Associations between Retinal Markers of Microvascular Disease and Cognitive Impairment in Newly Diagnosed Type 2 Diabetes Mellitus: A Case Control Study

Objective

To investigate associations between retinal microvascular changes and cognitive impairment in newly diagnosed type 2 diabetes mellitus.

Design

Case control study.

Setting

A primary care cohort with newly diagnosed type 2 diabetes mellitus.

Methods

For this analysis, we compared 69 cases with lowest decile scores (for the cohort) on the Modified Telephone Interview for Cognitive Status and 68 controls randomly selected from the remainder of the cohort. Retinal images were rated and the following measures compared between cases and controls: retinal vessel calibre, arterio-venous ratio, retinal fractal dimension, and simple and curvature retinal vessel tortuosity.

Results

Total and venular (but not arteriolar) simple retinal vessel tortuosity levels were significantly higher in cases than controls (t = 2.45, p = 0.015; t = 2.53, p = 0.013 respectively). The associations persisted after adjustment for demographic factors, retinopathy, neuropathy, obesity and blood pressure. There were no other significant differences between cases and controls in retinal measures.

Conclusions

A novel association was found between higher venular tortuosity and cognitive impairment in newly diagnosed type 2 diabetes mellitus. This might be accounted for by factors such as hypoxia, thrombus formation, increased vasoendothelial growth factor release and inflammation affecting both the visible retinal and the unobserved cerebral microvasculature.     

Evaluation of the Retinal Vasculature in Hypertension and Chronic Kidney Disease in an Elderly Population of Irish Nuns

Background

Chronic kidney disease (CKD) and hypertension are global public health problems associated with considerable morbidity, premature mortality and attendant healthcare costs. Previous studies have highlighted that non-invasive examination of the retinal microcirculation can detect microvascular pathology that is associated with systemic disorders of the circulatory system such as hypertension. We examined the associations between retinal vessel caliber (RVC) and fractal dimension (D_F), with both hypertension and CKD in elderly Irish nuns.

Methods

Data from 1233 participants in the cross-sectional observational Irish Nun Eye Study (INES) were assessed from digital photographs with a standardized protocol using computer-assisted software. Multivariate regression analyses were used to assess associations with hypertension and CKD, with adjustment for age, body mass index (BMI), refraction, fellow eye RVC, smoking, alcohol consumption, ischemic heart disease (IHD), cerebrovascular accident (CVA), diabetes and medication use.

Results

In total, 1122 (91%) participants (mean age: 76.3 [range: 56–100] years) had gradable retinal images of sufficient quality for blood vessel assessment. Hypertension was significantly associated with a narrower central retinal arteriolar equivalent (CRAE) in a fully adjusted analysis (P = 0.002; effect size = -2.16 μm; 95% confidence intervals [CI]: -3.51, -0.81 μm). No significant associations between other retinal vascular parameters and hypertension or between any retinal vascular parameters and CKD were found.

Conclusions

Individuals with hypertension have significantly narrower retinal arterioles which may afford an earlier opportunity for tailored prevention and treatment options to optimize the structure and function of the microvasculature, providing additional clinical utility. No significant associations between retinal vascular parameters and CKD were detected.     

Interactions of the Gasotransmitters Contribute to Microvascular Tone (Dys)regulation in the Preterm Neonate

Background & Aims

Hydrogen sulphide (H₂S), nitric oxide (NO), and carbon monoxide (CO) are involved in transitional microvascular tone dysregulation in the preterm infant; however there is conflicting evidence on the interaction of these gasotransmitters, and their overall contribution to the microcirculation in newborns is not known. The aim of this study was to measure the levels of all 3 gasotransmitters, characterise their interrelationships and elucidate their combined effects on microvascular blood flow.

Methods

90 preterm neonates were studied at 24h postnatal age. Microvascular studies were performed by laser Doppler. Arterial COHb levels (a measure of CO) were determined through co-oximetry. NO was measured as nitrate and nitrite in urine. H₂S was measured as thiosulphate by liquid chromatography. Relationships between levels of the gasotransmitters and microvascular blood flow were assessed through partial correlation controlling for the influence of gestational age. Structural equation modelling was used to examine the combination of these effects on microvascular blood flow and derive a theoretical model of their interactions.

Results

No relationship was observed between NO and CO (p = 0.18, r = 0.18). A positive relationship between NO and H₂S (p = 0.008, r = 0.28) and an inverse relationship between CO and H₂S (p = 0.01, r = -0.33) exists. Structural equation modelling was used to examine the combination of these effects on microvascular blood flow. The model with the best fit is presented.

Conclusions

The relationships between NO and H₂S, and CO and H₂S may be of importance in the preterm newborn, particularly as NO levels in males are associated with higher H₂S levels and higher microvascular blood flow and CO in females appears to convey protection against vascular dysregulation. Here we present a theoretical model of these interactions and their overall effects on microvascular flow in the preterm newborn, upon which future mechanistic studies may be based.     

Association between Retinal Arteriolar and Venule Calibre with Prevalent Heart Failure: A Cross-Sectional Study

Background

There is evidence to suggest that microvascular disease, particularly diabetic retinopathy, plays a role in the pathogenesis of HF. However, whether changes in retinal vessel calibre predicts HF is unclear. The purpose of this study was to examine the association of retinal microvascular structure with prevalent heart failure (HF).

Methods

The Australian Heart Eye Study (AHES) is a cross-sectional study that surveyed 1680 participants who presented to a tertiary referral hospital for the evaluation of potential coronary artery disease by coronary angiography. Retinal vessel calibre was graded using retinal photography and participants’ self-reported echocardiography-confirmed HF was obtained via an extensive medical questionnaire.

Results

There were 107 participants (8.1%) with prevalent self-reported HF. Persons with wider retinal arteriolar calibre (comparing highest versus lowest tertile or reference) were more likely to have prevalent HF (OR 3.5; 95% CI, 1.7–7.2) when adjusted for age and sex. After further adjustment for body mass index, hypertension, diabetes, smoking status, triglycerides and estimated glomerular filtration rate, this association remained significant (OR 4.5; 95% CI, 2.0–9.8). After further stratification, this association remained significant among participants with diabetes (OR 10.3; 95% CI, 2.7–39.3) but not in those without diabetes (OR 2.7; 95% CI, 0.9–7.5). The strength of this association was not dependent on the length of history of diabetes, or retinopathy status. There was no significant association between retinal venular calibre and prevalence of HF.

Conclusions

Wider retinal arteriolar diameter was significantly and independently associated with prevalent HF in participants of a cross-sectional study. This association was significant stronger among participants with diabetes compared to without diabetes. No association was found between retinal venule calibre with prevalent HF.     

Body Mass Index and Decline of Cognitive Function

Background

The association between body mass index (BMI) and cognitive function is a public health issue. This study investigated the relationship between obesity and cognitive impairment which was assessed by the Korean version of the Mini-mental state examination (K-MMSE) among mid- and old-aged people in South Korea.

Methods

A cohort of 5,125 adults, age 45 or older with normal cognitive function (K-MMSE≥24) at baseline (2006), was derived from the Korean Longitudinal Study of Aging (KLoSA) 2006~2012. The association between baseline BMI and risk of cognitive impairment was assessed using multiple logistic regression models. We also assessed baseline BMI and change of cognitive function over the 6-year follow-up using multiple linear regressions.

Results

During the follow-up, 358 cases of severe cognitive impairment were identified. Those with baseline BMI≥25 kg/m² than normal-weight (18.5≤BMI<23 kg/m²) were marginally less likely to experience the development of severe cognitive impairment (adjusted odds ratio [aOR] = 0.73, 95% CI = 0.52 to 1.03; P_trend = 0.03). This relationship was stronger among female (aOR = 0.63, 95% CI = 0.40 to 1.00; P_trend = 0.01) and participants with low-normal K-MMSE score (MMSE: 24–26) at baseline (aOR = 0.59, 95% CI = 0.35 to 0.98; P_trend<0.01). In addition, a slower decline of cognitive function was observed in obese individuals than those with normal weight, especially among women and those with low-normal K-MMSE score at baseline.

Conclusion

In this nationally representative study, we found that obesity was associated with lower risk of cognitive decline among mid- and old-age population.     

Renal Interstitial Arteriosclerotic Lesions in Lupus Nephritis Patients: A Cohort Study from China

Objective

The aim of this study was to evaluate renal arteriosclerotic lesions in patients with lupus nephritis and investigate their associations with clinical and pathological characteristics, especially cardio-vascular features.

Design

A retrospective cohort study.

Participants

Seventy-nine patients with renal biopsy-proven lupus nephritis, diagnosed between January 2000 and June 2008 from Peking University First Hospital.

Results

In clinico-pathological data, patients with arteriosclerosis had higher ratio of hypertension and more severe renal injury indices compared with patients with no renal vascular lesions. More importantly, patients with renal arteriosclerosis had worse cardiac structure and function under transthoracic echocardiographic examination. Patients with renal arteriosclerosis tend to have higher ratios of combined endpoints compared with those of no renal vascular lesions, although the difference didn’t reach statistical meanings (P = 0.104).

Conclusion

Renal arteriosclerotic lesion was common and associated with vascular immune complex deposits in lupus nephritis. It might have a certain degree of association with poor outcomes and cardiovascular events, which needs further explorations.     

Vitamin D Status at Birth and Future Risk of Attention Deficit/Hyperactivity Disorder (ADHD)

Objective

To investigate whether children with Attention Deficit/Hyperactivity Disorder have lower levels of Vitamin D₃ at birth than matched controls.

Material

Umbilical cord blood samples collected at birth from 202 children later diagnosed with Attention Deficit/Hyperactivity Disorder were analysed for vitamin D content and compared with 202 matched controls. 25-OH vitamin D₃ was analysed by liquid chromatography tandem mass spectrometry.

Results

No differences in cord blood vitamin D concentration were found between children with Attention Deficit/Hyperactivity Disorder (median 13.0 ng/ml) and controls (median 13.5 ng/ml) (p = 0.43). In a logistic regression analysis, Attention Deficit/Hyperactivity Disorder showed a significant association with maternal age (odds ratio: 0.96, 95% confidence interval: 0.92–0.99) but not with vitamin D levels (odds ratio: 0.99, 95% confidence interval: 0.97–1.02).

Conclusion

We found no difference in intrauterine vitamin D levels between children later developing Attention Deficit/Hyperactivity Disorder and matched control children. However, the statistical power of the study was too weak to detect an eventual small to medium size association between vitamin D levels and Attention Deficit/Hyperactivity Disorder.     

Inverse Association of Serum Vitamin D in Relation to Carotid Intima-Media Thickness in Chinese Postmenopausal Women

Objective

This study aimed to investigate the relationship between serum vitamin D level and carotid intima-media thickness (C-IMT) in Chinese postmenopausal women.

Methods

Nine hundred and twenty six Chinese postmenopausal women without carotid artery plaque or history of cardiovascular disease were selected for analysis. Measurements of serum 25 hydroxyvitamin D₃ (25(OH)D₃) concentration and C-IMT were made by electrochemiluminescence immunoassay and B-mode ultrasound, respectively. Trend analysis was conducted according to tertiles of C-IMT.

Results

The median serum 25(OH)D₃ level was 11.03 ng/mL, with an interquartile range of 8.22–14.70. A decreasing trend of serum 25(OH)D₃ level was accompanied by increased C-IMT tertiles (P for trend = 0.001). Correlation analysis found an inverse relationship between serum 25(OH)D₃ level and C-IMT (r = –0.113, P = 0.001). After adjustment for confounding factors, multiple regression analysis showed that serum 25(OH)D₃ level independently and negatively associated with C-IMT (Standard β = –0.112, P < 0.001). Moreover, the inverse correlation of serum 25(OH)D₃ with C-IMT was also found in a subgroup of women with normal glucose tolerance, blood pressure and body mass index, and without undergoing lipid-lowering therapy (standard β = –0.140, P = 0.018).

Conclusions

Serum 25(OH)D₃ level was inversely correlated with C-IMT in Chinese postmenopausal women.     

Investigating the Molecular Basis of Retinal Degeneration in a Familial Cohort of Pakistani Decent by Exome Sequencing

Purpose

To define the molecular basis of retinal degeneration in consanguineous Pakistani pedigrees with early onset retinal degeneration.

Methods

A cohort of 277 individuals representing 26 pedigrees from the Punjab province of Pakistan was analyzed. Exomes were captured with commercial kits and sequenced on an Illumina HiSeq 2500. Candidate variants were identified using standard tools and analyzed using exomeSuite to detect all potentially pathogenic changes in genes implicated in retinal degeneration. Segregation analysis was performed by dideoxy sequencing and novel variants were additionally investigated for their presence in ethnicity-matched controls.

Results

We identified a total of nine causal mutations, including six novel variants in RPE65, LCA5, USH2A, CNGB1, FAM161A, CERKL and GUCY2D as the underlying cause of inherited retinal degenerations in 13 of 26 pedigrees. In addition to the causal variants, a total of 200 variants each observed in five or more unrelated pedigrees investigated in this study that were absent from the dbSNP, HapMap, 1000 Genomes, NHLBI ESP6500, and ExAC databases were identified, suggesting that they are common in, and unique to the Pakistani population.

Conclusions

We identified causal mutations associated with retinal degeneration in nearly half of the pedigrees investigated in this study through next generation whole exome sequencing. All novel variants detected in this study through exome sequencing have been cataloged providing a reference database of variants common in, and unique to the Pakistani population.     

Associations between Skeletal Growth in Childhood and Cognitive Function in Mid-Life in a 53-Year Prospective Birth Cohort Study

Background

Several studies have found that shorter stature (height and limb length) in late life is associated with dementia and cognitive impairment. The extent to which childhood environment and early life cognitive function accounts for these associations is not clear.

Methods

We investigated associations of adult trunk height and leg length with cognitive function in middle age, analysing data from the MRC National Survey of Health and Development: a cohort followed from birth to age 53, 1677 of whom had data on all covariates. The four cognitive tests measured verbal ability, word list memory, verbal fluency and speed/concentration. Early life environmental measures included parental education, poverty, parental divorce, physical health, cognitive ability at age 15, own education and own adult social class.

Results

After adjusting for gender, shorter trunk length was associated with lower cognitive function on all four tests and shorter leg length with lower verbal intelligence and word list memory. These associations were only partially attenuated following adjustment for childhood adversity/health but were substantially accounted for by cognitive ability at age 15.

Conclusions

Shorter stature was associated with lower cognitive function at age 53, the majority of this association being accounted for by cognitive function at age 15. Reduced cognitive reserve may well account for later associations between anthropometric measures and dementia.     

Enhancing Cognitive Abilities with Comprehensive Training: A Large,Online, Randomized,Active-Controlled Trial

Background

A variety of studies have demonstrated gains in cognitive ability following cognitive training interventions. However, other studies have not shown such gains, and questions remain regarding the efficacy of specific cognitive training interventions. Cognitive training research often involves programs made up of just one or a few exercises, targeting limited and specific cognitive endpoints. In addition, cognitive training studies typically involve small samples that may be insufficient for reliable measurement of change. Other studies have utilized training periods that were too short to generate reliable gains in cognitive performance.

Methods

The present study evaluated an online cognitive training program comprised of 49 exercises targeting a variety of cognitive capacities. The cognitive training program was compared to an active control condition in which participants completed crossword puzzles. All participants were recruited, trained, and tested online (N = 4,715 fully evaluable participants). Participants in both groups were instructed to complete one approximately 15-minute session at least 5 days per week for 10 weeks.

Results

Participants randomly assigned to the treatment group improved significantly more on the primary outcome measure, an aggregate measure of neuropsychological performance, than did the active control group (Cohen’s d effect size = 0.255; 95% confidence interval = [0.198, 0.312]). Treatment participants showed greater improvements than controls on speed of processing, short-term memory, working memory, problem solving, and fluid reasoning assessments. Participants in the treatment group also showed greater improvements on self-reported measures of cognitive functioning, particularly on those items related to concentration compared to the control group (Cohen’s d = 0.249; 95% confidence interval = [0.191, 0.306]).

Conclusion

Taken together, these results indicate that a varied training program composed of a number of tasks targeted to different cognitive functions can show transfer to a wide range of untrained measures of cognitive performance.

Trial Registration

ClinicalTrials.gov NCT-02367898     

Fractal parameters and vascular networks: facts & artifacts

Background

Several fractal and non-fractal parameters have been considered for the quantitative assessment of the vascular architecture, using a variety of test specimens and of computational tools. The fractal parameters have the advantage of being scale invariant, i.e. to be independent of the magnification and resolution of the images to be investigated, making easier the comparison among different setups and experiments.

Results

The success of several commercial and/or free codes in computing the fractal parameters has been tested on well known exact models. Based on such a preliminary study, we selected the code Frac-lac in order to analyze images obtained by visualizing the angiogenetic process occurring in chick Chorio Allontoic Membranes (CAM), assumed to be paradigmatic of a realistic 2D vascular network. Among the parameters investigated, the fractal dimension D_f proved to be the most robust estimator for CAM vascular networks. Moreover, only D_f was able to discriminate between effective and elusive increases in vascularization after drug-induced angiogenic stimulations on CAMs.

Conclusion

The fractal dimension D_f is likely to be the most promising tool for monitoring the effectiveness of anti-angiogenic therapies in various clinical contexts.     

Relationship between Auditory and Cognitive Abilities in Older Adults

Objective

The objective was to evaluate the association of peripheral and central hearing abilities with cognitive function in older adults.

Methods

Recruited from epidemiological studies of aging and cognition at the Rush Alzheimer’s Disease Center, participants were a community-dwelling cohort of older adults (range 63–98 years) without diagnosis of dementia. The cohort contained roughly equal numbers of Black (n=61) and White (n=63) subjects with groups similar in terms of age, gender, and years of education. Auditory abilities were measured with pure-tone audiometry, speech-in-noise perception, and discrimination thresholds for both static and dynamic spectral patterns. Cognitive performance was evaluated with a 12-test battery assessing episodic, semantic, and working memory, perceptual speed, and visuospatial abilities.

Results

Among the auditory measures, only the static and dynamic spectral-pattern discrimination thresholds were associated with cognitive performance in a regression model that included the demographic covariates race, age, gender, and years of education. Subsequent analysis indicated substantial shared variance among the covariates race and both measures of spectral-pattern discrimination in accounting for cognitive performance. Among cognitive measures, working memory and visuospatial abilities showed the strongest interrelationship to spectral-pattern discrimination performance.

Conclusions

For a cohort of older adults without diagnosis of dementia, neither hearing thresholds nor speech-in-noise ability showed significant association with a summary measure of global cognition. In contrast, the two auditory metrics of spectral-pattern discrimination ability significantly contributed to a regression model prediction of cognitive performance, demonstrating association of central auditory ability to cognitive status using auditory metrics that avoided the confounding effect of speech materials.     

An Investigation of Emotion Recognition and Theory of Mind in People with Chronic Heart Failure

Objectives

Cognitive deficits are common in patients with chronic heart failure (CHF), but no study has investigated whether these deficits extend to social cognition. The present study provided the first empirical assessment of emotion recognition and theory of mind (ToM) in patients with CHF. In addition, it assessed whether each of these social cognitive constructs was associated with more general cognitive impairment.

Methods

A group comparison design was used, with 31 CHF patients compared to 38 demographically matched controls. The Ekman Faces test was used to assess emotion recognition, and the Mind in the Eyes test to measure ToM. Measures assessing global cognition, executive functions, and verbal memory were also administered.

Results

There were no differences between groups on emotion recognition or ToM. The CHF group’s performance was poorer on some executive measures, but memory was relatively preserved. In the CHF group, both emotion recognition performance and ToM ability correlated moderately with global cognition (r = .38, p = .034; r = .49, p = .005, respectively), but not with executive function or verbal memory.

Conclusion

CHF patients with lower cognitive ability were more likely to have difficulty recognizing emotions and inferring the mental states of others. Clinical implications of these findings are discussed.     

In Vitro and In Vivo Characterization of the Alkaloid Nuciferine

Rationale

The sacred lotus (Nelumbo nucifera) contains many phytochemicals and has a history of human use. To determine which compounds may be responsible for reported psychotropic effects, we used in silico predictions of the identified phytochemicals. Nuciferine, an alkaloid component of Nelumbo nucifera and Nymphaea caerulea, had a predicted molecular profile similar to antipsychotic compounds. Our study characterizes nuciferine using in vitro and in vivo pharmacological assays.

Methods

Nuciferine was first characterized in silico using the similarity ensemble approach, and was followed by further characterization and validation using the Psychoactive Drug Screening Program of the National Institute of Mental Health. Nuciferine was then tested in vivo in the head-twitch response, pre-pulse inhibition, hyperlocomotor activity, and drug discrimination paradigms.

Results

Nuciferine shares a receptor profile similar to aripiprazole-like antipsychotic drugs. Nuciferine was an antagonist at 5-HT_2A, 5-HT_2C, and 5-HT_2B, an inverse agonist at 5-HT₇, a partial agonist at D_2, D₅ and 5-HT₆, an agonist at 5-HT_1A and D₄ receptors, and inhibited the dopamine transporter. In rodent models relevant to antipsychotic drug action, nuciferine blocked head-twitch responses and discriminative stimulus effects of a 5-HT_2A agonist, substituted for clozapine discriminative stimulus, enhanced amphetamine induced locomotor activity, inhibited phencyclidine (PCP)-induced locomotor activity, and rescued PCP-induced disruption of prepulse inhibition without induction of catalepsy.

Conclusions

The molecular profile of nuciferine was similar but not identical to that shared with several approved antipsychotic drugs suggesting that nuciferine has atypical antipsychotic-like actions.     

25-Hydroxyvitamin D3 Deficiency Independently Predicts Cognitive Impairment in Patients with Systemic Lupus Erythematosus

Objectives

Cognitive dysfunction has been reported in 20–80% of SLE patients. Converging evidence has indicated the importance of vitamin D as a neuroimmunomodulator for cognitive function. In this study, we evaluated the relationship between vitamin D and cognitive dysfunction.

Methods

Consecutive age- and gender-matched SLE patients and healthy controls (HCs) were administered Automated Neuropsychological Assessment Metrics in this cross-sectional study. The primary outcome was the total throughput score (TTS). Anxiety and depression were measured using the Hospital Anxiety and Depression Scale (HADS). Levels of 25-hydroxyvitamin D [25(OH)D₃ and total 25(OH)D] were measured using Liquid Chromatography-Tandem Mass Spectrometry.

Results

In total, 61 SLE patients and 61 HCs were studied. SLE patients scored significantly lower than HCs in the TTS (p = 0.004). There were no statistically significant differences in 25(OH)D₃ levels, total 25(OH)D levels and total 25(OH)D deficiency between SLE patients and HCs. However, more SLE patients had 25(OH)D₃ deficiency compared to HCs [12 (19.7%) versus 2 (3.3%), p = 0.003]. Deficiency of 25(OH)D₃ (β = -63.667, SE = 27.456, p = 0.025), but not other vitamin D variables, independently predicted worse TTS after adjusting for age, education, gender, ethnicity, HADS-Total, duration of SLE, SELENA-SLEDAI, SLICC/ACR Damage Index and cumulative steroid dose in SLE patients. Age (β = -4.261, SE = 0.866, p < 0.001) was the only predictor of TTS after adjusting for education, gender, ethnicity, HADS-Total, vitamin D levels or status in HCs.

Conclusions

Deficiency of 25(OH)D₃, a potentially modifiable risk factor, independently predicted cognitive impairment in SLE patients.     

Time Out-of-Home and Cognitive,Physical, and Emotional Wellbeing of Older Adults: A Longitudinal Mixed Effects Model

Background

Time out-of-home has been linked with numerous health outcomes, including cognitive decline, poor physical ability and low emotional state. Comprehensive characterization of this important health metric would potentially enable objective monitoring of key health outcomes. The objective of this study is to determine the relationship between time out-of-home and cognitive status, physical ability and emotional state.

Methods and Findings

Participants included 85 independent older adults, age 65–96 years (M = 86.36; SD = 6.79) who lived alone, from the Intelligent Systems for Assessing Aging Changes (ISAAC) and the ORCATECH Life Laboratory cohorts. Factors hypothesized to affect time out-of-home were assessed on three different temporal levels: yearly (cognitive status, loneliness, clinical walking speed), weekly (pain and mood) or daily (time out-of-home, in-home walking speed, weather, and season). Subject characteristics including age, race, and gender were assessed at baseline. Total daily time out-of-home in hours was assessed objectively and unobtrusively for up to one year using an in-home activity sensor platform. A longitudinal tobit mixed effects regression model was used to relate daily time out-of-home to cognitive status, physical ability and emotional state. More hours spend outside the home was associated with better cognitive function as assessed using the Clinical Dementia Rating (CDR) Scale, where higher scores indicate lower cognitive function (β _CDR = -1.69, p<0.001). More hours outside the home was also associated with superior physical ability (β _Pain = -0.123, p<0.001) and improved emotional state (β _Lonely = -0.046, p<0.001; β _{Low mood} = -0.520, p<0.001). Weather, season, and weekday also affected the daily time out-of-home.

Conclusions

These results suggest that objective longitudinal monitoring of time out-of-home may enable unobtrusive assessment of cognitive, physical and emotional state. In addition, these results indicate that the factors affecting out-of-home behavior are complex, with factors such as living environment, weather and season significantly affecting time out-of-home. Studies investigating the relationship between time out-of-home and health outcomes may be optimized by taking into account the environment and life factors presented here.     

KLHL12 Promotes Non-Lysine Ubiquitination of the Dopamine Receptors D4.2 and D4.4, but Not of the ADHD-Associated D4.7 Variant

Dopamine D₄ Receptor Polymorphism

The dopamine D₄ receptor has an important polymorphism in its third intracellular loop that is intensively studied and has been associated with several abnormal conditions, among others, attention deficit hyperactivity disorder.

KLHL12 Promotes Ubiquitination of the Dopamine D₄ Receptor on Non-Lysine Residues

In previous studies we have shown that KLHL12, a BTB-Kelch protein, specifically interacts with the polymorphic repeats of the dopamine D₄ receptor and enhances its ubiquitination, which, however, has no influence on receptor degradation. In this study we provide evidence that KLHL12 promotes ubiquitination of the dopamine D₄ receptor on non-lysine residues. By using lysine-deficient receptor mutants and chemical approaches we concluded that ubiquitination on cysteine, serine and/or threonine is possible.

Differential Ubiquitination of the Dopamine D₄ Receptor Polymorphic Variants

Additionally, we show that the dopamine D_4.7 receptor variant, which is associated with a predisposition to develop attention deficient hyperactivity disorder, is differentially ubiquitinated compared to the other common receptor variants D_4.2 and D_4.4. Together, our study suggests that GPCR ubiquitination is a complex and variable process.     

Significant Effects of Oral Phenylbutyrate and Vitamin D3 Adjunctive Therapy in Pulmonary Tuberculosis: A Randomized Controlled Trial

Background

Development of new tuberculosis (TB) drugs and alternative treatment strategies are urgently required to control the global spread of TB. Previous results have shown that vitamin D₃ (vitD₃) and 4-phenyl butyrate (PBA) are potent inducers of the host defense peptide LL-37 that possess anti-mycobacterial effects.

Objective

To examine if oral adjunctive therapy with 5,000IU vitD₃ or 2x500 mg PBA or PBA+vitD₃ to standard chemotherapy would lead to enhanced recovery in sputum smear-positive pulmonary TB patients.

Methods

Adult TB patients (n = 288) were enrolled in a randomized, double-blind, placebo-controlled trial conducted in Bangladesh. Primary endpoints included proportions of patients with a negative sputum culture at week 4 and reduction in clinical symptoms at week 8. Clinical assessments and sputum smear microscopy were performed weekly up to week 4, fortnightly up to week 12 and at week 24; TB culture was performed at week 0, 4 and 8; concentrations of LL-37 in cells, 25-hydroxyvitamin D₃ (25(OH)D₃) in plasma and ex vivo bactericidal function of monocyte-derived macrophages (MDM) were determined at week 0, 4, 8, 12 and additionally at week 24 for plasma 25(OH)D₃.

Results

At week 4, 71% (46/65) of the patients in the PBA+vitD₃-group (p = 0.001) and 61.3% (38/62) in the vitD₃-group (p = 0.032) were culture negative compared to 42.2% (27/64) in the placebo-group. The odds of sputum culture being negative at week 4 was 3.42 times higher in the PBA+vitD₃-group (p = 0.001) and 2.2 times higher in vitD₃-group (p = 0.032) compared to placebo. The concentration of LL-37 in MDM was significantly higher in the PBA-group compared to placebo at week 12 (p = 0.034). Decline in intracellular Mtb growth in MDM was earlier in the PBA-group compared to placebo (log rank 11.38, p = 0.01).

Conclusion

Adjunct therapy with PBA+vitD₃ or vitD₃ or PBA to standard short-course therapy demonstrated beneficial effects towards clinical recovery and holds potential for host-directed-therapy in the treatment of TB.

Trial Registration

clinicaltrials.gov NCT01580007     

Retinal Arteriolar Morphometry Based on Full Width at Half Maximum Analysis of Spectral-Domain Optical Coherence Tomography Images

Objectives

In this study, we develop a microdensitometry method using full width at half maximum (FWHM) analysis of the retinal vascular structure in a spectral-domain optical coherence tomography (SD-OCT) image and present the application of this method in the morphometry of arteriolar changes during hypertension.

Methods

Two raters using manual and FWHM methods measured retinal vessel outer and lumen diameters in SD-OCT images. Inter-rater reproducibility was measured using coefficients of variation (CV), intraclass correlation coefficient and a Bland-Altman plot. OCT images from forty-three eyes of 43 hypertensive patients and 40 eyes of 40 controls were analyzed using an FWHM approach; wall thickness, wall cross-sectional area (WCSA) and wall to lumen ratio (WLR) were subsequently calculated.

Results

Mean difference in inter-rater agreement ranged from -2.713 to 2.658 μm when using a manual method, and ranged from -0.008 to 0.131 μm when using a FWHM approach. The inter-rater CVs were significantly less for the FWHM approach versus the manual method (P < 0.05). Compared with controls, the wall thickness, WCSA and WLR of retinal arterioles were increased in the hypertensive patients, particular in diabetic hypertensive patients.

Conclusions

The microdensitometry method using a FWHM algorithm markedly improved inter-rater reproducibility of arteriolar morphometric analysis, and SD-OCT may represent a promising noninvasive method for in vivo arteriolar morphometry.