girls. Consequent with this geometry configuration, girls observed 6.6% higher stresses in the medial femoral neck than boys. When considering LMF, the sexual differences on the derived bone strength indices were attenuated, suggesting that differences in muscle loads may reflect an innate disadvantage in bone strength in girls, as consequence of their lower muscular acquisition. In summary, we show that bone sexual dimorphism is already present at 6 years of age, with boys having stronger bones than girls, the relation of which is influenced by body composition and likely attributable to differential adaptation to mechanical loading. Our results support the view that early life interventions (ie, increased physical activity) targeted during the pre‐ and peripubertal stages may be of high importance, particularly in girls, because before puberty onset, muscle mass is strongly associated with bone density and geometry in children. © 2015 American Society for Bone and Mineral Research.