Long-term benefits of hematopoietic stem cell-based macrophage/microglia delivery of GDNF to the CNS in a mouse model of Parkinson's disease.

Glial cell line-derived neurotrophic factor (GDNF) protects dopaminergic neurons in various models of Parkinson's disease (PD). Cell-based GDNF gene delivery mitigates neurodegeneration and improves both motor and non-motor functions in PD mice. As PD is a chronic condition, this study aims to investigate the long-lasting benefits of hematopoietic stem cell (HSC)-based macrophage/microglia-mediated CNS GDNF (MMC-GDNF) delivery in an MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model. The results indicate that GDNF treatment effectively ameliorated MPTP-induced motor deficits for up to 12 months, which coincided with the protection of nigral dopaminergic neurons and their striatal terminals. Also, the HSC-derived macrophages/microglia were recruited selectively to the neurodegenerative areas of the substantia nigra. The therapeutic benefits appear to involve two mechanisms: (1) macrophage/microglia release of GDNF-containing exosomes, which are transferred to target neurons, and (2) direct release of GDNF by macrophage/microglia, which diffuses to target neurons. Furthermore, the study found that plasma GDNF levels were significantly increased from baseline and remained stable over time, potentially serving as a convenient biomarker for future clinical trials. Notably, no weight loss, altered food intake, cerebellar pathology, or other adverse effects were observed. Overall, this study provides compelling evidence for the long-term therapeutic efficacy and safety of HSC-based MMC-GDNF delivery in the treatment of PD.

Large-scale provocation studies identify maladaptive responses to ubiquitous aeroallergens as a correlate of severe allergic rhinoconjunctivitis and asthma.

BACKGROUND: Allergic asthma (AA) and allergic rhinoconjunctivitis (ARC) are common comorbid environmentally triggered diseases. We hypothesized that severe AA/ARC reflects a maladaptive or unrestrained response to ubiquitous aeroallergens. METHODS: We performed provocation studies wherein six separate cohorts of persons (total n = 217) with ARC, with or without AA, were challenged once or more with fixed concentrations of seasonal or perennial aeroallergens in an aeroallergen challenge chamber (ACC). RESULTS: Aeroallergen challenges elicited fully or partially restrained vs. unrestrained evoked symptom responsiveness, corresponding to the resilient and adaptive vs. maladaptive AA/ARC phenotypes, respectively. The maladaptive phenotype was evoked more commonly during challenge with a non-endemic versus endemic seasonal aeroallergen. In an AA cohort, symptom responses evoked after house dust mite (HDM) challenges vs. recorded in the natural environment were more accurate and precise predictors of asthma severity and control, lung function (FEV1), and mechanistic correlates of maladaptation. Correlates included elevated levels of peripheral blood CD4+ and CD8+ T-cells, eosinophils, and T-cell activation, as well as gene expression proxies for ineffectual epithelial injury/repair responses. Evoked symptom severity after HDM challenge appeared to be more closely related to levels of CD4+ and CD8+ T-cells than eosinophils, neutrophils, or HDM-specific IgE. CONCLUSIONS: Provocation studies support the concept that resilience, adaptation, and maladaptation to environmental disease triggers calibrate AA/ARC severity. Despite the ubiquity of aeroallergens, in response to these disease triggers in controlled settings (ie, ACC), most atopic persons manifest the resilient or adaptive phenotype. Thus, ARC/AA disease progression may reflect the failure to preserve the resilient or adaptive phenotype. The triangulation of CD8+ T-cell activation, airway epithelial injury/repair processes and maladaptation in mediating AA disease severity needs more investigation.

Repetitive aeroallergen challenges elucidate maladaptive epithelial and inflammatory traits that underpin allergic airway diseases.

BACKGROUND: Signifying the 2-compartments/1-disease paradigm, allergic rhinoconjunctivitis (ARC) and asthma (AA) are prevalent, comorbid conditions triggered by environmental factors (eg, house dust mites [HDMs]). However, despite the ubiquity of triggers, progression to severe ARC/AA is infrequent, suggesting either resilience or adaptation. OBJECTIVE: We sought to determine whether ARC/AA severity relates to maladaptive responses to disease triggers. METHODS: Adults with HDM-associated ARC were challenged repetitively with HDMs in an aeroallergen challenge chamber. Mechanistic traits associated with disease severity were identified. RESULTS: HDM challenges evoked maladaptive (persistently higher ARC symptoms), adaptive (progressive symptom reduction), and resilient (resistance to symptom induction) phenotypes. Symptom severity in the natural environment was an imprecise correlate of the phenotypes. Nasal airway traits, defined by low inflammation-effectual epithelial integrity, moderate inflammation-effectual epithelial integrity, and higher inflammation-ineffectual epithelial integrity, were hallmarks of the resilient, adaptive, and maladaptive evoked phenotypes, respectively. Highlighting a crosstalk mechanism, peripheral blood inflammatory tone calibrated these traits: ineffectual epithelial integrity associated with CD8+ T cells, whereas airway inflammation associated with both CD8+ T cells and eosinophils. Hallmark peripheral blood maladaptive traits were increased natural killer and CD8+ T cells, lower CD4+ mucosal-associated invariant T cells, and deficiencies along the TLR-IRF-IFN antiviral pathway. Maladaptive traits tracking HDM-associated ARC also contributed to AA risk and severity models. CONCLUSIONS: Repetitive challenges with HDMs revealed that maladaptation to disease triggers may underpin ARC/AA disease severity. A combinatorial therapeutic approach may involve reversal of loss-of-beneficial-function traits (ineffectual epithelial integrity, TLR-IRF-IFN deficiencies), mitigation of gain-of-adverse-function traits (inflammation), and blocking of a detrimental crosstalk between the peripheral blood and airway compartments.

Immunologic resilience and COVID-19 survival advantage.

BACKGROUND: The risk of severe coronavirus disease 2019 (COVID-19) varies significantly among persons of similar age and is higher in males. Age-independent, sex-biased differences in susceptibility to severe COVID-19 may be ascribable to deficits in a sexually dimorphic protective attribute that we termed immunologic resilience (IR). OBJECTIVE: We sought to examine whether deficits in IR that antedate or are induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection independently predict COVID-19 mortality. METHODS: IR levels were quantified with 2 novel metrics: immune health grades (IHG-I [best] to IHG-IV) to gauge CD8+ and CD4+ T-cell count equilibrium, and blood gene expression signatures. IR metrics were examined in a prospective COVID-19 cohort (n = 522); primary outcome was 30-day mortality. Associations of IR metrics with outcomes in non-COVID-19 cohorts (n = 13,461) provided the framework for linking pre-COVID-19 IR status to IR during COVID-19, as well as to COVID-19 outcomes. RESULTS: IHG-I, tracking high-grade equilibrium between CD8+ and CD4+ T-cell counts, was the most common grade (73%) among healthy adults, particularly in females. SARS-CoV-2 infection was associated with underrepresentation of IHG-I (21%) versus overrepresentation (77%) of IHG-II or IHG-IV, especially in males versus females (P < .01). Presentation with IHG-I was associated with 88% lower mortality, after controlling for age and sex; reduced risk of hospitalization and respiratory failure; lower plasma IL-6 levels; rapid clearance of nasopharyngeal SARS-CoV-2 burden; and gene expression signatures correlating with survival that signify immunocompetence and controlled inflammation. In non-COVID-19 cohorts, IR-preserving metrics were associated with resistance to progressive influenza or HIV infection, as well as lower 9-year mortality in the Framingham Heart Study, especially in females. CONCLUSIONS: Preservation of immunocompetence with controlled inflammation during antigenic challenges is a hallmark of IR and associates with longevity and AIDS resistance. Independent of age, a male-biased proclivity to degrade IR before and/or during SARS-CoV-2 infection predisposes to severe COVID-19.

Functional anatomy of extraocular muscles during human vergence compensation of horizontal heterophoria.

We employed magnetic resonance imaging to quantify human extraocular muscle (EOM) contractility during intermittent convergent and divergent strabismus with each eye viewing monocularly at 20 cm compared with centered target fusion. Contractility, indicated by posterior partial volume change, was analyzed in transverse rectus and in medial and lateral superior oblique (SO) muscle compartments. In five subjects with intermittent esotropia, abduction of the deviated eye to monocular target fixation was associated with significant whole lateral rectus (LR) contraction, but with medial rectus (MR) relaxation that was significantly greater in the superior than inferior compartment. Esotropic eye abduction to binocular fusion was associated with similar relaxation in the two MR compartments, but with greater contraction in the LR's superior than inferior compartment. The whole diverging eye SO muscle relaxed. In three subjects with intermittent exotropia, converging eye fusional adduction was associated with significant whole LR relaxation and with MR contraction attributable to significantly greater contraction in the superior than inferior compartment. In adduction of the exotropic eye to monocular target fixation but not fusional adduction, the whole SO exhibited significant relaxation. Rectus pulley positions were not significantly altered by fusion of either form of intermittent strabismus. Globe rotational axis was eccentric in intermittent strabismus, rolling the eye so that rectus EOM lever arms facilitated vergence. These results confirm, and extend to fusion of intermittent horizontal strabismus, differential compartmental function in horizontal rectus EOMs and suggest a novel role for the SO in compensation of both intermittent esotropia and exotropia. NEW & NOTEWORTHY Disjunctive eye movements normally permit binocular fixation in near visual space but also compensate for mechanical imbalances in binocular alignment developing over the life span. Magnetic resonance imaging of the extraocular muscles demonstrates important differential function in muscle compartments during compensation of large-angle intermittent convergent and divergent strabismus in humans. Eye translation during rotation also enhances vergence compensation of intermittent strabismus.

CCL3L1 and CCR5 influence cell-mediated immunity and affect HIV-AIDS pathogenesis via viral entry-independent mechanisms.

Although host defense against human immunodeficiency virus 1 (HIV-1) relies mainly on cell-mediated immunity (CMI), the determinants of CMI in humans are poorly understood. Here we demonstrate that variations in the genes encoding the chemokine CCL3L1 and HIV coreceptor CCR5 influence CMI in both healthy and HIV-infected individuals. CCL3L1-CCR5 genotypes associated with altered CMI in healthy subjects were similar to those that influence the risk of HIV transmission, viral burden and disease progression. However, CCL3L1-CCR5 genotypes also modify HIV clinical course independently of their effects on viral load and CMI. These results identify CCL3L1 and CCR5 as major determinants of CMI and demonstrate that these host factors influence HIV pathogenesis through their effects on both CMI and other viral entry-independent mechanisms.

Functional anatomy of human extraocular muscles during fusional divergence.

We employed magnetic resonance imaging to quantify human extraocular muscle contractility during centered target fusion and fusional divergence repeated with each eye viewing monocularly at 20 cm through 8Δ and at 400 cm through 4Δ base in prism. Contractility, indicated by posterior partial volume (PPV) change, was analyzed in transverse rectus and in medial and lateral superior oblique (SO) muscle compartments and by cross-sectional area change in the inferior oblique (IO). At 20 cm, 3.1 ± 0.5° (SE) diverging eye abduction in 10 subjects was associated with 4.2 ± 1.5% whole lateral rectus (LR) PPV increase ( P < 0.05) and 1.7 ± 1.1% overall medial rectus (MR) PPV decrease attributable to 3.1 ± 1.8% reduction in the superior compartment ( P < 0.025), without change in its inferior compartment or in muscles of the aligned eye. At 400 cm, 2.2 ± 0.5° diverging eye abduction in nine subjects was associated with 6.1 ± 1.3% whole LR PPV increase ( P < 10-5) but no change in MR, with compartmentally similar relaxation in the LR and MR of the aligned eye. Unlike convergence, there were no IO or SO contractile changes for divergence to either target nor any change in rectus pulley positions. Results confirm and extend to proximal divergence the unique role of the superior MR compartment, yet no MR role for far divergence. Corelaxation of aligned eye LR and MR combined with failure of MR relaxation during divergence is consistent with the limited behavioral range of divergence. NEW & NOTEWORTHY Magnetic resonance imaging shows that the lateral rectus muscle must overcome continued contraction by its opponent the medial rectus when humans diverge their visual axes to achieve single, binocular vision. While the upper but not lower compartment of the medial rectus assists by relaxing for near targets, it does not do so when targets are far away. This behavior violates Sherrington's law of reciprocal action of antagonists and conventional assumptions about the ocular motor system.

The Globe's Eccentric Rotational Axis: Why Medial Rectus Surgery Is More Potent than Lateral Rectus Surgery.

PURPOSE: Tables typically recommend greater lateral rectus (LR) than medial rectus (MR) surgical doses for horizontal strabismus of any given magnitude, a difference unexplained by mechanical models that assume globe rotation about its center. We tested this assumption during horizontal ductions. DESIGN: Prospective observational study. PARTICIPANTS: Eighteen adult subjects with normal binocular vision. METHODS: Surface coil magnetic resonance imaging at 390 or 430 µm resolution was obtained using 2-mm-thick contiguous axial planes while subjects fixated targets in central, right, and left gaze. Angular displacements of lines connecting the corneal apex through the minor lens axis to the retina were measured to approximate clinical ductions. Globe centers were calculated from their area centroids. Apparent lens and globe-optic nerve (ON) junction rotations around the globe center were then compared with clinical ductions. MAIN OUTCOME MEASURES: Apparent angular rotations of lenses and globe-ON junctions during horizontal ductions. RESULTS: Globe-ON junctions appeared to rotate significantly less around globe centers than did lenses for abduction (20.6°±4.7° vs. 27.4°±7.4°, ± standard deviation (SD), P < 0.001) and adduction (25.3°±6.7° vs. 31.9°±8.3°, P < 0.001). Both rotations differed significantly from clinical adduction (27.9°±8.3°, P < 0.007), but only in abduction was globe-ON junction rotation significantly less than clinical abduction (28.6°±9.4°, P < 0.001). The true geometric globe rotational center was 2.2±0.5 mm medial and 0.8±1.0 mm posterior to the geometric globe center and was displaced farther medially and posteriorly during adduction. This eccentricity imbues each millimeter of MR recession with approximately 30% more trigonometric rotational effect than equivalent LR recession. CONCLUSIONS: The medial and posterior eccentricities of the normal ocular rotational axis profoundly influence horizontal rectus action. The proximity of the globe's rotational axis to the MR shortens its lever arm relative to the LR, explaining why mechanical effects of smaller MR recessions are equivalent to larger LR recessions.

Epigenetic mechanisms, T-cell activation, and CCR5 genetics interact to regulate T-cell expression of CCR5, the major HIV-1 coreceptor.

T-cell expression levels of CC chemokine receptor 5 (CCR5) are a critical determinant of HIV/AIDS susceptibility, and manifest wide variations (i) between T-cell subsets and among individuals and (ii) in T-cell activation-induced increases in expression levels. We demonstrate that a unifying mechanism for this variation is differences in constitutive and T-cell activation-induced DNA methylation status of CCR5 cis-regulatory regions (cis-regions). Commencing at an evolutionarily conserved CpG (CpG -41), CCR5 cis-regions manifest lower vs. higher methylation in T cells with higher vs. lower CCR5 levels (memory vs. naïve T cells) and in memory T cells with higher vs. lower CCR5 levels. HIV-related and in vitro induced T-cell activation is associated with demethylation of these cis-regions. CCR5 haplotypes associated with increased vs. decreased gene/surface expression levels and HIV/AIDS susceptibility magnify vs. dampen T-cell activation-associated demethylation. Methylation status of CCR5 intron 2 explains a larger proportion of the variation in CCR5 levels than genotype or T-cell activation. The ancestral, protective CCR5-HHA haplotype bears a polymorphism at CpG -41 that is (i) specific to southern Africa, (ii) abrogates binding of the transcription factor CREB1 to this cis-region, and (iii) exhibits a trend for overrepresentation in persons with reduced susceptibility to HIV and disease progression. Genotypes lacking the CCR5-Δ32 mutation but with hypermethylated cis-regions have CCR5 levels similar to genotypes heterozygous for CCR5-Δ32. In HIV-infected individuals, CCR5 cis-regions remain demethylated, despite restoration of CD4+ counts (≥800 cells per mm(3)) with antiretroviral therapy. Thus, methylation content of CCR5 cis-regions is a central epigenetic determinant of T-cell CCR5 levels, and possibly HIV-related outcomes.

Preservation of epithelial cell barrier function and muted inflammation in resistance to allergic rhinoconjunctivitis from house dust mite challenge.

BACKGROUND: An emerging paradigm holds that resistance to the development of allergic diseases, including allergic rhinoconjunctivitis, relates to an intact epithelial/epidermal barrier during early childhood. Conceivably, the immunologic and genomic footprint of this resistance is preserved in nonatopic, nonallergic adults and is unmasked during exposure to an aeroallergen. OBJECTIVE: The aim of this study was to obtain direct support of the epithelial/epidermal barrier model for allergic rhinoconjunctivitis. METHODS: Twenty-three adults allergic to house dust mites (HDMs) (M+) and 15 nonsensitive, nonallergic (M-) participants completed 3-hour exposures to aerosolized HDM (Dermatophagoides pteronyssinus) powder on 4 consecutive days in an allergen challenge chamber. We analyzed: (1) peripheral blood leukocyte levels and immune responses; and (2) RNA sequencing-derived expression profiles of nasal cells, before and after HDM exposure. RESULTS: On HDM challenge: (1) only M+ persons developed allergic rhinoconjunctivitis symptoms; and (2) peripheral blood leukocyte levels/responses and gene expression patterns in nasal cells were largely concordant between M+ and M- participants; gross differences in these parameters were not observed at baseline (pre-exposure). Two key differences were observed. First, peripheral blood CD4+ and CD8+ T-cell activation levels initially decreased in M- participants versus increased in M+ participants. Second, in M- compared with M+ participants, genes that promoted epidermal/epithelial barrier function (eg, filament-aggregating protein [filaggrin]) versus inflammation (eg, chemokines) and innate immunity (interferon) were upregulated versus muted, respectively. CONCLUSION: An imprint of resistance to HDM challenge in nonatopic, nonallergic adults was muted T-cell activation in the peripheral blood and inflammatory response in the nasal compartment, coupled with upregulation of genes that promote epidermal/epithelial cell barrier function.

Nox2 mediates skeletal muscle insulin resistance induced by a high fat diet.

Inflammation and oxidative stress through the production of reactive oxygen species (ROS) are consistently associated with metabolic syndrome/type 2 diabetes. Although the role of Nox2, a major ROS-generating enzyme, is well described in host defense and inflammation, little is known about its potential role in insulin resistance in skeletal muscle. Insulin resistance induced by a high fat diet was mitigated in Nox2-null mice compared with wild-type mice after 3 or 9 months on the diet. High fat feeding increased Nox2 expression, superoxide production, and impaired insulin signaling in skeletal muscle tissue of wild-type mice but not in Nox2-null mice. Exposure of C2C12 cultured myotubes to either high glucose concentration, palmitate, or H2O2 decreases insulin-induced Akt phosphorylation and glucose uptake. Pretreatment with catalase abrogated these effects, indicating a key role for H2O2 in mediating insulin resistance. Down-regulation of Nox2 in C2C12 cells by shRNA prevented insulin resistance induced by high glucose or palmitate but not H2O2. These data indicate that increased production of ROS in insulin resistance induced by high glucose in skeletal muscle cells is a consequence of Nox2 activation. This is the first report to show that Nox2 is a key mediator of insulin resistance in skeletal muscle.

Functional morphometry demonstrates extraocular muscle compartmental contraction during vertical gaze changes.

Anatomical studies demonstrate selective compartmental innervation of most human extraocular muscles (EOMs), suggesting the potential for differential compartmental control. This was supported by magnetic resonance imaging (MRI) demonstrating differential lateral rectus (LR) compartmental contraction during ocular counterrolling, differential medial rectus (MR) compartmental contraction during asymmetric convergence, and differential LR, inferior rectus (IR), and superior oblique (SO) compartmental contraction during vertical vergence. To ascertain possible differential compartmental EOM contraction during vertical ductions, surface coil MRI was performed over a range of target-controlled vertical gaze positions in 25 orbits of 13 normal volunteers. Cross-sectional areas and partial volumes of EOMs were analyzed in contiguous, quasi-coronal 2-mm image planes spanning origins to globe equator to determine morphometric features correlating best with contractility. Confirming and extending prior findings for horizontal EOMs during horizontal ductions, the percent change in posterior partial volume (PPV) of vertical EOMs from 8 to 14 mm posterior to the globe correlated best with vertical duction. EOMs were then divided into equal transverse compartments to evaluate the effect of vertical gaze on changes in PPV. Differential contractile changes were detected in the two compartments of the same EOM during infraduction for the IR medial vs. lateral (+4.4%, P = 0.03), LR inferior vs. superior (+4.0%, P = 0.0002), MR superior vs. inferior (-6.0%, P = 0.001), and SO lateral vs. medial (+9.7%, P = 0.007) compartments, with no differential contractile changes in the superior rectus. These findings suggest that differential compartmental activity occurs during normal vertical ductions. Thus all EOMs may contribute to cyclovertical actions.

Enhanced CD4+ T-cell recovery with earlier HIV-1 antiretroviral therapy.

BACKGROUND: The relationship between the timing of the initiation of antiretroviral therapy (ART) after infection with human immunodeficiency virus type 1 (HIV-1) and the recovery of CD4+ T-cell counts is unknown. METHODS: In a prospective, observational cohort of persons with acute or early HIV-1 infection, we determined the trajectory of CD4+ counts over a 48-month period in partially overlapping study sets: study set 1 included 384 participants during the time window in which they were not receiving ART and study set 2 included 213 participants who received ART soon after study entry or sometime thereafter and had a suppressed plasma HIV viral load. We investigated the likelihood and rate of CD4+ T-cell recovery to 900 or more cells per cubic millimeter within 48 months while the participants were receiving viral-load-suppressive ART. RESULTS: Among the participants who were not receiving ART, CD4+ counts increased spontaneously, soon after HIV-1 infection, from the level at study entry (median, 495 cells per cubic millimeter; interquartile range, 383 to 622), reached a peak value (median, 763 cells per cubic millimeter; interquartile range, 573 to 987) within approximately 4 months after the estimated date of infection, and declined progressively thereafter. Recovery of CD4+ counts to 900 or more cells per cubic millimeter was seen in approximately 64% of the participants who initiated ART earlier (≤4 months after the estimated date of HIV infection) as compared with approximately 34% of participants who initiated ART later (>4 months) (P<0.001). After adjustment for whether ART was initiated when the CD4+ count was 500 or more cells per cubic millimeter or less than 500 cells per cubic millimeter, the likelihood that the count would increase to 900 or more cells per cubic millimeter was lower by 65% (odds ratio, 0.35), and the rate of recovery was slower by 56% (rate ratio, 0.44), if ART was initiated later rather than earlier. There was no association between the plasma HIV RNA level at the time of initiation of ART and CD4+ T-cell recovery. CONCLUSIONS: A transient, spontaneous restoration of CD4+ T-cell counts occurs in the 4-month time window after HIV-1 infection. Initiation of ART during this period is associated with an enhanced likelihood of recovery of CD4+ counts. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Rectus Pulley Displacements without Abnormal Oblique Contractility Explain Strabismus in Superior Oblique Palsy.

PURPOSE: Using high-resolution magnetic resonance imaging (MRI), we investigated whether rectus pulleys are significantly displaced in superior oblique (SO) palsy and whether displacements account for strabismus patterns. DESIGN: Prospective case-control study. PARTICIPANTS: Twenty-four patients diagnosed with SO palsy based on atrophy of the SO muscle on MRI and 19 age-matched orthotropic control subjects. METHODS: High-resolution, surface coil MRI scans were obtained in multiple, contiguous, quasicoronal planes during monocular central gaze fixation. Pulley locations in oculocentric coordinates in the following subgroups of patients with SO palsy were compared with normal results in subgroups of patients with SO palsy: unilateral versus bilateral, congenital versus acquired, and isotropic (round) versus anisotropic (elongated) SO atrophy. Expected effects of pulley displacements were modeled using Orbit 1.8 (Eidactics, San Francisco, CA) computational simulation. MAIN OUTCOME MEASURES: Rectus pulley positions and ocular torsion. RESULTS: Rectus pulleys typically were displaced in SO palsy. In unilateral SO palsy, on average the medial rectus (MR) pulley was displaced 1.1 mm superiorly, the superior rectus (SR) pulley was displaced 0.8 mm temporally, and the inferior rectus (IR) pulley was displaced 0.6 mm superiorly and 0.9 mm nasally from normal. Displacements were similar in bilateral SO palsy, with the SR pulley additionally displaced 0.9 mm superiorly. However, the lateral rectus pulley was not displaced in either unilateral or bilateral SO palsy. The SR and MR pulleys were displaced in congenital SO palsy, whereas the IR and MR pulleys were displaced in acquired palsy. Pulley positions did not differ between isotropic and anisotropic palsy or between patients with cyclotropia of less than 7° versus cyclotropia of 7° or more. Simulations predicted that the observed pulley displacements alone could cause patterns of incomitant strabismus typical of SO palsy, without requiring any abnormality of SO or inferior oblique strength. CONCLUSIONS: Rectus pulley displacements alone, without abnormal oblique muscle contractility, can create the clinical patterns of incomitant strabismus in SO palsy. This finding supports accumulating evidence that clinical binocular misalignment patterns are not reliable indicators of contractile function of the SO muscle. Ocular torsion does not correlate with and thus cannot account for pulley displacements in SO palsy.

Neutral point testing of color vision in the domestic cat.

Despite extensive study, the basic nature of feline spectral sensitivity is still unresolved. Most electrophysiological studies have demonstrated two photopic receptors within the cat's retina, one most sensitive to longer wavelengths near 560 nm and the other most sensitive to shorter wavelengths near 460 nm, providing the neuroretinal basis for dichromatic vision. A few studies, however, have detected a third photopic receptor most sensitive to medium wavelengths between 500 and 520 nm, overlapping in spectrally sensitivity with the feline scotopic receptor, that potentially could allow trichromatic vision. Indeed, one behavioral study has demonstrated trichromatic vision in cats, but a flaw within its experimental design raises the possibility that achromatic intensity cues might have allowed the accurate identification of medium wavelength targets. This study tested for a spectral neutral point in the domestic cat using a two-choice discrimination task. The positive targets were created using monochromatic light from various single wavelength light emitting diodes (LEDs) combined with a white light of variable intensity, while the negative targets were created using white light of variable intensity. Trials were performed with varying intensities of positive and negative targets, from brighter positive targets to brighter negative targets, to eliminate achromatic intensity cues. Two cats with prior experience with two-choice discrimination tasks, one male and one female, successfully discriminated monochromatic light from 456 nm to 497 nm and from 510 nm to 524 nm, but both failed to discriminate monochromatic light at 505 nm over multiple trials. These results provide strong evidence that cats are dichromatic with a neutral point near 505 nm. This neutral point is nearly identical to the neutral point of the human deuteuranope, making feline vision a more accurate a model for red-green colorblind individuals than normal trichromats.

Cockroach sensitization mitigates allergic rhinoconjunctivitis symptom severity in patients allergic to house dust mites and pollen.

BACKGROUND: Modifiers of symptom severity in patients with allergic rhinoconjunctivitis (AR) are imprecisely characterized. The hygiene hypothesis implicates childhood microbial exposure as a protective factor. Cockroach sensitization (C+) might be a proxy for microbial exposure. OBJECTIVE: We sought to determine whether C+ assayed by means of skin prick tests influenced AR symptom severity in controlled and natural settings. METHODS: Total symptom scores (TSSs) were recorded by 21 participants with house dust mite allergy (M+) in the natural setting and during repeated exposures of 3 hours per day to house dust mite allergen in an allergen challenge chamber (ACC). In M+ participants the peripheral blood and nasal cells were assayed for T-cell activation and transcriptomic profiles (by using RNA sequencing), respectively. Participants allergic to mountain cedar (n = 21), oak (n = 34), and ragweed (n = 23) recorded TSSs during separate out-of-season exposures to these pollens (any pollen sensitization [P+]) in the ACC; a subset recorded TSSs in the pollination seasons. RESULTS: The hierarchy of TSSs (highest to lowest) among M+ participants tracked the following skin prick test sensitization statuses: M+P+C- > M+P+C+ > M+P-C- > M+P-C+. In nasal cells and peripheral blood the immune/inflammatory responses were rapidly resolved in M+P+C+ compared with M+P+C- participants. Among those allergic to pollen, C+ was associated with a lower TSS during pollen challenges and the pollination season. After aggregated analysis of all 4 ACC studies, C+ status was associated with a 2.8-fold greater likelihood of a lower TSS compared with C- status (odds ratio, 2.78; 95% CI, 1.18-6.67; P = .02). CONCLUSIONS: C+ status is associated with mitigation of AR symptom severity in adults with AR.

Magnetic resonance imaging demonstrates compartmental muscle mechanisms of human vertical fusional vergence.

Vertical fusional vergence (VFV) normally compensates for slight vertical heterophorias. We employed magnetic resonance imaging to clarify extraocular muscle contributions to VFV induced by monocular two-prism diopter (1.15°) base-up prism in 14 normal adults. Fusion during prism viewing requires monocular infraduction. Scans were repeated without prism, and with prism shifted contralaterally. Contractility indicated by morphometric indexes was separately analyzed in medial and lateral vertical rectus and superior oblique (SO) putative compartments, and superior and inferior horizontal rectus extraocular muscle putative compartments, but in the whole inferior oblique (IO). Images confirmed appropriate VFV that was implemented by the inferior rectus (IR) medial compartment contracting ipsilateral and relaxing contralateral to prism. There was no significant contractility in the IR lateral compartment. The superior but not inferior lateral rectus (LR) compartment contracted significantly in the prism viewing eye, but not contralateral to prism. The IO contracted ipsilateral but not contralateral to the prism. In the infraducting eye, the SO medial compartment relaxed significantly, while the lateral compartment was unchanged; contralateral to prism, the SO lateral compartment contracted, while the medial compartment was unchanged. There was no contractility in the superior or medial rectus muscles in either eye. There was no globe retraction. We conclude that the vertical component of VFV is primarily implemented by IR medial compartment contraction. Since appropriate vertical rotation is not directly implemented, or is opposed, by associated differential LR and SO compartmental activity, and IO contraction, these actions probably implement a torsional component of VFV.

Magnetic resonance imaging of differential compartmental function of horizontal rectus extraocular muscles during conjugate and converged ocular adduction.

Activity in horizontal rectus extraocular muscles (EOMs) was investigated by magnetic resonance imaging (MRI) of humans during asymmetric convergence to a monocularly aligned target at 15-cm distance or monocular fixation of afocal targets placed over a wide range of conjugate abduction through adduction. Cross sections and posterior partial volumes (PPVs) of EOMs were determined from quasi-coronal image planes and were separately analyzed in the inferior vs. superior compartments, defined by lines bisecting their maximum vertical dimensions. Both inferior and superior compartments of medial (MR) and lateral (LR) rectus exhibited contractile changes in PPV and maximum cross section for both asymmetric convergence and a comparable range of conjugate adduction. Both LR compartments, and the inferior MR compartment, exhibited similar decreases in contractility correlating with relaxation during both convergence and conjugate adduction. In contrast, the superior MR compartment exhibited roughly three times the contractility in conjugate adduction as in similar-magnitude convergence. In the aligned eye that did not move during convergence, summed contractility in all compartments of MR and LR exhibited corelaxation consistent with published EOM force measurements in this paradigm (Miller JM, Bockisch CJ, Pavlovski DS. J Neurophysiol 87: 2421-2433, 2002; Miller JM, Davison RC, Gamlin PD. J Neurophysiol 105: 2863-2873, 2011). The superior MR compartment also exhibited significantly greater contractility than the other compartments over the maximum achievable horizontal globe rotation from abduction to adduction. These findings suggest that the superior MR compartment is controlled differentially from the inferior compartment and suggest that its activity is reduced during convergence as a component of generally altered extraocular mechanics.

Resistance to high-fat diet-induced weight gain in transgenic mice overexpressing human wild-type α-synuclein: A model for metabolic dysfunction in Parkinson's disease.

Unintentional weight loss, primarily due to the loss of fat mass rather than muscle mass, is common among patients with Parkinson's disease (PD) and is associated with poor quality of life and accelerated disease progression. Since transgenic mice overexpressing human wild-type α-synuclein (α-Syn mice) are modestly leaner than control mice, and since diabetes, a metabolic disorder, is a major risk factor for PD, we reasoned that high-fat diet-induced diabetes/metabolic dysregulation in α-Syn mice may serve as a robust tool for exploring how early α-synuclein pathology contributes to metabolic dysregulation, leading to weight loss in PD. Thus, α-Syn and age-matched controls were fed a high-fat diet (HFD) chow (60% fat calories) ad libitum for four months. Compared with controls on HFD (control-HFD), α-Syn mice on HFD (α-Syn-HFD) were dramatically leaner. The resistance to gaining weight in α-Syn-HFD mice was accompanied by improved glucose tolerance, a dramatic decrease in fat mass, and an increase in energy expenditure. Despite this leaner phenotype and better glucose tolerance, the mortality was much higher in male α-Syn-HFD mice than in all controls, but was unaffected in females, suggesting protective effects of female sex hormones, as well as lower α-synuclein levels. Immunoblot analysis of insulin signaling in the olfactory bulb, the proposed initial seeding site of α-synuclein pathology, revealed a decrease of IGF-IRß, p GSK, and p mTOR in α-Syn-HFD mice. Since GSK-3ß and mTOR regulate synaptic plasticity, we assessed levels of PSD-95 and synaptophysin in the olfactory bulb. As anticipated, we observed a significant decrease in the levels of PSD-95, along with a potentially compensatory increase in synaptophysin levels. Our results show that α-Syn mice, when challenged with diet-induced diabetes/metabolic dysregulation, clearly reveal a profile of robust metabolic dysfunction, thus providing a sensitive tool for assessing the underlying mechanism of metabolic dysfunction and its impact on weight loss and disease progression in PD. We propose a role for olfactory dysfunction in PD-related unintentional weight loss and suggest that strategies aimed at increasing body weight/BMI will improve the quality of life and prognosis for people living with PD.