De novo discovery of serotonin N-acetyltransferase inhibitors

Serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase, AANAT) is a member of the GCN5 N-acetyltransferase (GNAT) superfamily and catalyzes the penultimate step in the biosynthesis of melatonin; a large daily rhythm in AANAT activity drives the daily rhythm in circulating melatonin. We have used a structure-based computational approach to identify the first druglike and selective inhibitors of AANAT. Approximately 1.2 million compounds were virtually screened by 3D high-throughput docking into the active site of X-ray structures for AANAT, and in total 241 compounds were tested as inhibitors. One compound class, containing a rhodanine scaffold, exhibited low micromolar competitive inhibition against acetyl-CoA (AcCoA) and proved to be effective in blocking melatonin production in pineal cells. Compounds from this class are predicted to bind as bisubstrate inhibitors through interactions with the AcCoA and serotonin binding sites. Overall, this study demonstrates the feasibility of using virtual screening to identify small molecules that are selective inhibitors of AANAT.     

Auditory training improves neural timing in the human brainstem

The auditory brainstem response reflects neural encoding of the acoustic characteristic of a speech syllable with remarkable precision. Some children with learning impairments demonstrate abnormalities in this preconscious measure of neural encoding especially in background noise. This study investigated whether auditory training targeted to remediate perceptually-based learning problems would alter the neural brainstem encoding of the acoustic sound structure of speech in such children. Nine subjects, clinically diagnosed with a language-based learning problem (e.g., dyslexia), worked with auditory perceptual training software. Prior to beginning and within three months after completing the training program, brainstem responses to the syllable /da/ were recorded in quiet and background noise. Subjects underwent additional auditory neurophysiological, perceptual, and cognitive testing. Ten control subjects, who did not participate in any remediation program, underwent the same battery of tests at time intervals equivalent to the trained subjects. Transient and sustained (frequency-following response) components of the brainstem response were evaluated. The primary pathway afferent volley -- neural events occurring earlier than 11 ms after stimulus onset -- did not demonstrate plasticity. However, quiet-to-noise inter-response correlations of the sustained response ( approximately 11-50 ms) increased significantly in the trained children, reflecting improved stimulus encoding precision, whereas control subjects did not exhibit this change. Thus, auditory training can alter the preconscious neural encoding of complex sounds by improving neural synchrony in the auditory brainstem. Additionally, several measures of brainstem response timing were related to changes in cortical physiology, as well as perceptual, academic, and cognitive measures from pre- to post-training.     

Tutorial on maximum inspiratory and expiratory mouth pressures in individuals with idiopathic Parkinson disease (IPD) and the preliminary results of an expiratory muscle strength training program

Respiratory symptoms are recognized as sequelae of motor dysfunction in idiopathic Parkinson's disease (IPD) and these symptoms have the potential to cause problems with swallow, cough, voice and speech. Specifically, maneuvers that require rapid activation and coordination of upper airway and chest wall musculature become progressively impaired as motor dysfunction progresses during the natural course of the disease. This study reports on the maximum inspiratory and expiratory pressures produced by 28 participants (average age 64) diagnosed with moderate to severe IPD (average stage 2.5 with a range of 2.0-3.0). All measures were collected during the "medication on" state. Outcomes of a specific respiratory muscle strength training technique for improving maximum expiratory pressure are reported for three of the patients in this study. Techniques that focus on strengthening the respiratory muscles in patients with IPD (other than with low load breathing exercises), have not been previously reported. The results of this pilot study demonstrate that respiratory muscle weakness may be an important factor in the respiratory complications in IPD and that respiratory muscle strength training has the potential to improve expiratory muscle strength for this population. This improvement has the potential to positively impact high forced respiratory activities, such as forced breathing maneuvers, swallow, cough and speech functions that require greater magnitude and duration of expiration.     

A history of alcohol dependence augments HIV-associated neurocognitive deficits in persons aged 60 and older

Excessive alcohol use is common among people living with HIV. Given the growing prevalence of older HIV+ adults and observations indicating higher risk for neurocognitive impairment in older adults with either HIV infection or alcoholism, an increased understanding of their combined impact in the context of this increasingly aged population is crucial. We conducted comprehensive neurocognitive assessment in 112 older HIV+ individuals aged 50 to 69 years. Regression analyses were conducted to examine the interaction between age and the presence of lifetime alcohol dependence on neurocognitive measures, controlling for years of education, hepatitis C serostatus, and lifetime non-alcohol substance use disorder. Significant interactions of age and alcohol dependence history were found for global neurocognitive function, which was driven by the domains of executive function, processing speed, and semantic memory. Follow-up analyses indicated adverse effects of alcohol use history on neurocognitive measures that were evident only in HIV+ individuals 60 years and older. While mounting evidence in younger cohorts indicates adverse synergistic HIV/alcohol effects on neurocognitive function, our novel preliminary findings in this elderly HIV+ cohort demonstrated the importance of even a relatively distant alcohol use history on the expression of HIV-associated neurocognitive disorders that may not become apparent until much later in life.     

The After Breast Cancer Pooling Project: rationale, methodology, and breast cancer survivor characteristics

The After Breast Cancer Pooling Project was established to examine the role of physical activity, adiposity, dietary factors, supplement use, and quality of life (QOL) in breast cancer prognosis. This paper presents pooled and harmonized data on post-diagnosis lifestyle factors, clinical prognostic factors, and breast cancer outcomes from four prospective cohorts of breast cancer survivors (three US-based and one from Shanghai, China) for 18,314 invasive breast cancer cases diagnosed between 1976 and 2006. Most participants were diagnosed with stage I-II breast cancer (84.7%). About 60% of breast tumors were estrogen receptor (ER)+/progesterone receptor (PR)+; 21% were ER-/PR-. Among 8,118 participants with information on HER-2 tumor status, 74.8% were HER-2- and 18.5% were HER-2+. At 1-2 years post-diagnosis (on average), 17.9% of participants were obese (BMI ≥ 30 kg/m2), 32.6% were overweight (BMI 25-29 kg/m2), and 59.9% met the 2008 Physical Activity Guidelines for Americans (≥ 2.5 h per week of moderate activity). During follow-up (mean = 8.4 years), 3,736 deaths (2,614 from breast cancer) and 3,564 recurrences have been documented. After accounting for differences in year of diagnosis and timing of post-diagnosis enrollment, five-year overall survival estimates were similar across cohorts. This pooling project of 18,000 breast cancer survivors enables the evaluation of associations of post-diagnosis lifestyle factors, QOL, and breast cancer outcomes with an adequate sample size for investigation of heterogeneity by hormone receptor status and other clinical predictors. The project sets the stage for international collaborations for the investigation of modifiable predictors for breast cancer outcomes.