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Alcohol use is associated with memory problems in young adults with HIV, but the cognitive mechanisms of that association are not known. Sixty adults (aged 19–24 years) living with HIV were administered the Alcohol, Smoking, and Substance Involvement Screening Test to assess alcohol use, Behavior Rating Inventory of Executive Function for self-reported executive functions, and the Prospective and Retrospective Memory Questionnaire (PRMQ) for dailiy memory functioning. Controlling for mood, self-reported executive functions fully mediated the relationship between alcohol use and memory (indirect effect b=.568, 95%CI [.209,.888]). Findings suggest that self-reported executive dysregulation of memory processes (e.g., Strategic encoding and retrieval) may drive the effects of alcohol use on daily memory symptoms. [ABSTRACT FROM AUTHOR]

Subjective cognitive decline (SCD) is a risk factor for dementia that may occur at higher rates in people with HIV (PWH). Prospective memory (PM) is an aspect of cognition that may help us better understand how SCD impacts daily life. Paricipants were 62 PWH aged ≥ 50 years and 33 seronegative individuals. SCD was operationalized as normatively elevated cognitive symptoms on standardized questionnaires, but with normatively unimpaired performance-based cognition and no current affective disorders. PM was measured with the Comprehensive Assessment of Prospective Memory (CAPM), the Cambridge Test of Prospective Memory (CAMPROMPT), and an experimental computerized time-based PM task. A logistic regression revealed that older PWH had a three-fold increased likelihood for SCD. Among the PWH, SCD was associated with more frequent PM symptoms and poorer accuracy on the time-based scale of the CAMPROMPT. These findings suggest that SCD disrupts PM in older PWH. [ABSTRACT FROM AUTHOR]

Objective:Prospective memory (PM) or "remembering to remember" has been shown to be reduced in Veterans with histories of mild traumatic brain injury (mTBI), particularly on tasks with high strategic demands such as recalling time-based information in the absence of external cues. This study examined whether time monitoring during a PM task was reduced in Veterans with a history of mTBI and was associated with time-based PM performance. Method:Veterans with a history of mTBI (n = 49) and Veterans without a history of TBI (n = 16) completed the Memory for Intentions Screening Test (MIST) as a measure of PM during which their time monitoring (i.e. number of clock checks) was recorded. Results:Adjusting for age, education, depression, and PTSD symptoms, negative binomial regression revealed that the mTBI group checked the clock less frequently compared to the control group (Cohen's d = 0.84, p = 0.005). Within the mTBI group, less frequent time monitoring across the entire MIST task was associated with poorer time-based MIST performance (rs =.57, p < 0.001), but not with event-based MIST (rs =.04, p = 0.768). Conclusions:Veterans with a history of mTBI evidenced significantly reduced time monitoring during a PM task compared to Veterans without a history mTBI, which was associated with strategically-demanding PM. Current findings provide that mTBI-associated difficulties with strategic aspects of PM may be due to reduced time monitoring. Future studies are needed to determine if reduced time monitoring also contributes to mTBI-associated PM difficulties in the real-world (e.g. medication non-adherence). [ABSTRACT FROM AUTHOR]

ObjectiveThe Internet serves an increasingly critical role in health behaviors for older adults with chronic medical conditions. Guided by theories of health behaviors and literacy, this study examined whether the relationship between educational attainment and online pharmacy skills in older persons with HIV disease (PWH) is mediated by health literacy. Design: Participants included 98 PWH age 50 and older who completed the Test of Online Pharmacy Skills (TOPS), which required them to navigate an experimenter-controlled online pharmacy to perform several naturalistic tasks (e.g., refill an existing prescription). Participants also completed the Medication-Management Test-Revised (MMT-R). Results: Mediation analyses revealed a significant indirect effect of education on both online pharmacy accuracy and MMT-R, which was fully mediated by health literacy. In contrast, there was no direct or indirect effect of education on online pharmacy speed when health literacy was included as a mediator. Conclusion: Health literacy plays an important role in the relationship between years of education attained and the ability of older PWH to successfully navigate online pharmacy tasks and manage their medications. Future studies might examine whether interventions to improve electronic health literacy among older PWH who have lower educational attainment have beneficial effects on online health behaviors. [ABSTRACT FROM AUTHOR]

Objective Mild traumatic brain injury (mTBI) and posttraumatic stress disorder (PTSD) frequently co-occur and are associated with neurocognitive intra-individual variability (IIV) and difficulty with prospective memory (PM). The current study aimed to examine associations between IIV and PM in this comorbid group. Method Fifty veterans with a history of blast mTBI and current comorbid PTSD completed a standardized neurocognitive battery to measure IIV, and the Memory for Intentions Screening Test measuring PM. Results Adjusting for age, education, and race, higher IIV was associated with poorer time-based PM (p  < .001, f2  = .34), but not event-based PM. In a subset of the sample with self-report data, higher IIV was associated with poorer self-reported retrospective memory, but not PM. Conclusions Cognitive variability on a standardized neuropsychological battery was associated with strategically demanding PM, which is an ecologically relevant ability and highlights the possible connection between subtle cognitive difficulties in-clinic and those experienced in daily life. [ABSTRACT FROM AUTHOR]

Objective: Memory symptoms and objective impairment are common in HIV disease and are associated with disability. A paradoxical issue is that objective episodic memory failures can interfere with accurate recall of memory symptoms. The present study assessed whether responses on a self-report scale of memory symptoms demonstrate measurement invariance in persons with and without objective HIV-associated memory impairment. Method: In total, 505 persons with HIV completed the Prospective and Retrospective Memory Questionnaire (PRMQ). Objective memory impairment (n = 141) was determined using a 1-SD cutoff on clinical tests of episodic memory. PRMQ measurement invariance was assessed by confirmatory factor analyses examining a one-factor model with increasing cross-group equality constraints imposed on factor loadings and item thresholds (i.e., configural, weak, and strong invariance). Results: Configural model fit indicated that identical items measured a one-factor model for both groups. Comparison to the weak model indicated that factor loadings were equivalent across groups. However, there was evidence of partial strong invariance, with two PRMQ item thresholds differing across memory impairment groups. Post hoc analyses using a 1.5-SD memory impairment cutoff (n = 77) revealed both partial weak and partial strong invariance, such that PRMQ item loadings differed across memory groups for three items. Conclusions: The PRMQ demonstrated a robust factor structure among persons with and without objective HIV-associated memory impairment. However, on select PRMQ items, individuals with memory impairment reported observed scores that were relatively higher than their latent score, while items were more strongly associated with the memory factor in a group with greater memory impairment. [ABSTRACT FROM AUTHOR]

Objective: Older adults commonly experience declines in everyday functioning, the reasons for which are multifactorial. Prospective memory (PM), or remembering to carry out intended actions, can be an executively demanding cognitive process that declines with older age and is independently associated with a variety of everyday functions (e.g. taking medication). This study examined the hypothesis that PM mediates the relationship between older age and poorer everyday functioning. Method: A total of 468 community-dwelling adults (ages 18–75) with a range of medical comorbidities (e.g. viral infection) were classified as dependent on four well-validated measures of manifest everyday functioning: activities of daily living, employment status, the Karnofsky Scale of Performance Status, and self-reported cognitive symptoms. Participants completed the Memory for Intentions Test (MIsT) to measure PM, alongside clinical tests of executive functions and retrospective memory. Results: Controlling for education and comorbidities, bootstrap analysis revealed a significant direct effect of age on everyday functioning and a significant mediated effect of age on everyday functioning through the indirect effect of time-based b =.006 [.003,.010] and event-based PM (b =.005, [.002,.009]), as well as slightly smaller effects for executive functions (b =.003, [.001,.005]) and retrospective memory (b =.002, [.001,.005]). Conclusions: These cross-sectional data suggest that executively demanding aspects of declarative memory play an important partial mediating role between an individual factor (i.e. age) and daily life activities, and highlight the possible benefit of targeting PM for improving everyday functioning in older adults. [ABSTRACT FROM AUTHOR]

Objective: We investigated the construct and criterion validity of the source memory (SM) indices within the California Verbal Learning Test-II (CVLT-II). Method: Participants included 77 individuals with HIV-associated neurocognitive disorders (HAND+), 287 HIV + neurocognitively normal individuals (HAND−) and 203 seronegative HIV comparisons (HIV−). CVLT-II SM impairment status (normative scores ≤1 standard deviation) was determined using Total Across-List Intrusions and Source Recognition Discriminability (d′). Participants also completed a comprehensive neuropsychological battery, assessments of everyday functioning and experimental measures of SM. Results: CVLT-II SM impairment was significantly associated with increased errors on experimental SM measures and lower scores on measures of passage recall and executive functions, but not visuospatial skills. In a logistic regression controlling for clinicodemographic factors, CVLT-II SM impairment was a significant independent predictor of HAND, with the HAND + group showing higher rates of SM impairment than both the HAND − and HIV − groups. Finally, CVLT-II SM impairment was significantly related to a composite measure of everyday functioning, but this effect disappeared after adjusting for covariates. Note that, the overall pattern of findings across this study also held when CVLT-3 normative standards were applied to the SM indices. Conclusions: Results provide initial support for the construct and criterion validity of a CVLT-II SM index in the setting of HIV disease. Future studies should examine the validity of CVLT-II SM variables in other neuropsychological populations. [ABSTRACT FROM AUTHOR]

Focuses on the fictitious character Janie in Zora Neale Hurston's book `Their Eyes Were Watching God.' Link between god-authority and father-sexuality; The book as an act of wish-fulfillment; References to the ideas of Sigmund Freud.

Among individuals living with HIV disease, approximately 60% experience problems with everyday functioning. The present study investigated the utility of the UCSD Performance-based Skills Assessment-Brief Version (UPSA-B) as a measure of functional capacity in HIV. We utilized a cross-sectional three-group design comparing individuals with HIV- associated neurocognitive disorder (HAND) (HIV + HAND+; n = 27), HIV+ neurocognitively normal individuals (HIV + HAND-; n = 51), and an HIV- comparison group (HIV-; n = 28) with broadly comparable demographics and non-HIV comorbidities. Participants were administered the UPSA-B, the Medication Management Test-Revised (MMT-R), and were assessed for manifest everyday functioning and quality of life, as part of a standardized clinical neurocognitive research battery. Results indicated that the HIV + HAND+ group had significantly lower UPSA-B scores than the HIV + HAND-group, but did not differ from the HIV- group. Among HIV+ individuals, UPSA-B scores were significantly related to MMT-R scores, all neurocognitive domains assessed, and education, but the UPSA-B was not related to manifest everyday functioning (e.g., unemployment), health-related quality of life, or HIV disease variables. Findings provide mixed support for the construct validity of the UPSA-B in HIV. Individuals impaired on the UPSA-B may be at increased risk for HAND, but the extent to which it detects general manifest everyday functioning problems is uncertain. [ABSTRACT FROM AUTHOR]

West Nile Virus (WNV) can be a neuroinvasive pathogen that may produce persistent mild-to-moderate neurocognitive impairments in some infected persons. Intra-individual variability (IIV) is an index of a person’s performance across a neuropsychological test or battery, which is an indicator of neurocognitive control and integrity of prefrontal systems. The present study examined possible associations of IIV to neurological health and well-being in WNV infection. Participants included 84 adults with a range of clinical WNV disease (31 West Nile Encephalitis, 16 West Nile Meningitis, 37 West Nile Fever) who completed the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). IIV was operationalized as covariance of variation (CoV), or the intra-individual standard deviation across 5 age-adjusted RBANS standard scores divided by the mean of standard scores. Participants were assessed for health-related quality of life (QoL) using the RAND 36-item short form health survey (SF-36). Analyses revealed that the West Nile Encephalitis group had higher neurocognitive CoV compared to the West Nile Fever group, and this difference was associated with a medium effect size (Cohen’s d = .52). Mixed linear models controlling for estimated IQ, activities of daily living, depression, neuroinvasive disease groups, and fatigue showed that higher RBANS CoV was associated with lower physical, but not mental health QoL. In persons with WNV infection, there is a modest association between elevations in IIV and encephalitis, and even subtle disruptions in neuropsychological functioning show relationships with important self-reported functioning as measured by physical health quality of life. Future studies should examine whether IIV predicts long-term health outcomes (e.g., mortality) in individuals infected with WNV. [ABSTRACT FROM AUTHOR]

Objective: Prospective memory (PM) is described as the capacity to form and maintain an intention that is executed in response to a specific cue. Neural injury and associated neurocognitive disorders are common among persons living with HIV disease, who might therefore be susceptible to impairment in PM. Method: This literature review utilized a structured qualitative approach to summarize and evaluate our current understanding of PM functioning in people living with HIV disease. 33 studies of PM in HIV+ persons met criteria for inclusion. Results: Findings showed that HIV is associated with moderate deficits in PM, which appear to be largely independent of commonly observed comorbid factors. The pattern of PM deficits reveals dysregulation of strategic processes that is consistent with the frontal systems pathology and associated executive dysfunction that characterizes HIV-associated neural injury. The literature also suggests that HIV-associated PM deficits present a strong risk of concurrent problems in a wide range of health behaviors (e.g. medication non-adherence) and activities of daily living (e.g. employment). Early attempts to improve PM in HIV disease have revealed that supporting strategic processes might be effective for some individuals. Conclusions: HIV-associated PM deficits are common and exert a significant adverse effect on the daily lives and health of infected persons. Much work remains to be done to understand the cognitive architecture of HIV-associated PM deficits and the most efficient means to enhance PM functioning and improve health outcomes in persons living with HIV. [ABSTRACT FROM AUTHOR]

HIV-associated neurocognitive disorders (HAND) occur in approximately 50% of HIV-infected individuals, yet available diagnostic criteria yield varying prevalence rates. This study examined the frequency, reliability, and sensitivity to everyday functioning problems of three HAND diagnostic criteria (DSM-5, Frascati, Gisslén). Participants included 361 adults with HIV disease and 199 seronegative adults. Neurocognitive status as defined by each of the three diagnostic systems was determined via a comprehensive neuropsychological battery. Everyday functioning was evaluated through self-report and clinician ratings. Results of logistic regressions revealed an association of HIV serostatus with Frascati-defined neurocognitive impairment ( p = .027, OR = 1.7[1.1, 2.7]), but not DSM-5 or Gisslén-defined criteria ( ps > .05). Frascati and DSM-5 criteria demonstrated agreement on 71% of observations, Frascati and Gisslén showed agreement on 80%, and DSM-5 and Gisslén criteria showed agreement on 46%, though reliability across the three criteria was poor. Only Frascati-defined neurocognitive impairment significantly predicted everyday functioning problems ( p = .002, OR = 2.3[1.4, 3.8]). However, when both neurocognitive and complaint criteria were considered, the DSM-5 guidelines demonstrated significant relationships to everyday functioning, serostatus, and also increased reliability overtime compared to neurocognitive criteria alone (all ps < .05). A subset ( n = 118) of the HIV+ group was assessed again after 14.0 (2.2) months. DSM-5 criteria evidenced significantly higher rates of incident neurocognitive disorder compared to both Frascati ( p = .003) and Gisslén ( p = .021) guidelines, while there were fewer remitting neurocognitive disorder diagnoses when Gisslén criteria were applied to the study sample compared to Frascati ( p = .04). Future studies should aim to identify gold standard biological markers (e.g., neuropathology) and clinical outcomes associated with specific diagnostic criteria. [ABSTRACT FROM AUTHOR]

There is debate as to whether the neurocognitive changes associated with HIV infection represent an acceleration of the typical aging process or more simply reflect a greater accentuated risk for age-related declines. We aimed to determine whether accelerated neurocognitive aging is observable in a sample of older HIV-infected individuals compared to age-matched seronegatives and older old (i.e., aged ≥65) seronegative adults. Participants in a cross-sectional design included 48 HIV-seronegative (O−) and 40 HIV-positive (O+) participants between the ages of 50-65 (mean ages = 55 and 56, respectively) and 40 HIV-seronegative participants aged ≥65 (OO−; mean age = 74) who were comparable for other demographics. All participants were administered a brief neurocognitive battery of attention, episodic memory, speeded executive functions, and confrontation naming (i.e., Boston Naming Test). The O+ group performed more poorly than the O− group (i.e., accentuated aging), but not differently from the OO− on digit span and initial recall of a supraspan word list, consistent with an accelerating aging profile. However, the O+ group's performance was comparable to the O− group on all other neurocognitive tests ( ps > 0.05). These data partially support a model of accelerated neurocognitive aging in HIV infection, which was observed in the domain of auditory verbal attention, but not in the areas of memory, language, or speeded executive functions. Future studies should examine whether HIV-infected adults over 65 evidence accelerated aging in downstream neurocognitive domains and subsequent everyday functioning outcomes. [ABSTRACT FROM AUTHOR]

One important limitation of prior studies examining functional decline in Huntington’s disease (HD) has been the reliance on self-reported measures of ability. Since report-based methods can be biased by lack of insight, depression, and cognitive impairment, contrasting self-reported ability with measures that assess capacity may lead to a more comprehensive estimation of real-world functioning. The present study examined self-reported ability to perform instrumental activities of daily living (iADLs) and performance-based financial management capacity in 20 patients diagnosed with mild-moderate Huntington’s disease (HD) and 20 demographically similar healthy adults. HD patients reported significantly greater declines in their ability to manage finances. On the capacity measure of financial management, HD patients performed significantly below healthy adults. Additionally, in the HD group there were no significant correlations between self-reported ability and capacity measures of financial management. HD patients endorsed declines in global iADL ability and exhibited deficits in functional capacity when performing a financial management task. Capacity measures may aid in assessing the extent to which HD patients accurately estimate real-world iADL performance, and the present findings suggest that such measures of capacity may be related to the cognitive, but not motor or affective, symptoms of HD. [ABSTRACT FROM PUBLISHER]

Objective: HIV is associated with frontostriatal dysregulation and executive dysfunction. This study evaluated whether HIV-infected individuals evidence deficits in random number generation (RNG), which is a strategic task requiring paced, rule-guided production of digits. Method: In total, 74 HIV+ adults and 54 seronegative comparison participants completed a comprehensive research neuropsychological battery. Participants produced a random digit sequence by avoiding any order and using numbers 1 through 10 for 100 s at a pace of 1 digit/s. Outcomes included intrusions, repetitions, seriation (1-2-3-4), and cycling (median length of gaps between repeating digits). Results: HIV disease was associated with higher levels of seriation and cycling (ps < .05) but not intrusions or repetitions (ps > .10). Among HIV+ individuals, higher seriation was associated with neuropsychological performance including poorer auditory attention, verbal learning, and delayed memory, whereas higher cycling scores were associated with poorer delayed memory and verbal fluency (ps < .05). Higher seriation also was independently associated with self-reported declines in activities of daily living (ADLs) in the HIV+ group. Conclusions: Individuals living with HIV disease evidence moderate difficulties in inhibiting statistically unlikely non-random sequences, which showed medium associations with higher order verbal abilities and may contribute to greater declines in everyday functioning outcomes. Future studies might examine RNG's role in health behaviors such as medical decision-making or medication adherence. [ABSTRACT FROM AUTHOR]

The current study examined the individual and combined effects of age and HIV serostatus on anxiety symptoms and diagnoses among a community sample. Participants included 163 Older (50+ years) HIV+ persons, 113 Younger (<40) HIV+ persons, 95 Older HIV- persons, and 75 Younger HIV- persons who completed the Profile of Mood States and the Composite International Diagnostic Interview as part of a baseline neuroAIDS research assessment. Results showed that HIV infection was associated with significantly higher rates of anxiety symptoms as well as 12-month and lifetime diagnoses of Generalized Anxiety Disorder (GAD) and Panic Disorder (PD). There was no significant effect of age and no significant interaction between HIV serostatus and age; however, Older HIV+ participants were significantly older at onset of anxiety diagnoses as compared to their Younger HIV+ counterparts. Among both Older and Younger HIV+ participants, there were high rates of comorbidity between anxiety disorders and Major Depressive and methamphetamine use disorders. Across the lifespan, HIV-associated neurocognitive disorders interacted with 12-month anxiety disorders to increase risk of poorer everyday functioning outcomes. Overall, these data suggest that HIV disease and its comorbidities are related to elevated anxiety symptoms and diagnoses in both younger and older adults. [ABSTRACT FROM PUBLISHER]

We examined the performance of healthy young ( n = 57) and older adults ( n = 43) genotyped as apolipoprotein E-ε4 (APOE-ε4) carriers or APOE-ε4 non-carriers on a delayed match-to-sample task involving varying degrees of spatial interference hypothesized to assess spatial pattern separation. Older adult ε4 carriers were further divided into “impaired” and “unimpaired” groups based on their performance on a standardized test of verbal memory. We found that performance on the spatial pattern separation test increased as a function of decreased spatial interference across all groups. The older ε4 carriers in the impaired group performed significantly worse ( p < .05) than unimpaired ε4 carriers, ε4 non-carriers, and young adults. The data suggest that spatial pattern separation may be less efficient in a subset of healthy older adults with subtle memory decline who are carriers of the ε4 allele. However, pattern separation performance may be comparable to that of young adults in a subset of older adult ε4 carriers and more broadly among non-carriers. Our findings offer additional evidence that pattern separation may vary in older adults, and they provide novel insight into pattern separation efficiency in ε4-positive older adults. [ABSTRACT FROM AUTHOR]

With the rising number of individuals in their 50s and 60s who are infected with HIV, concerns have emerged about possible increases in the rates of non-HIV-associated dementias. The current study examined the prevalence of mild cognitive impairment (MCI) in older HIV-infected adults, since MCI is an intermediate state between typical cognitive aging and dementia that emerges in this age range. Participants included 75 adults with HIV disease aged 50 years and older who were on combination antiretroviral therapy (cART) and had undetectable plasma viral loads and 80 demographically similar HIV-seronegative comparison subjects. Participants completed a research neuropsychological evaluation that was used to classify MCI according to the comprehensive diagnostic scheme described by Bondi et al. (J Alzheimers Dis 42:275-289, 2014). HIV-infected persons were over seven times more likely to have an MCI designation (16 %) than their seronegative counterparts (2.5 %). Within the HIV+ cohort, MCI had minimal overlap with diagnoses of asymptomatic neurocognitive impairment and was significantly associated with older age, lower Karnofsky Scale of Performance Scores, and mild difficulties performing instrumental activities of daily living (iADLs). HIV infection in older adults is associated with a notably elevated concurrent risk of MCI, which may increase the likelihood of developing non-HIV-associated dementias as this population ages further. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to determine the combined effects of age and HIV infection on the risk of incident neurocognitive disorders.Method: A total of 146 neurocognitively normal participants were enrolled at baseline into one of four groups based on age (≤40 years and ≥50 years) and HIV serostatus resulting in 24 younger HIV−, 27 younger HIV+, 39 older HIV−, and 56 older HIV+ individuals. All participants were administered a standardized clinical neuropsychological battery at baseline and 14.3 ± .2 months later.Results: A logistic regression predicting incident neurocognitive disorders from HIV, age group, and their interaction was significant (χ2[4] = 13.56,p = .009), with a significant main effect of HIV serostatus (χ2[1] = 5.01,p = .025), but no main effect of age or age by HIV interaction (ps > .10). Specifically, 15.7% of the HIV+ individuals had an incident neurocognitive disorder as compared to 3.2% of the HIV− group (odds ratio = 4.8 [1.2, 32.6]). Among older HIV+ adults, lower baseline cognitive reserve, prospective memory, and verbal fluency each predicted incident neurocognitive disorders at follow-up.Conclusions: Independent of age, HIV infection confers a nearly fivefold risk for developing a neurocognitive disorder over approximately one year. Individuals with lower cognitive reserve and mild weaknesses in higher-order neurocognitive functions may be targeted for closer clinical monitoring and preventative measures. [ABSTRACT FROM PUBLISHER]

In the common genetic disorder autosomal dominant polycystic kidney disease (ADPKD), kidney function is disrupted by multiple fluid-filled epithelial cysts. Cyst growth in ADPKD involves fluid accumulation within the cyst lumen driven by cystic fibrosis transmembrane conductance regulator (CFTR)- mediated transepithelial Cl- secretion. This suggests that inhibitors of the CFTR Cl- channel might retard cyst growth. This review considers how knowledge of CFTR structure and function and its role in transepithelial salt and water movements provides insight into the mechanism of action of CFTR inhibitors. Some small molecules, termed open-channel blockers, inhibit directly the CFTR Cl- channel by physically obstructing the CFTR pore and preventing Cl- flow. By contrast, other small molecules, termed allosteric inhibitors, bind to CFTR at a site remote from the channel pore and interfere with conformational changes that open the pore. The application of high-throughput screening to CFTR drug discovery has led to the identification of new inhibitors of the CFTR Cl- channel including the thiazolidinone CFTRinh-172 and the glycine hydrazide GlyH-101. The demonstration that CFTR inhibitors retard cyst expansion and kidney enlargement in mouse models of ADPKD provides proof of concept for the use of small-molecule CFTR inhibitors in the treatment of ADPKD. [ABSTRACT FROM AUTHOR]

The cystic fibrosis transmembrane conductance regulator (CFTR) plays a fundamental role in fluid and electrolyte transport across epithelial tissues. Based on its structure, function and regulation, CFTR is an ATP-binding cassette (ABC) transporter. These transporters are assembled from two membrane-spanning domains (MSDs) and two nucleotide-binding domains (NBDs). In the vast majority of ABC transporters, the NBDs form a common engine that utilises the energy of ATP hydrolysis to pump a wide spectrum of substrates through diverse transmembrane pathways formed by the MSDs. By contrast, in CFTR the MSDs form a pathway for passive anion flow that is gated by cycles of ATP binding and hydrolysis by the NBDs. Here, we consider how the interaction of ATP with two ATP-binding sites, formed by the NBDs, powers conformational changes in CFTR structure to gate the channel pore. We explore how conserved sequences from both NBDs form ATP-binding sites at the interface of an NBD dimer and highlight the distinct roles that each binding site plays during the gating cycle. Knowledge of how ATP gates the CFTR Cl− channel is critical for understanding CFTR's physiological role, its malfunction in disease and the mechanism of action of small molecules that modulate CFTR channel gating. [ABSTRACT FROM AUTHOR]

Adenosylcobalamin (Ado-B12) is both the cofactor and inducer of ethanolamine ammonia lyase (EA-lyase), a catabolic enzyme for ethanolamine. De novo synthesis of Ado-B12 by Salmonella enterica occurs only under anaerobic conditions. Therefore, aerobic growth on ethanolamine requires import of Ado-B12 or a precursor (CN-B12 or OH-B12) that can be adenosylated internally. Several known enzymes adenosylate corrinoids. The CobA enzyme transfers adenosine from ATP to a biosynthetic intermediate in de novo B12 synthesis and to imported CN-B12, OH-B12, or Cbi (a B12 precursor). The PduO adenosyl transferase is encoded in an operon (pdu) for cobalamin-dependent propanediol degradation and is induced by propanediol. Evidence is presented here that a third transferase (EutT) is encoded within the operon for ethanolamine utilization (eut). Surprisingly, these three transferases share no apparent sequence similarity. CobA produces sufficient Ado-B12 to initiate eut operon induction and to serve as a cofactor for EA-lyase when B12 levels are high. Once the eut operon is induced, the EutT transferase supplies more Ado-B12 during the period of high demand. Another protein encoded in the operon (EutA) protects EA-lyase from inhibition by CN-B12 but does so without adenosylation of this corrinoid. [ABSTRACT FROM AUTHOR]

Comments on the findings of a study appearing in the August 2004 issue of the "Journal of General Physiology" regarding cystic fibrosis transmembrane conductance regulator (CFTR) pharmacology. Absence of potent, specific inhibitors of anion channels and implications for CFTR pharmacology studies; Discovery of a glycine hydrazides and its impact on CFTR inhibitors; Relationship between the chemical structure of glycine hydrazides and CFTR inhibition.

Presents information on a study which proposed the use of vector quantizer encoder distortion in identifying image blur. Details on vector quantizer; Modeling of blur functions; Conclusion.

Presents information on a study which focused on an improved version of an algorithm designed to perform image restoration via nonlinear interpolative vector quantization (VQ). Theory and design of the nonlinear interpolative VQ image restoration algorithm; Codebook design and lapped decoding highlights; Simulation results; Conclusions.

Objective Mild Traumatic Brain Injury (mTBI) and Posttraumatic Stress Disorder (PTSD) frequently co-occur in service members, and each are associated with increased neurocognitive intraindividual variability (IIV), a proposed indicator of subtle disruptions in executive control, and prospective memory (PM), or "remembering to remember." The current study sought to examine possible associations between IIV and PM performances among Veterans with comorbid mTBI and PTSD. Methods 46 OEF/OIF/OND Veterans with a history of mTBI and current PTSD enrolled in a VA research study of mTBI completed a standardized neurocognitive battery of 12 measures used to calculate the coefficient of variation (CoV) as an index of IIV, and the Memory for Intentions Screening Test (MIST) as a measure of PM. Veterans also completed clinical questionnaires (i.e. Patient Health Questionnaire-9, PTSD Checklist-Military), and a subset of the sample (n = 31) Veterans completed the Prospective and Retrospective Memory Questionnaire (PRMQ) as a measure of self-reported PM. Results Controlling for age and education, higher CoV was associated with time-based MIST scores (β = −0.02, p = 0.008, η2 = 0.16) and event-based MIST scores (β = −0.02, p = 0.031, η2 = 0.11). CoV was not associated with mood factors in the sample (ps >0.10). In a subset of the total sample, higher CoV was associated with elevated self-reported PM symptoms (r = −0.36, p = 0.046). Conclusions Among Veterans with a history of mTBI and current PTSD, elevated variability of performances across neurocognitive measures was associated with poorer performance-based PM and self-reported PM symptoms. Future studies are needed to examine IIV as a predictor of real-world PM performances (e.g. medication adherence). [ABSTRACT FROM AUTHOR]

Presents a study on the pharmacological agents that interact directly with the cystic fibrosis transmembrane conductance regulator (CFTR) chlorine channel. Agents which stimulate CFTR by interacting with the nucleotide-binding domains that control channel gating; CFTR inhibitors characterized by binding within the channel pore and preventing chlorine permeation; Use of molecular pharmacology of CFTR in the treatment of diseases caused by CFTR dysfunction.

Tests the hypothesis that one membrane-spanning domain--nucleotide binding domain (MSD-NBD) motif could form a chlorine channel at the amino terminal of the cystic fibrosis transmembrane conductance regulator (CFTR). Expression of D836X generates cAMP-regulated chlorine currents; Regulation of D836X chlorine channels by intracellular nucleotides; Implications for cystic fibrosis.

Reports that, when expressed in heterologous epithelial cells, missense mutations associated with cystic fibrosis in which arginine is replaced by histidine, tryptophan or proline were correctly processed and generated cyclic AMP-regulated apical Cl- currents. Cystic fibrosis transmembrane conductance regulator (CFTR); Fischer Rat Thyroid (FRT) epithelia; Whole-cell properties of R117H; Further details.

Studies the ethanolamine utilization operon of Salmonella typhimurium bacterium. Operon's role in the utilization of ethanolamine as a carbon, nitrogen an energy source; Activity of the positive regulatory protein EutR in the presence of ethanolamine and adenosyl-cobalamine.

Describes studies designed to develop an expression system for cystic fibrosis transmembrane conductance regulator (CFTR) in the apical membrane of Fischer rat thyroid epithelia. CFTR expression systems; Measurements of apical membrane chloride current; Immunoprecipitation; Immunofluorescence studies.

Discusses the structure and function of the cystic fibrosis transmembrane regulator (CFTR) chloride channel. Topology; Domain structure; Biophysical properties of channel pore; Identification of residues that influence conduction and that line the pore; Ion selectivity; Contribution of the intracellular and extracellular loops; Regulating effect of adenosine 5'-triphosphate hydrolysis.

Provides information on the presentation of a novel technique for image restoratin based on nonlinear interpolative vector quantization (NLVQ). Information on the image restoration; Detailed information on nonlinear VQ image restoration; Conclusion reached.

Cystic fibrosis transmembrane conductance regulator (CFTR) correctors are small molecules that target the most common cause of cystic fibrosis: misfolded F508del-CFTR. Using differential scanning fluorimetry, Sampson et al. (2010) identify a CFTR corrector that interacts directly with the CFTR domain affected by the F508del mutation. [Copyright &y& Elsevier]

Deletion of phenylalanine 508 (F508del) in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel is the most common cause of cystic fibrosis. The F508 residue is located on nucleotide-binding domain 1 (NBD1) in contact with the cytosolic extensions of the transmembrane helices, in particular intracellular loop 4 (ICL4). To investigate how absence of F508 at this interface impacts the CFTR protein, we carried out a mutagenesis scan of ICL4 by introducing secondsite mutations at 11 positions in cis with F508del. Using an image-based fluorescence assay, we measured how each mutation affected membrane proximity and ion-channel function. The scan strongly validated the effectiveness of R1070W at rescuing F508del defects. Molecular dynamics simulations highlighted two features characterizing the ICL4/NBD1 interface of F508del/R1070W-CFTR: flexibility, with frequent transient formation of interdomain hydrogen bonds, and loosely stacked aromatic sidechains (F1068, R1070W, and F1074, mimicking F1068, F508, and F1074 in WT CFTR). F508del-CFTR displayed a distorted aromatic stack, with F1068 displaced toward the space vacated by F508, while in F508del/R1070F-CFTR, which largely retained F508del defects, R1070F could not form hydrogen bonds and the interface was less flexible. Other ICL4 second-site mutations which partially rescued F508del-CFTR included F1068M and F1074M. Methionine side chains allow hydrophobic interactions without the steric rigidity of aromatic rings, possibly conferring flexibility to accommodate the absence of F508 and retain a dynamic interface. These studies highlight how both hydrophobic interactions and conformational flexibility might be important at the ICL4/NBD1 interface, suggesting possible structural underpinnings of F508del-induced dysfunction. [ABSTRACT FROM AUTHOR]

Background: Pulmonary ionocytes have been identified in the airway epithelium as a small population of ion transporting cells expressing high levels of CFTR (cystic fibrosis transmembrane conductance regulator), the gene mutated in cystic fibrosis. By providing an infinite source of airway epithelial cells (AECs), the use of human induced pluripotent stem cells (hiPSCs) could overcome some challenges of studying ionocytes. However, the production of AEC epithelia containing ionocytes from hiPSCs has proven difficult. Here, we present a platform to produce hiPSC-derived AECs (hiPSC-AECs) including ionocytes and investigate their role in the airway epithelium. Methods: hiPSCs were differentiated into lung progenitors, which were expanded as 3D organoids and matured by air-liquid interface culture as polarised hiPSC-AEC epithelia. Using CRISPR/Cas9 technology, we generated a hiPSCs knockout (KO) for FOXI1, a transcription factor that is essential for ionocyte specification. Differences between FOXI1 KO hiPSC-AECs and their wild-type (WT) isogenic controls were investigated by assessing gene and protein expression, epithelial composition, cilia coverage and motility, pH and transepithelial barrier properties. Results: Mature hiPSC-AEC epithelia contained basal cells, secretory cells, ciliated cells with motile cilia, pulmonary neuroendocrine cells (PNECs) and ionocytes. There was no difference between FOXI1 WT and KO hiPSCs in terms of their capacity to differentiate into airway progenitors. However, FOXI1 KO led to mature hiPSC-AEC epithelia without ionocytes with reduced capacity to produce ciliated cells. Conclusion: Our results suggest that ionocytes could have role beyond transepithelial ion transport by regulating epithelial properties and homeostasis in the airway epithelium. [ABSTRACT FROM AUTHOR]

Age and HIV disease have additive effects on neural systems that support motor functioning. The current study examined the combined impact of aging and HIV on extrapyramidal motor functions, which were hypothesized to influence on activities of daily living (ADLs) and quality of life (QoL). Participants included 336 adults classified by HIV serostatus and age. A research nurse administered the Unified Parkinson's Disease Rating Scale (UPDRS) and participants completed the modified Lawton & Brody ADL and the Short Form Survey Instrument (SF-36) questionnaires as part of a larger neuropsychological research battery. A convenience subset of 172 participants completed a 14-month follow-up evaluation. At baseline, only older age was associated with mild extrapyramidal signs; however, at 14-month follow-up, independent adverse effects of both HIV status and age group were observed on a 3-level UPDRS change variable. Among older HIV+ adults, the presence of mild UPDRS motor signs was independently associated with basic and instrumental ADL dependence, as well as lower physical (ps <.05), but not mental QoL. In the modern treatment era, older HIV+ adults show higher frequency of mild extrapyramidal signs as compared to younger individuals (but not older HIV− persons) and are at higher risk of incident extrapyramidal signs relative to HIV− persons (but not younger HIV+ persons). When present in older HIV+ adults, extrapyramidal signs are of mild severity but nevertheless increase the risk of daily functioning problems and lower health-related physical QoL. [ABSTRACT FROM AUTHOR]

The authors comment on a study published in this issue of the journal which suggested that individual airway surface epithelial cells oscillate between absorptive and secretory states. Included is a list of principal observations underlying the fluid recirculation model. The authors believe that the study's bioelectric measurements of the airway epithelium are a major technical achievement. They contend that it highlights the flaw in bidirectional models of ion transport by airway epithelia.

The article introduces a series of studies on the physiology of anion transport.

Over the past decade, the improvement in cancer diagnostics and therapeutics has extended the overall survival of patients diagnosed with cancer including brain cancer. However, despite these unprecedented medical successes, patients continue to experience numerous neurologic complications after treatment that interfere with their independence, functionality, and overall quality of life. These include, among others, cognitive impairment, endocrinopathies, peripheral and cranial neuropathies, and vasculopathy. This article describes the long-term neurologic complications cancer survivors commonly experience to increase awareness of these complications and discuss treatments when available. Further research is necessary to understanding of mechanisms of neurologic injury and advance diagnosis and treatment. Effective patient education, monitoring, and managing neurologic issues after cancer treatment may improve independence, functionality, and quality of life during survivorship. [ABSTRACT FROM AUTHOR]