Effect of Anti-CD4 Antibody UB-421 on HIV-1 Rebound after Treatment Interruption.

BACKGROUND: Administration of a single broadly neutralizing human immunodeficiency virus (HIV)-specific antibody to HIV-infected persons leads to the development of antibody-resistant virus in the absence of antiretroviral therapy (ART). It is possible that monotherapy with UB-421, an antibody that blocks the virus-binding site on human CD4+ T cells, could induce sustained virologic suppression without induction of resistance in HIV-infected persons after analytic treatment interruption. METHODS: We conducted a nonrandomized, open-label, phase 2 clinical study evaluating the safety, pharmacokinetics, and antiviral activity of UB-421 monotherapy in HIV-infected persons undergoing analytic treatment interruption. All the participants had undetectable plasma viremia (<20 copies of HIV RNA per milliliter) at the screening visit. After discontinuation of ART, participants received eight intravenous infusions of UB-421, at a dose of either 10 mg per kilogram of body weight every week (Cohort 1) or 25 mg per kilogram every 2 weeks (Cohort 2). The primary outcome was the time to viral rebound (≥400 copies per milliliter). RESULTS: A total of 29 participants were enrolled, 14 in Cohort 1 and 15 in Cohort 2. Administration of UB-421 maintained virologic suppression (<20 copies per milliliter) in all the participants (94.5% of measurements at study visits 2 through 9) during analytic treatment interruption, with intermittent viral blips (range, 21 to 142 copies per milliliter) observed in 8 participants (28%). No study participants had plasma viral rebound to more than 400 copies per milliliter. CD4+ T-cell counts remained stable throughout the duration of the study. Rash, mostly of grade 1, was a common and transient adverse event; one participant discontinued the study drug owing to a rash. A decrease in the population of CD4+ regulatory T cells was observed during UB-421 monotherapy. CONCLUSIONS: UB-421 maintained virologic suppression (during the 8 to 16 weeks of study) in participants in the absence of ART. One participant discontinued therapy owing to a rash. (Funded by United Biomedical and others; ClinicalTrials.gov number, NCT02369146.).

External airway splint placement for severe pediatric tracheobronchomalacia.

OBJECTIVE: To present external airway splinting with bioabsorbable airway supportive devices (ASD) for severe, life-threatening cases of pediatric tracheomalacia (TM) or tracheobronchomalacia (TBM). METHODS: A retrospective cohort was performed for 5 pediatric patients with severe TM or TBM who underwent ASD placement. Devices were designed and 3D-printed from a bioabsorbable material, polycaprolactone (PCL). Pre-operative planning included 3-dimensional airway modeling of tracheal collapse and tracheal suture placement using nonlinear finite element (FE) methods. Pre-operative modeling revealed that triads along the ASD open edges and center were the most effective suture locations for optimizing airway patency. Pediatric cardiothoracic surgery and otolaryngology applied the ASDs by suspending the trachea to the ASD with synchronous bronchoscopy. Respiratory needs were trended for all cases. Data from pediatric patients with tracheostomy and diagnosis of TM or TBM, but without ASD, were included for discussion. RESULTS: Five patients (2 Females, 3 Males, ages 2-9 months at time of ASD) were included. Three patients were unable to wean from respiratory support after vascular ring division; all three weaned to room air post-ASD. Two patients received tracheostomies prior to ASD placement, but continued to experience apparent life-threatening events (ALTE) and required ventilation with supraphysiologic ventilator settings. One patient weaned respiratory support successfully after ASD placement. The last patient died post-ASD due to significant respiratory co-morbidity. CONCLUSION: ASD can significantly benefit patients with severe, unrelenting tracheomalacia or tracheobronchomalacia. Proper multidisciplinary case deliberation and selection are key to success with ASD. Pre-operative airway modeling allows proper suture placement to optimally address the underlying airway collapse.

IgE-neutralizing UB-221 mAb, distinct from omalizumab and ligelizumab, exhibits CD23-mediated IgE downregulation and relieves urticaria symptoms.

Over the last 2 decades, omalizumab is the only anti-IgE antibody that has been approved for asthma and chronic spontaneous urticaria (CSU). Ligelizumab, a higher-affinity anti-IgE mAb and the only rival viable candidate in late-stage clinical trials, showed anti-CSU efficacy superior to that of omalizumab in phase IIb but not in phase III. This report features the antigenic-functional characteristics of UB-221, an anti-IgE mAb of a newer class that is distinct from omalizumab and ligelizumab. UB-221, in free form, bound abundantly to CD23-occupied IgE and, in oligomeric mAb-IgE complex forms, freely engaged CD23, while ligelizumab reacted limitedly and omalizumab stayed inert toward CD23; these observations are consistent with UB-221 outperforming ligelizumab and omalizumab in CD23-mediated downregulation of IgE production. UB-221 bound IgE with a strong affinity to prevent FcԑRI-mediated basophil activation and degranulation, exhibiting superior IgE-neutralizing activity to that of omalizumab. UB-221 and ligelizumab bound cellular IgE and effectively neutralized IgE in sera of patients with atopic dermatitis with equal strength, while omalizumab lagged behind. A single UB-221 dose administered to cynomolgus macaques and human IgE (ε, κ)-knockin mice could induce rapid, pronounced serum-IgE reduction. A single UB-221 dose administered to patients with CSU in a first-in-human trial exhibited durable disease symptom relief in parallel with a rapid reduction in serum free-IgE level.

Cytoarchitectural characteristics associated with cognitive flexibility in raccoons.

With rates of psychiatric illnesses such as depression continuing to rise, additional preclinical models are needed to facilitate translational neuroscience research. In the current study, the raccoon (Procyon lotor) was investigated due to its similarities with primate brains, including comparable proportional neuronal densities, cortical magnification of the forepaw area, and cortical gyrification. Specifically, we report on the cytoarchitectural characteristics of raccoons profiled as high, intermediate, or low solvers in a multiaccess problem-solving task. Isotropic fractionation indicated that high-solvers had significantly more cells in the hippocampus (HC) than the other solving groups; further, a nonsignificant trend suggested that this increase in cell profile density was due to increased nonneuronal (e.g., glial) cells. Group differences were not observed in the cellular density of the somatosensory cortex. Thionin-based staining confirmed the presence of von Economo neurons (VENs) in the frontoinsular cortex, although no impact of solving ability on VEN cell profile density levels was observed. Elongated fusiform cells were quantified in the HC dentate gyrus where high-solvers were observed to have higher levels of this cell type than the other solving groups. In sum, the current findings suggest that varying cytoarchitectural phenotypes contribute to cognitive flexibility. Additional research is necessary to determine the translational value of cytoarchitectural distribution patterns on adaptive behavioral outcomes associated with cognitive performance and mental health.

Adenoviral delivery of interleukin-10 fails to attenuate experimental Lyme disease.

Production of interleukin-10 (IL-10) by C57BL/6 mice following infection with Borrelia burgdorferi has been proposed as a mechanism whereby resistance to the development of experimental Lyme arthritis is maintained. In the current study, we sought to determine the role of IL-10 during infection of arthritis- and carditis-susceptible C3H mice. Infection of C3H IL-10(-/-) mice led to increased joint swelling and arthritis severity scores over those of wild-type C3H mice. Measurement of B. burgdorferi numbers in joints or disseminated tissues indicated a more efficient clearance of spirochetes in the absence of IL-10, similar to that reported in C57BL/6 IL-10(-/-) mice. However, in contrast to previous in vitro work, infection of C3H IL-10(-/-) mice led to decreased in vivo expression of the cytokines KC, IL-1beta, IL-4, and IL-12p70 in the infected joints. Finally, adenoviral expression of IL-10 in the infected joints of C3H mice was unable to modulate the development of severe Lyme arthritis and had no effect on spirochete clearance or Borrelia-specific antibody production. Development of Lyme carditis appeared to be independent of modulation by IL-10. These results suggest that IL-10 limits the development of joint inflammation in both arthritis-resistant and -susceptible mouse strains infected with B. burgdorferi and that increased IL-10 production cannot rescue genetic susceptibility to development of pathology in this model.

Sideslip of the medial rectus muscle during vertical eye rotation.

PURPOSE: The kinematics of eye rotation is not entirely elucidated despite two centuries of fascination with the deceptively simple yet geometrically complex nature of the movement. Recently, the traditional view that oculorotatory muscles except the superior oblique muscle exert straight pull on the globe has been challenged by the claim that the muscles also go through a connective tissue pulley-like structure that holds them steady during eye rotation. Although earlier studies failed to observe sideslippage at the posterior part of muscles, a finding supportive of the pulley hypothesis, the conclusions should not be taken as conclusive given short-comings in the techniques used in the studies. METHODS: The authors developed a novel method of image analysis to improve spatial resolution and applied the method for investigating the medial rectus muscle, the entire length of which can easily be identified in magnetic resonance images. RESULTS: Contrary to previous reports, vertical sideslippage was observed at the posterior part of the muscle during vertical eye rotation between two tertiary eye positions. Furthermore, the sideslip varied as a function of horizontal eye position, in accordance with the half-angle rule of Listing's law. CONCLUSIONS: These findings are more consistent with the traditional view of the restrained shortest-path model than with the pulley model and have further implications for basic and clinical understanding of ocular kinematics.

Assessing the diagnostic test accuracy of natriuretic peptides and ECG in the diagnosis of left ventricular systolic dysfunction: a systematic review and meta-analysis.

BACKGROUND: In 2003 the National Institute of Clinical Excellence published guidelines recommending the use of brain natriuretic peptide (BNP) and the electrocardiogram (ECG) as part of the diagnostic work up of individuals with heart failure. However, the guideline did not address whether one test was superior to the other or whether performing both tests was superior to performing single tests. AIM: To investigate the relative test accuracy of the ECG, BNP, N terminal-pro brain natriuretic peptide (NT-proBNP) and combinations of two or more tests in the diagnosis of left ventricular systolic dysfunction (LVSD) in the primary care setting. DESIGN OF STUDY: Cohort studies making within-subject comparisons of intervention diagnostic test(s) with reference standard results. METHOD: Standard systematic review methodology was followed. RESULTS: Thirty-two primary studies met the review inclusion criteria. Studies were of variable quality and highly clinically heterogeneous, therefore restricting the use of meta-analysis. Within these limitations BNP, NT-proBNP and the ECG all had similar test sensitivity (>80% in the majority of studies). Specificity of the three tests was not as good. Three studies directly comparing BNP and the ECG found no difference in sensitivity and limited support for improved specificity of BNP. Two studies found no difference in sensitivity and limited evidence for an improvement in specificity for the combination of the ECG and BNP compared to single tests. CONCLUSION: On the basis of existing evidence, the ECG, BNP and NT-proBNP are useful in excluding a diagnosis of LVSD (good sensitivity). However, use of abnormal test results to select individuals for echocardiography may overwhelm services. There is currently no evidence to justify the use of one test over another or the use of tests in combination. The additional cost of BNP is not self-evidently justified by improved test accuracy. Further research is needed to directly compare the diagnostic performance of these tests in homogeneous, representative primary care populations.

Sleeping posture and intraocular pressure.

INTRODUCTION: This prospective observational case series aimed to determine whether the lateral decubitus position, which is commonly adopted during sleep, has an effect on intraocular pressure (IOP) in normal controls. METHODS: Patients without glaucoma were recruited from those visiting outpatient clinics for non-glaucomatous conditions. The left eye of each patient was included. IOP was first measured using Tono-Pen® XL applanation tonometer in the supine position, following which a second measurement was immediately obtained for the left lateral head position. Measurements were obtained with the patient lying on one soft and one hard pillow for each position, and patients remained awake during these measurements. One tonometry reading was obtained for each position. Readings were recorded only when the average of four independent readings produced a statistical confidence index of 5%. Results were analysed using the paired Student's t-test for comparison of the means. RESULTS: IOP in the left lateral decubitus position (17.48 ± 3.18 mmHg) was significantly higher than in the supine position (14.48 ± 3.09 mmHg) when using soft pillows (p < 0.001). When hard pillows were used, IOP in the left lateral decubitus position also exceeded that measured in the supine position (16.65 ± 3.54 mmHg vs. 13.65 ± 3.58 mmHg; p < 0.001). There was no statistically significant difference in the IOPs measured for the same position when different kinds of pillows were used. CONCLUSION: The lateral decubitus position adopted during sleep is associated with changes in IOP in healthy volunteers.

Behavioral characterization of amygdala involvement in mediating intra-accumbens opioid-driven feeding behavior.

The present experiments were conducted to provide a more detailed behavioral analysis of the dissociable roles of the basolateral (BLA) and central nucleus (CeA) of the amygdala in mediating intra-accumbens (Acb) opioid-induced feeding of a high-fat diet. Confirming previous findings, temporary inactivation of the CeA with the GABAA agonist muscimol reduced DAMGO (D-Ala2-NMe-Phe4-Glyol5-enkephalin)-induced and baseline food intake, whereas intra-BLA muscimol selectively blocked only DAMGO-induced food intake, leaving baseline feeding intact. However, although inactivation of the BLA reduced DAMGO-induced food intake to control levels, this treatment led to exaggerated number and duration of food hopper entries after food intake had ended. A subsequent experiment under conditions of limited access to the diet found the identical pattern of behavior following intra-Acb administration of DAMGO, regardless of whether the BLA was inactivated. Last, BLA inactivation was shown to have no influence on feeding driven by a state of negative-energy balance (24-hr food deprivation), demonstrating a specific influence of the BLA on opioid-driven feeding. These findings suggest that BLA mediates palatability-driven feeding and that this influence is particular to the consummatory act of ingestion.

MRI-guided access to the retropharynx.

PURPOSE: To describe MR-guided access to the retropharynx for precise fine-needle aspiration cytology (FNAC), and other indications for needle placement. MATERIALS AND METHODS: A retrospective review was made of 15 procedures that had been performed on 14 patients. These patients had a retropharyngeal mass on MRI and had undergone MR-guided minimally invasive access to the retropharynx for either diagnostic or therapeutic intervention in the period of October 1989 to January 2000. RESULTS: All 14 patients underwent MR-guided access to the retropharynx for FNAC without immediate or delayed complications. MRI confirmed that the biopsy needle was within the retropharyngeal mass in all patients. MR-guided FNAC revealed five true-positive, five true-negative, four indeterminate, and no false-positive cases. Ten of the 14 patients (71%) had diagnostic aspirations. In one patient with retropharyngeal extension of carcinoma, an MR-guided approach was used for the experimental interstitial laser therapy (ILT). CONCLUSION: The results suggest that an MR-guided retromandibular approach to biopsy of retropharyngeal mass is minimally invasive and safe.