Retromer in Alzheimer disease, Parkinson disease and other neurological disorders.

Retromer is a protein assembly that has a central role in endosomal trafficking, and retromer dysfunction has been linked to a growing number of neurological disorders. First linked to Alzheimer disease, retromer dysfunction causes a range of pathophysiological consequences that have been shown to contribute to the core pathological features of the disease. Genetic studies have established that retromer dysfunction is also pathogenically linked to Parkinson disease, although the biological mechanisms that mediate this link are only now being elucidated.

Neurobiological roots of language in primate audition: common computational properties.

Here, we present a new perspective on an old question: how does the neurobiology of human language relate to brain systems in nonhuman primates? We argue that higher-order language combinatorics, including sentence and discourse processing, can be situated in a unified, cross-species dorsal-ventral streams architecture for higher auditory processing, and that the functions of the dorsal and ventral streams in higher-order language processing can be grounded in their respective computational properties in primate audition. This view challenges an assumption, common in the cognitive sciences, that a nonhuman primate model forms an inherently inadequate basis for modeling higher-level language functions.

Anhedonia in the psychosis risk syndrome: associations with social impairment and basal orbitofrontal cortical activity.

Background/objectives: Anhedonia is associated with poor social function in schizophrenia. Here, we examined this association in individuals at clinical high risk (CHR) for schizophrenia and related psychotic disorders, taking into account social anxiety. We then explored correlations between anhedonia and basal metabolic activity in selected forebrain regions implicated in reward processing.

The use of pharmacological retromer chaperones in Alzheimer's disease and other endosomal-related disorders.

The retromer is an evolutionary conserved multiprotein complex involved in the sorting and retrograde trafficking of cargo from endosomal compartments to the Golgi network and to the cell surface. The neuronal retromer traffics the amyloid precursor protein away from the endosomes, a site where amyloid precursor protein is enzymatically cleaved into pathogenic fragments in Alzheimer's disease. In recent years, deficiencies in retromer-mediated transport have been implicated in several neurological and non-neurological diseases, including Parkinson's disease, suggesting that improving the efficacy of the retromer trafficking pathway would result in decreased pathology.

Trabecular bone density of the proximal tibia as it relates to failure of a total knee replacement.

The relationship between post-operative bone density and subsequent failure of total knee replacement (TKR) is not known. This retrospective study aimed to determine the relationship between bone density and failure, both overall and according to failure mechanism. All 54 aseptic failures occurring in 50 patients from 7760 consecutive primary cemented TKRs between 1983 and 2004 were matched with non-failing TKRs, and 47 failures in 44 patients involved tibial failures with the matching characteristics of age (65.

Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults.

The dentate gyrus (DG) is a region in the hippocampal formation whose function declines in association with human aging and is therefore considered to be a possible source of age-related memory decline. Causal evidence is needed, however, to show that DG-associated memory decline in otherwise healthy elders can be improved by interventions that enhance DG function. We addressed this issue by first using a high-resolution variant of functional magnetic resonance imaging (fMRI) to map the precise site of age-related DG dysfunction and to develop a cognitive task whose function localized to this anatomical site.

Isolating pathogenic mechanisms embedded within the hippocampal circuit through regional vulnerability.

Some of the most common and devastating disorders of the brain target the hippocampal formation. The hippocampal formation is a complex circuit of interconnected regions, and it is assumed that clues into the causes of these disorders are embedded within the circuit. Neuroimaging tools have been optimized to interrogate the malfunctioning hippocampal circuit, and by applying these tools to patients in the earliest stages of disease and to animal models, patterns of regional vulnerability have been established for Alzheimer's disease, schizophrenia, and cognitive aging.

Molecular epidemiology, phylogeny and evolution of the filarial nematode Wuchereria bancrofti.

Wuchereria bancrofti (Wb) is the most widely distributed of the three nematodes known to cause lymphatic filariasis (LF), the other two being Brugia malayi and Brugia timori. Current tools available to monitor LF are limited to diagnostic tests targeting DNA repeats, filarial antigens, and anti-filarial antibodies. While these tools are useful for detection and surveillance, elimination programs have yet to take full advantage of molecular typing for inferring infection history, strain fingerprinting, and evolution.

Genetic variants in a 'cAMP element binding protein' (CREB)-dependent histone acetylation pathway influence memory performance in cognitively healthy elderly individuals.

The molecular pathways underlying age-related memory changes remain unclear. There is a substantial genetic contribution to memory performance through life span. A recent study has implicated RbAp48, which mediates its effect on age-related memory decline by interacting with cyclic adenosine monophosphate responsive element binding protein (CREB)1 binding protein and influencing this histone acetylation pathway.

The impact of perceived frailty on surgeons' estimates of surgical risk.

Background: Physicians are only moderately accurate in estimating surgical risk based on clinical vignettes. We assessed the impact of perceived frailty by measuring the influence of a short video of a standardized patient on surgical risk estimates.

Methods: Thoracic surgeons and cardiothoracic trainees estimated the risk of major complications for lobectomy based on clinical vignettes of varied risk categories (low, average, high).

New evidence about language and cognitive development based on a longitudinal study: hypotheses for intervention.

We review findings from a four-year longitudinal study of language learning conducted on two samples: a sample of typically developing children whose parents vary substantially in socioeconomic status, and a sample of children with pre- or perinatal brain injury. This design enables us to study language development across a wide range of language learning environments and a wide range of language learners. We videotaped samples of children's and parents' speech and gestures during spontaneous interactions at home every four months, and then we transcribed and coded the tapes.

Thoracic surgeons' perception of frail behavior in videos of standardized patients.

Background: Frailty is a predictor of poor outcomes following many types of operations. We measured thoracic surgeons' accuracy in assessing patient frailty using videos of standardized patients demonstrating signs of physical frailty. We compared their performance to that of geriatrics specialists.

An investigation into the clinical utility of ipsilateral/contralateral asymmetries in bone-conduction auditory steady-state responses.

Objective: To determine whether ipsilateral/contralateral asymmetries in the bone-conduction (BC) ASSR are robust enough in infants to be used clinically to isolate the test ear.

Design: Retrospective investigation of three two-channel BC ASSR datasets.

Subjects: Forty-eight adults (mean age 26.

Interneuron precursor transplants in adult hippocampus reverse psychosis-relevant features in a mouse model of hippocampal disinhibition.

GABAergic interneuron hypofunction is hypothesized to underlie hippocampal dysfunction in schizophrenia. Here, we use the cyclin D2 knockout (Ccnd2(-/-)) mouse model to test potential links between hippocampal interneuron deficits and psychosis-relevant neurobehavioral phenotypes. Ccnd2(-/-) mice show cortical PV(+) interneuron reductions, prominently in hippocampus, associated with deficits in synaptic inhibition, increased in vivo spike activity of projection neurons, and increased in vivo basal metabolic activity (assessed with fMRI) in hippocampus.

Pharmacological chaperones stabilize retromer to limit APP processing.

Retromer is a multiprotein complex that trafficks cargo out of endosomes. The neuronal retromer traffics the amyloid-precursor protein (APP) away from endosomes, a site where APP is cleaved into pathogenic fragments in Alzheimer's disease. Here we determined whether pharmacological chaperones can enhance retromer stability and function.

Impacts of the ubiquitous factor Zelda on Bicoid-dependent DNA binding and transcription in Drosophila.

In vivo cross-linking studies suggest that the Drosophila transcription factor Bicoid (Bcd) binds to several thousand sites during early embryogenesis, but it is not clear how many of these binding events are functionally important. In contrast, reporter gene studies have identified >60 Bcd-dependent enhancers, all of which contain clusters of the consensus binding sequence TAATCC. These studies also identified clusters of TAATCC motifs (inactive fragments) that failed to drive Bcd-dependent activation.

Comparisons of auditory steady state response and behavioral air conduction and bone conduction thresholds for infants and adults with normal hearing.

Objective: To improve understanding of normal responses in infants by comparing air conduction (AC) and bone conduction (BC) auditory thresholds using both the auditory steady state response (ASSR) and behavioral testing methods in normal-hearing infants (6 to 18 months of age) and adults. At present, there are no correction factors available for estimating BC behavioral thresholds from BC ASSR thresholds, which is a barrier to clinical implementation of the ASSR. In addition, previous studies have reported infant-adult differences in AC and BC sensitivity, which suggest a "maturational" air-bone gap (ABG) that is not attributable to a conductive pathology; no study has yet compared AC and BC thresholds for either ASSR or behavioral methods in the same individuals.

Prevention of post-stroke generalized anxiety disorder, using escitalopram or problem-solving therapy.

This study examined the efficacy of antidepressant treatment for preventing the onset of generalized anxiety disorder (GAD) among patients with recent stroke. Of 799 patients assessed, 176 were randomized, and 149 patients without evidence of GAD at the initial visit were included in this double-blind treatment with escitalopram (N=47) or placebo (N=49) or non-blinded problem-solving therapy (PST; 12 total sessions; N=53). Participants given placebo over 12 months were 4.