Isoform-specific requirement for Akt1 in the developmental regulation of cellular metabolism during lactation

SummaryThe metabolic demands and synthetic capacity of the lactating mammary gland exceed that of any other tissue, thereby providing a useful paradigm for understanding the developmental regulation of cellular metabolism. By evaluating mice bearing targeted deletions in Akt1 or Akt2, we demonstrate that Akt1 is specifically required for lactating mice to synthesize sufficient quantities of milk to support their offspring. Whereas cellular proliferation, differentiation, and apoptosis are unaffected, loss of Akt1 disrupts the coordinate regulation of metabolic pathways that normally occurs at the onset of lactation. This results in a failure to upregulate glucose uptake, Glut1 surface localization, lipid synthesis, and multiple lipogenic enzymes, as well as a failure to downregulate lipid catabolic enzymes. These findings demonstrate that Akt1 is required in an isoform-specific manner for orchestrating many of the developmental changes in cellular metabolism that occur at the onset of lactation and establish a role for Akt1 in glucose metabolism

Neonatal cerebrovascular autoregulation.

Cerebrovascular pressure autoregulation is the physiologic mechanism that holds cerebral blood flow (CBF) relatively constant across changes in cerebral perfusion pressure (CPP). Cerebral vasoreactivity refers to the vasoconstriction and vasodilation that occur during fluctuations in arterial blood pressure (ABP) to maintain autoregulation. These are vital protective mechanisms of the brain. Impairments in pressure autoregulation increase the risk of brain injury and persistent neurologic disability. Autoregulation may be impaired during various neonatal disease states including prematurity, hypoxic-ischemic encephalopathy (HIE), intraventricular hemorrhage, congenital cardiac disease, and infants requiring extracorporeal membrane oxygenation (ECMO). Because infants are exquisitely sensitive to changes in cerebral blood flow (CBF), both hypoperfusion and hyperperfusion can cause significant neurologic injury. We will review neonatal pressure autoregulation and autoregulation monitoring techniques with a focus on brain protection. Current clinical therapies have failed to fully prevent permanent brain injuries in neonates. Adjuvant treatments that support and optimize autoregulation may improve neurologic outcomes

Identification of Older Adults at Risk for Falls with Drug-Based Indices

Purpose/Hypothesis: Falls in the older adult population are the leading cause of fatal and non-fatal injuries in America. Polypharmacy, the use of multiple medications, has been identified as a major risk factor for falls in older adults. A variety of medication screens exist that identify adverse effects of medications which can directly impact fall risk; however, current screening measures have limitations. The Quantitative Drug Index (QDI) is a new, clinically anchored index to quantify all potential adverse effects associated with drug-mediated fall risk. The purpose of this study was to validate the QDI as a fall risk screening tool. Number of Subjects: 138 adults were recruited from local senior centers and screened. Inclusion criteria: community-dwelling, age 60 to 89 years, and currently prescribed at least one medication. Exclusion criteria: progressive neurological disorders, unstable medical conditions, cognitive impairment, severe depression or anxiety, severe lower extremity impairment that would impact mobility, and severe vision impairment. Materials and Methods: Mobility and balance outcome measures related to fall risk included: 30-second chair stand test, 10-meter walk test, Timed Up and Go (TUG) and Dynamic Gait Index (DGI). Self-report measures of fall risk included fall history, Fall Risk Questionnaire (FRQ) and Activity-specific Balance Confidence scale (ABC). The QDI was derived from each participant\u27s medications. Participants were classified as either fallers or nonfallers based on self-report history of falls within the past year. Nonparametric Spearman’s Rho correlations were used to determine relationships between faller status and measures of fall risk. A receiver operating characteristic (ROC) curve analysis determined cutoff scores for outcome measures related to faller status. Results: A fair to moderate relationship between the QDI and several physical performance and self-report measures was identified: FRQ (r=0.363), ABC (r=-0.401), DGI (r=-0.360). However, little to no relationship was found between faller status and QDI score (r=0.221). The ROC analysis determined the area under the curve for QDI was 0.63 with a cutoff score of 2.5 yielding sensitivity of 78% and specificity of 47%. Conclusions: The development of the QDI was an interdisciplinary effort between pharmacists and physical therapists to screen for fall risk in older individuals. The QDI offers a better way to quantify the adverse effects of drugs on mobility compared with simple drug counts. The QDI alone does not identify individuals at fall risk; however, the QDI is significantly correlated to several measures of fall risk, including FRQ, ABC, and DGI. The ROC Curve Analysis identified a cutoff score for fall risk for the QDI which was found to have similar sensitivity and specificity to the TUG. Clinical Relevance: The QDI could be incorporated into electronic medical records to identify patients who may be at fall risk and would be appropriate for further balance and mobility evaluation

Pathogenic tau species drive a psychosis-like phenotype in a mouse model of Alzheimer\u27s disease

Psychotic Alzheimer\u27s disease (AD + P) is a rapidly progressive variant of AD associated with an increased burden of frontal tau pathology that affects up to 50% of those with AD, and is observed more commonly in females. To date, there are no safe and effective medication interventions with an indication for treatment in this condition, and there has been only very limited exploration of potential animal models for preclinical drug development. Pathogenic tau is over represented in the frontal cortex in AD + P, especially in females. In order to develop a candidate animal model of AD + P, we employed a tau mouse model with a heavy burden of frontal tau pathology, the rTg(tauP301L)4510 mouse, hereafter termed rTg4510. We explored deficits of prepulse inhibition of acoustic startle (PPI), a model of psychosis in rodents, and the correlation between pathogenic phospho-tau species associated with AD + P and PPI deficits in female mice. We found that female rTg4510 mice exhibit increasing PPI deficits relative to littermate controls from 4.5 to 5.5 months of age, and that these deficits are driven by insoluble fractions of the phospho-tau species pSer396/404, pSer202, and pThr231 found to be associated with human AD + P. This preliminary data suggests the utility of the rTg4510 mouse as a candidate disease model of human female AD + P. Further work expanded to include both genders and other behavioral outcome measures relevant to AD + P is necessary. (C) 2014 Elsevier B.V. All rights reserved