Acyltransferase families that act on thioesters: Sequences, structures, and mechanisms.

Acyltransferases (AT) are enzymes that catalyze the transfer of acyl group to a receptor molecule. This review focuses on ATs that act on thioester-containing substrates. Although many ATs can recognize a wide variety of substrates, sequence similarity analysis allowed us to classify the ATs into fifteen distinct families. Each AT family is originated from enzymes experimentally characterized to have AT activity, classified according to sequence similarity, and confirmed with tertiary structure similarity for families that have crystallized structures available. All the sequences and structures of the AT families described here are present in the thioester-active enzyme (ThYme) database. The AT sequences and structures classified into families and available in the ThYme database could contribute to enlightening the understanding acyl transfer to thioester-containing substrates, most commonly coenzyme A, which occur in multiple metabolic pathways, mostly with fatty acids.

Reaction time measures of non-chromatic contamination in opponent stimuli.

Simple visual reaction times (RTs) are highly sensitive to the presence of transient activity. Transient and sustained visual mechanisms generate different RT versus contrast functions because they have different gains. To identify non-chromatic (transient) activity, we can compare RT versus contrast functions obtained with either fast or slow onset stimuli. To test this, the stimulus adopted was a temporal modulation along the red-green axis, introducing non-chromatic components by varying the red-green ratio. The technique was sensitive to departures from isoluminance for all observers; therefore, we present this method as a way to detect transient contamination in a chromatic stimulus.

The role of dark adaptation in understanding early AMD.

The main aim of the paper is to discuss current knowledge on how Age Related Macular Degeneration (AMD) affects Dark Adaptation (DA). The paper is divided into three parts. Firstly, we outline some of the molecular mechanisms that control DA. Secondly, we review the psychophysical issues and the corresponding analytical techniques. Finally, we characterise the link between slowed DA and the morphological abnormalities in early AMD. Historically, DA has been regarded as too cumbersome for widespread clinical application. Yet the technique is extremely useful; it is widely accepted that the psychophysically obtained slope of the second rod-mediated phase of the dark adaptation function is an accurate assay of photoreceptor pigment regeneration kinetics. Technological developments have prompted new ways of generating the DA curve, but analytical problems remain. A simple potential solution to these, based on the application of a novel fast mathematical algorithm, is presented. This allows the calculation of the parameters of the DA curve in real time. Improving current management of AMD will depend on identifying a satisfactory endpoint for evaluating future therapeutic strategies. This must be implemented before the onset of severe disease. Morphological changes progress too slowly to act as a satisfactory endpoint for new therapies whereas functional changes, such as those seen in DA, may have more potential in this regard. It is important to recognise, however, that the functional changes are not confined to rods and that building a mathematical model of the DA curve enables the separation of rod and cone dysfunction and allows more versatility in terms of the range of disease severity that can be monitored. Examples are presented that show how analysing the DA curve into its constituent components can improve our understanding of the morphological changes in early AMD.

The Assessment of Visual Fields in Infants Using Saccadic Vector Optokinetic Perimetry (SVOP): A Feasibility Study.

Purpose: To examine the feasibility of saccadic vector optokinetic perimetry (SVOP), an automated eye tracking perimeter, as a tool for visual field (VF) assessment in infants. Methods: Thirteen healthy infants aged between 3.5 and 12.0 months were tested binocularly using an adapted SVOP protocol. SVOP uses eye tracking technology to measure gaze responses to stimuli presented on a computer screen. Modifications of SVOP for testing infants included adjusting the fixation target to display a short animation, increasing the stimulus size to equivalent to Goldmann V, and introducing a tiered test pattern strategy. Binocular, single-quadrant confrontation VF testing and Keeler preferential looking cards visual acuity testing was also performed. Results: Using multiple test attempts when required, all but the youngest infant (12 of 13 [92.3%]) successfully completed a 4-point screening test. Seven infants (53.8%) successfully completed the 12-point test, four (30.8%) successfully completed the 20-point test, and three (23.1%) successfully completed the 40-point test. The effect of multiple test attempts and the complexity of the test pattern (number of test points) on performance was investigated, including test completion rate, percentage of correctly seen stimuli, and average time per tested stimulus. Conclusions: The modified SVOP test strategy allowed successful assessment of binocular VFs in healthy infants. Future data collection from larger cohorts of infants is needed to derive normative limits of detection and assess accuracy in detecting and monitoring infant VF abnormalities. Translational Relevance: Eye tracking perimetry may provide a useful method of automated VF assessment in infants.

Medical student misconceptions in cardiovascular physiology.

Students find cardiovascular physiology challenging. Misunderstandings can be due to the nature of the subject, the way it is taught, and prior knowledge, which impede learning of new concepts. Some misunderstood concepts can be corrected with teaching (i.e., preconceptions), whereas others are resistant to instruction (i.e., misconceptions). A set of questions, specifically created by a panel of physiology experts to probe difficult cardiovascular concepts, was used to identify preconceptions, misconceptions, and the effect of education level on question performance. The introductory cardiovascular lecture used in this study was created based on these questions. In-class polling of medical students' (n = 736) performance was performed using the Turning-Point clicker response system during lecture instruction. Results were compared with published data from undergraduates (n = 1,076) who completed the same questions but without prior instruction. To our knowledge, there have been no studies directly comparing performance using the same instrument and large numbers of undergraduate and medical students. A higher education level was associated with increased performance (preconceptions), whereas several concepts resistant to instruction (misconceptions) were identified. Findings suggest that prior knowledge interfered with the acquisition of medical knowledge. Based on these results, potential causes for these misconceptions and remedial teaching suggestions are discussed.

A case control study examining the feasibility of using eye tracking perimetry to differentiate patients with glaucoma from healthy controls.

To explore the feasibility of using Saccadic Vector Optokinetic Perimetry (SVOP) to differentiate glaucomatous and healthy eyes. A prospective case-control study was performed using a convenience sample recruited from a single university glaucoma clinic and a group of healthy controls. SVOP and standard automated perimetry (SAP) was performed with testing order randomised. The reference standard was a diagnosis of glaucoma based a comprehensive ophthalmic examination and abnormality on standard automated perimetry (SAP). The index test was SVOP. 31 patients with glaucoma and 24 healthy subjects were included. Mean SAP mean deviation (MD) in those with glaucoma was - 8.7 ± 7.4 dB, with mean SAP and SVOP sensitivities of 23.3 ± 0.9 dB and 22.1 ± 4.3 dB respectively. Participants with glaucoma were significantly older. On average, SAP sensitivity was 1.2 ± 1.4 dB higher than SVOP (95% limits of agreement = - 1.6 to 4.0 dB). SVOP sensitivity had good ability to differentiate healthy and glaucomatous eyes with a 95% CI for area under the curve (AUC) of 0.84 to 0.96, similar to the performance of SAP sensitivity (95% CI 0.86 to 0.97, P = 0.60). For 80% specificity, SVOP had a 95% CI sensitivity of 75.7% to 94.8% compared to 77.8% to 96.0% for SAP. SVOP took considerably longer to perform (514 ± 54 s compared to 267 ± 76 s for SAP). Eye tracking perimetry may be useful for detection of glaucoma but further studies are needed to evaluate SVOP within its intended sphere of use, using an appropriate design and independent reference standard.

Perspectives of crisis intervention for people diagnosed with "borderline personality disorder": An integrative review.

WHAT IS KNOWN ON THE SUBJECT?: People diagnosed with "BPD" often experience crisis and use services "BPD" is a controversial diagnosis, and the experience of crisis and crisis intervention is not well understood WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: People diagnosed with "BPD" have different experiences of crisis, and using the diagnosis alone as a basis for deciding care and treatment is not appropriate There are many human factors which can influence how professionals deliver care to people diagnosed with "BPD" WHAT ARE THE IMPLICATIONS FOR PRACTICE?: The education of staff, views on responsibility, team conflicts and access to clinical supervision can have an impact on how care is delivered, and should be addressed by organizations providing crisis care. Access to care often occurs when a person is self-harming or suicidal, but does not address underlying distress. Crisis care should go beyond managing behaviour and address any underlying needs. ABSTRACT: Introduction "Borderline personality disorder" ("BPD") is associated with frequent use of crisis intervention services. However, no robust evidence base supports specific interventions, and people's experiences are not well understood. Aim To explore the experiences of stakeholders involved in the crisis care of people diagnosed with "BPD." Method Integrative review with nine databases searched January 2000 to November 2017. The search filtered 3,169 titles and abstracts with 46 full-text articles appraised and included. Results Four themes were constructed from thematic analysis: crisis as a recurrent multidimensional cycle, variations and dynamics impacting on crisis intervention, impact of interpersonal dynamics and communication on crisis, and balancing decision-making and responsibility in managing crisis. Discussion Crisis is a multidimensional subjective experience, which also contributes to distress for family carers and professionals. Crisis interventions had limited and subjective benefit. They are influenced by accessibility of services, different understandings of "BPD" and human dynamics in complex decision-making, and can be experienced as helpful or harmful. Implications for practice Subjectivity of crisis experiences shows limitations of the diagnostic model of "BPD," emphasizing that interventions should remain person-centred. While thresholds for intervention are often met after self-harm or suicidality, professionals should review approaches to care and support people with underlying distress.

Development of an Age-corrected Normative Database for Saccadic Vector Optokinetic Perimetry (SVOP).

PRECIS: Normal age-corrected threshold sensitivity values were determined for a new eye tracking perimeter and compared with standard automated perimetry (SAP). PURPOSE: The purpose of this study was to determine threshold visual field sensitivities in normal subjects performing saccadic vector optokinetic perimetry (SVOP), a new eye tracking perimeter. PATIENTS AND METHODS: A total of 113 healthy participants performed SVOP and SAP in both eyes with the order of testing randomized. The relationship between SAP and SVOP sensitivity was examined using Bland-Altman plots and 95% limits of agreement. The relationship between sensitivity and age was examined by pointwise linear regression and age-corrected normal threshold sensitivities were calculated. RESULTS: After excluding unreliable tests, 97 participants with a mean age of 65.9±10.1 years were included. Average SAP mean deviation was -0.87±1.56 dB, SAP sensitivity was 29.20±1.68 dB and SVOP sensitivity was 32.18±1.96 dB. SVOP had a longer test duration (431±110 compared with 307±42 seconds for SAP, P<0.001). On average, the mean sensitivity obtained using SVOP was 2.98 dB higher than average SAP sensitivity, with 95% limits of agreement of -0.11 to 6.15 dB. For each decade older, SAP sensitivity decreased by 0.93 dB (95% confidence interval: 1.21 to 0.64) and SVOP sensitivity decreased by 1.15 dB (95% confidence interval: 1.47 to 0.84). CONCLUSIONS: The results provide age-corrected normative values for threshold sensitivities from SVOP. Overall, SVOP provided a similar shaped hill of vision as SAP however threshold sensitivities were higher, meaning results are not interchangeable.

Speed and accuracy of saccades in patients with glaucoma evaluated using an eye tracking perimeter.

BACKGROUND: To examine the speed and accuracy of saccadic eye movements during a novel eye tracking threshold visual field assessment and determine whether eye movement parameters may improve ability to detect glaucoma. METHODS: A prospective study including both eyes of 31 patients with glaucoma and 23 controls. Standard automated perimetry (SAP) and eye tracking perimetry (saccadic vector optokinetic perimetry, SVOP) was performed. SVOP provided data on threshold sensitivity, saccade latency, and two measures of accuracy of saccades (direction bias and amplitude bias). The relationship between eye movement parameters and severity of glaucoma was examined and Receiver Operating Characteristic curves were used to assess ability to detect glaucoma. RESULTS: Patients with glaucoma had significantly slower saccades (602.9 ± 50.0 ms versus 578.3 ± 44.6 ms for controls, P = 0.009) and reduced saccade accuracy (direction bias = 7.4 ± 1.8 versus 6.5 ± 1.5 degrees, P = 0.006). There was a significant slowing of saccades and saccades became less accurate with worsening SAP sensitivity. Slower saccades were associated with increased odds of glaucoma; however, the AUC for saccade latency was only 0.635 compared to 0.914 for SVOP sensitivity. CONCLUSION: Patients with glaucoma had significant differences in eye movements compared to healthy subjects, with a relationship between slower and less accurate eye movements and worse glaucoma severity. However, in a multivariable model, eye movement parameters were not of additional benefit in differentiating eyes with glaucoma from healthy controls.

FEMA GRAS assessment of natural flavor complexes: Clove, cinnamon leaf and West Indian bay leaf-derived flavoring ingredients.

In 2015, the Expert Panel of the Flavor and Extract Manufacturers Association initiated the safety re-evaluation of over 250 natural flavor complexes (NFCs) used as flavor ingredients. This publication, 4th in a series focusing on the safety evaluation of NFCs, presents an evaluation of NFCs rich in hydroxyallylbenzene and hydroxypropenylbenzene constituents using a procedure initially published in 2005 and updated in 2018 that evaluates the safety of naturally occurring mixtures for their intended use as flavoring ingredients. The procedure requires the characterization of the chemical composition for each NFC and subsequent organization of the constituents into defined congeneric groups. The safety of each NFC is evaluated using the conservative threshold of toxicological concern (TTC) approach together with studies on absorption, metabolism and toxicology of the NFC and its constituent congeneric groups. By the application of this procedure, seven NFCs, derived from clove, cinnamon leaf and West Indian bay leaf were affirmed as "generally recognized as safe (GRAS)" under their conditions of intended use as flavor ingredients. An eighth NFC, an oleoresin of West Indian bay leaf, was affirmed based on its estimated intake, which is below the TTC of 0.15 µg/person per day for compounds with structural alerts for genotoxicity.

Chromatic fading following complete adaptation to unique hues.

Profound vision loss occurs after prolonged exposure to an unchanging featureless visual environment. The effect is sometimes called visual fade. Here we investigate this phenomenon in the color domain using two different experiments. In the first experiment we determine the time needed for a colored background to appear achromatic. Four backgrounds were tested. Each represented the observers' four unique hues. This adaptation time was compared with time to recover after adaptation Hue shifts at the end of the adaptation period were also measured. There were wide individual differences in adaptation times and recovery times. Overall recovery was faster than adaptation (p < 0.02). There were minimal shifts in hue. In the second experiment the changes in saturation (Munsell chroma) and lightness (Munsell value) of the background were monitored at six time intervals during the adapting process. Again asymmetric matching with Munsell samples was used. There were two distinct components to both the adaptation and recovery phases; one fast with time constant <1s, the other slow with time constant between 40 and 160s. The experiments show that the special case of visual fade involving color represents the sensory basis for many color-related effects involving adaptation.

Developments in non-invasive visual electrophysiology.

To study the physiology of the primate visual system, non-invasive electrophysiological techniques are of major importance. Two main techniques are available: the electroretinogram (ERG), a mass potential originating in the retina, and the visual evoked potential (VEP), which reflects activity in the primary visual cortex. In this overview, the history and the state of the art of these techniques are briefly presented as an introduction to the special issue "New Developments in non-invasive visual electrophysiology". The overview and the special issue can be used as the starting point for exciting new developments in the electrophysiology of primate and mammalian vision.

Anomalous pupillary responses to M-cone onsets are linked to ${\rm L}{:}{\rm M}$L:M ratio.

M-cone stimulation induces a pupil constriction to stimulus offset, whereas, with L cones, the pupil responds conventionally with a constriction to onset. To test the possibility that this paradox is linked to the ${\rm L}{:}{\rm M}$L:M ratio, we measured the strength of the effect by injecting a variable amount of positive or negative luminance contamination on either side of M-cone isolation and identifying a balance point at which the pupil responded equally to onset and offset. Nineteen individuals were recruited. In observers with low ${\rm L}{:}{\rm M}$L:M ratio, the paradoxical effect was weak. There was a significant relationship (${{r}^2} = {0.561}$r2=0.561) between the balance point and ${\rm L}{:}{\rm M}$L:M ratio. The effect is likely to be linked to strong inhibitory signals associated with cone-opponent pathways.

Atypical presentation of acute rheumatic fever (ARF) in a 25-year-old woman in the Caribbean: a challenging diagnosis.

A 25-year-old woman presented a challenging diagnosis of acute rheumatic fever (ARF). Initial symptoms included dry cough and three minor Jones criteria (unabating fever (38.4°C, 0d), elevated acute phase reactants (C-reactive protein, 13d) and joint pain (monoarthralgia) in her neck (0d)). ARF was diagnosed only after presentation of two major Jones criteria (polyarthritis/polyarthralgia (16d) and erythema marginatum (41d)) and positive antistreptolysin O titre (44d). Parotid swelling, peripheral oedema, elevated liver enzymes and diffuse lymphadenopathy complicated the diagnosis. Throat swab, chorea and carditis were negative or absent. Atypical ARF is challenging to recognise. There is no diagnostic test and its presentation is similar to that of other diseases. While the 2015 Jones criteria modification increased specificity of ARF diagnosis, atypical cases may still be missed, especially by physicians in developed countries. Suspicion of atypical ARF, especially after travel to high incidence regions, would allow for earlier treatment and prevention of rheumatic heart disease.

Using lectures to identify student misconceptions: a study on the paradoxical effects of hyperkalemia on vascular smooth muscle.

Medical students have difficulty understanding the mechanisms underlying hyperkalemia-mediated local control of blood flow. Such control mechanisms are crucial in the brain, kidney, and skeletal muscle vasculature. We aimed to identify medical students' misconceptions via assessment of students' in-class knowledge and, subsequently, improve future teaching of this concept. In-class polling was performed with the TurningPoint clicker response system (n = 860) to gauge students' understanding of three physiological concepts related to hyperkalemia: membrane potential (Vm), conductance, and smooth muscle response. Vm includes the concepts of equilibrium potential (Veq) for specific ions, as well as driving force (DF = Vm - Veq). Students understood the concept of DF (~70% answered correctly), suggesting their understanding of Vm. However, students misunderstood that hyperkalemia results in depolarization (~52% answered correctly) and leads to an increase in potassium conductance (~31% answered correctly). Clarification of the type of smooth muscle as vascular increased the percentage of correct responses (~51 to 73%). The data indicate that students lacked knowledge of specific potassium conductance in various muscle types, resulting in divergent responses, such as the canonical depolarization in skeletal muscle versus hyperpolarization in smooth muscle cells during hyperkalemia. Misunderstanding of this crucial concept of conductance is directly related to the students' performance. Furthermore, we connected the paradoxical effect of hyperkalemia to pathological acute and chronic hyperkalemia clinical scenarios.

IMPAIRED DARK ADAPTATION ASSOCIATED WITH A DISEASED BRUCH MEMBRANE IN PSEUDOXANTHOMA ELASTICUM.

PURPOSE: To characterize dark adaptation in patients with pseudoxanthoma elasticum, a systemic disease leading to calcification of elastic tissue including the Bruch membrane. METHODS: In this prospective case-control study, dark adaptation thresholds were measured using a Goldmann-Weekers dark adaptometer. Additional assessments included best-corrected visual acuity testing, contrast sensitivity, low luminance deficit, and vision-related quality of life. RESULTS: Dark adaptation thresholds were significantly higher, and adaptation periods were prolonged in patients with pseudoxanthoma elasticum (n = 35; 33 with 2 ABCC6 mutations) compared with controls (n = 35). The time to adapt 4 log units (20.6 ± 8.6 vs. 8.0 ± 1.3 minutes) and the mean dark adaptation threshold after 15 minutes (3.5 ± 1.1 vs. 1.8 ± 0.2 log units) were significantly different between patients and controls (both P < 0.001). Low luminance deficits (12.3 ± 6.4 vs. 6.1 ± 4.3 ETDRS letters), contrast sensitivity (1.4 ± 0.3 vs. 1.9 ± 0.1), and low luminance-related quality of life (LLQ score: 1,286 ± 355 vs. 2,167 ± 68) were also significantly worse in patients with pseudoxanthoma elasticum (all, P < 0.001). Two patients were treated with high-dose vitamin A which partially reversed impaired dark adaptation. CONCLUSION: Patients with pseudoxanthoma elasticum often have impaired dark adaptation. Positive effects of vitamin A supplementation may indicate restricted retinal access of vitamin A through the Bruch membrane as one possible underlying pathogenic factor.

FEMA GRAS assessment of natural flavor complexes: Cinnamomum and Myroxylon-derived flavoring ingredients.

In 2015, the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA) initiated a program for the re-evaluation of the safety of over 250 natural flavor complexes (NFCs) used as flavor ingredients. This publication, third in the series, considers NFCs composed primarily of constituents with the 3-phenyl-2-propenyl or a cinnamyl functional group, using the procedure outlined in 2005 and updated in 2018 to evaluate the safety of naturally-occurring mixtures for their intended use as flavor ingredients. The procedure relies on a complete chemical characterization of the NFC intended for commerce and organization of each NFC's chemical constituents into well-defined congeneric groups. The safety of the NFC is evaluated using the well-established and conservative threshold of toxicological concern (TTC) concept in addition to data on absorption, metabolism and toxicology of members of the congeneric groups and the NFC under evaluation. Six NFCs from the Myroxylon and Cinnamomum genera, Balsam Oil, Peru (FEMA 2117), Tolu Balsam Extract (FEMA 3069), Cassia Bark Extract (FEMA 2257), Cassia Bark Oil (FEMA 2258), Cinnamon Bark Extract (FEMA 2290) and Cinnamon Bark Oil (FEMA 2291) were evaluated and affirmed as generally recognized as safe (GRAS) under their conditions of intended use as flavor ingredients.

The Light and the Dark of Early and Intermediate AMD: Cone- and Rod-Mediated Changes Are Linked to Fundus Photograph and FAF Abnormalities.

Purpose: The purpose of this paper is to describe the extent to which scotopic and photopic measures of visual function predict color fundus photograph (CFP) and fundus autofluorescence (FAF) changes in early and intermediate nonexudative AMD. Methods: Sixty-nine observers were recruited: 56 AMD patients (mean age, 73 ± 12.98 years) and 13 controls (mean age, 67.77 ± 9.72 years). A nonmydriatic retinal camera was used to obtain stereo fundus photographs and FAF images were recorded with a cSLO Heidelberg Spectralis HRA+OCT. Visual acuity (VA) was measured using an Early Treatment of Diabetic Retinopathy Study chart. Contrast sensitivity (CS) was assessed with a Pelli-Robson chart. Dark adaptation (DA) curves were recorded at 3° eccentricity using a PC-based technique. Analysis of these curves yielded five parameters: cone threshold (CT), cone time constant (CC), cone-rod break (α), slope of the second rod component (S2), and rod-rod break (ß). Results: Both cone and rod sensitivity recovery were grossly abnormal in the patients. The rod recovery slope (S2) most accurately predicted the fundus photograph-based grade and the FAF classification (ρ = 0.61 and ρ = 0.60, respectively; both P < 0.0001). CS showed a strong association with FAF (ρ = 0.50, P < 0.0001) and with fundus photograph-based grade (ρ = 0.38, P < 0.002). There was no correlation between VA and either imaging method. Conclusions: Dynamic, rod-based measures most accurately reflect the severity of early AMD. Although less specific to AMD than DA changes, static photopic abnormalities such as CS also correspond with morphologic changes. Assessment of function in early AMD should include dynamic rod- and cone-mediated measurements of sensitivity recovery.

Effect of a small-group, active learning, tutorial-based, in-course enrichment program on student performance in medical physiology.

Physiology is one of the major foundational sciences for the medical curriculum. This discipline has proven challenging for students to master due to ineffective content acquisition and retention. Preliminary data obtained from a survey completed by "low-performance" students (those maintaining a grade average below the passing mark of 70%) at Morehouse School of Medicine reported that students lacked the ability to adequately recognize and extract important physiological concepts to successfully navigate multiple-choice assessments. It was hypothesized that a specially designed, small-group, active learning, physiology in-course enrichment program would minimize course assessment failure rates by enhancing the ability of low-performance students to effectively identify important course content, successfully perform on multiple-choice assessments, and, thereby, improve overall course performance. Using self-report surveys, study skills and test-taking deficiencies limiting successful comprehension of course material and examination performance were identified. Mini-quiz assessments and assignments in formulating multiple-choice examination questions were given to help students recognize and solidify core concepts and improve test-taking ability. Lastly, self-report surveys evaluated the effectiveness of the enrichment program on overall course performance. Results showed a marked improvement in student confidence levels with regards to approaching multiple-choice assessments, and a significant improvement in grades achieved in the physiology component of the first-year curriculum, as 100% of participants achieved a final passing grade average of ≥70%. It was concluded that students became more proficient in identifying, understanding, and applying core physiological concepts and more successful in mastering multiple-choice questions.