The MYH2 gene encodes the skeletal muscle myosin heavy chain IIA (MyHC-IIA) isoform, which is expressed in the fast twitch type 2A fibers. Autosomal dominant or recessive pathogenic variants in MYH2 ...lead to congenital myopathy clinically featured by ophthalmoparesis and predominantly proximal weakness. MYH2-myopathy is pathologically characterized by loss and atrophy of type 2A fibers. Additional myopathological abnormalities have included rimmed vacuoles containing small p62 positive inclusions, 15-20 nm tubulofilaments, minicores and dystrophic changes. We report an adult patient with late-pediatric onset MYH2-myopathy caused by two heterozygous pathogenic variants: c.3331C>T, p.Gln1111* predicted to result in truncation of the proximal tail region of MyHC-IIA, and c.1546T>G, p.Phe516Val, affecting a highly conserved amino acid within the highly conserved catalytic motor head relay loop. This missense variant is predicted to result in a less compact loop domain and in turn could affect the protein affinity state. The patient's genotype is accompanied by a novel myopathological phenotype characterized by centralized large myofilamentous tangles associated with clusters of nemaline rods, and ring fibers, in addition to the previously reported rimmed vacuoles, paucity and atrophy of type 2A fibers. Electron microscopy demonstrated wide areas of disorganized myofibrils which were oriented in various planes of direction and entrapped multiple nemaline rods, as corresponding to the large tangles with rods seen on light microscopy. Nemaline rods were rarely observed also in nuclei. We speculate that the mutated MyHC-IIA may influence myofibril disorganization. While nemaline rods have been described in myopathies caused by pathogenic variants in genes encoding several sarcomeric proteins, to our knowledge, nemaline rods have not been previously described in MYH2-myopathy.
Organ transplant recipients may not mount an adequate immune response to COVID‐19 infection and therefore may benefit greatly from passive immunization with anti‐spike monoclonal antibodies (mAbs), ...which have been shown to decrease hospitalization rates in the general outpatient population. We evaluated the efficacy of mAb therapy in decreasing hospitalizations or emergency room (ER) visits among kidney transplant recipients (KTR) with COVID‐19. We identified KTR with COVID‐19 between March 1, 2020 and April 30, 2021. Patients were excluded if they had multi‐organ transplant or hospital‐acquired COVID‐19. We studied 95 KTR; 20 received mAb. mAb administration was associated with a significant decrease in hospitalizations or ER visits (15% vs. 76%, p < 0.001). This association remained significant after adjustment for potential confounders, and analysis of mAb administration as a time‐dependent variable, with day of symptom onset as day 1 (adjusted HR 0.216, p = 0.04). Black or Hispanic patients were less likely to receive mAb and more likely to be admitted to the hospital or visit the ER. In our KTR population, mAb therapy for COVID‐19 may have helped decrease hospitalizations and ER visits. Healthcare inequities, including access to investigational treatments, have been exacerbated by the COVID‐19 pandemic. Antiviral mAbs are a promising therapeutic modality, especially for immunocompromised patients.
In kidney transplant recipients with COVID‐19, administration of anti‐spike monoclonal antibody is associated with a significant decrease in hospitalizations and emergency room visits but utilized less frequently in Black or Hispanic patients who were more likely to be hospitalized or visit the emergency room.
Abstract Adult articular cartilage has depth-dependent mechanical and biochemical properties which contribute to zone-specific functions. The compressive moduli of immature cartilage and ...tissue-engineered cartilage are known to be lower than those of adult cartilage. The objective of this study was to determine if such tissues exhibit depth-dependent compressive properties, and how these depth-varying properties were correlated with cell and matrix composition of the tissue. The compressive moduli of fetal and newborn bovine articular cartilage increased with depth ( p < 0.0 5 ) by a factor of 4–5 from the top 0.1 mm (28±13 kPa, 141±10 kPa, respectively) to 1 mm deep into the tissue. Likewise, the glycosaminoglycan and collagen content increased with depth (both p < 0.0 0 1 ), and correlated with the modulus (both p < 0.0 1 ). In contrast, tissue-engineered cartilage formed by either layering or mixing cells from the superficial and middle zone of articular cartilage exhibited similarly soft regions at both construct surfaces, as exemplified by large equilibrium strains. The properties of immature cartilage may provide a template for developing tissue-engineered cartilage which aims to repair cartilage defects by recapitulating the natural development and growth processes. These results suggest that while depth-dependent properties may be important to engineer into cartilage constructs, issues other than cell heterogeneity must be addressed to generate such tissues.
Transcription factors orchestrate T-lineage differentiation in the thymus. One critical checkpoint involves Notch1 signaling that instructs T-cell commitment at the expense of the B-lineage program. ...While GATA-3 is required for T-cell specification, its mechanism of action is poorly understood. We show that GATA-3 works in concert with Notch1 to commit thymic progenitors to the T-cell lineage via 2 distinct pathways. First, GATA-3 orchestrates a transcriptional “repertoire” that is required for thymocyte maturation up to and beyond the pro–T-cell stage. Second, GATA-3 critically suppresses a latent B-cell potential in pro–T cells. As such, GATA-3 is essential to sealing in Notch-induced T-cell fate in early thymocyte precursors by promoting T-cell identity through the repression of alternative developmental options.
•Gata3 is critical for the transition of “double-negative” (DN) thymocyte DN1 to DN2.•Gata3 represses a latent B-cell potential in DN thymocytes.
Cyclopentadienyl‐based (Cp‐based) tricarbonyl rhenium complexes Cp′Re(CO)3 are convenient precursors for the corresponding Cp‐based trioxorhenium complexes (Cp′ReO3), which are potential catalysts ...for the deoxydehydration (DODH) of diols to olefins. To evaluate the influence of different Cp substituents in Cp′ReO3 complexes in DODH, a series of alkyl‐substituted Cp′Re(CO)3 complexes (1a–8a) were synthesized. High yields (86–98 %) were obtained from the reactions of Re2(CO)10 with the corresponding Cp′H ligands (1–8). The C–O infrared absorptions of 1a–8a indicate that the electron‐donating character of the Cp ligand increases with the number of substituents attached directly to the Cp ring. Analogous aryl‐substituted complexes 10a–12a containing bulky phenyl groups were accessed through the salt metathesis of ReBr(CO)5 with the lithium salt of the deprotonated ligand (Cp′Li), and the aryl groups decreased the electron donation. Furthermore, an unusual 6+4 cycloaddition reaction of (CpMe4H)Re(CO)3 (8a) with excess ligand resulted in the highly asymmetric Cp′Re(CO)3 complex 9a. Finally, the reaction of the tetraphenylcyclopentadienone ligand with Re2(CO)10 was investigated and led to the isolation of two unusual compounds, namely, Re(CO)3 complexes of the Shvo‐type hydroxytetraphenylcyclopentadienyl ligand, Ph4Cp(OH)Re(CO)3 (13a), and a benzofuran‐fused cyclopentadienyl ligand, Ph3Cp(C6H4O)Re(CO)3 (14a). X‐ray crystal structures were obtained for the new Cp′Re(CO)3 complexes (CptBu2H3)Re(CO)3 (2a), 1,2,3‐Me3(tetrahydroindenyl)Re(CO)3 (7a), 9a, 13a, and 14a, which all have the typical three‐legged “piano‐stool” configuration.
A series of cyclopentadienyl‐substituted tricarbonyl rhenium complexes are synthesized, and their structure–activity relationships are evaluated. Some unusual reactivity through 6+4 cycloaddition or hydrogen transfer leads to new pathways for the modification of the cyclopentadienyl ligand.
Purpose:
The Medicare Consumer Assessments of Healthcare Providers and Systems (MCAHPS) survey, a primarily English-language mail survey with English and Spanish telephone follow-up, is the primary ...means of assessing the health care experiences of American seniors. We examine unit (whole survey) and item nonresponse for this survey to explore issues regarding surveying seniors about their health care.
Design and Methods:
We describe overall rates and analyze predictors of unit and item nonresponse for the 695,197 Medicare beneficiaries selected for the 2007 MCAHPS survey (335,249 unit respondents, 49% overall response rate).
Results:
Asians, African Americans, and Hispanics responded at adjusted response rates 7-17 percentage points lower than non-Hispanic Whites (p < .001 for each). Among seniors, response rates dropped beyond age 75. Asians and older beneficiaries were especially likely to respond by mail, and African Americans and Hispanics by phone. Breakoff from telephone surveys was most common among African Americans and older respondents. Among respondents, older age was the strongest predictor of item missingness (e.g., those 85 years and older failed to answer items at twice the rate of those aged 65-74 years, p < .001). Non-Hispanic Whites had lower rates of item missingness than other racial/ethnic groups (p < .001 for each; one-third lower than African Americans).
Implications:
Survey research on older adults, especially regarding racial/ethnic disparities in health care, could benefit from improved response rates. These results suggest that targeted prenotification materials and campaigns, tailored follow-up, targeted Spanish mailings, Chinese translations/calls, and adjustments to telephone protocols may improve representation and response.
Mannose‐binding lectin (MBL) is an important constituent of the innate immune system. This protein binds through multiple lectin domains to the repeating sugar arrays that decorate many microbial ...surfaces, and is then able to activate the complement system through a specific protease called MBL‐associated protease‐2. We have used flow cytometry to study both the binding of MBL to microorganisms and the subsequent activation of complement. For selected Gram‐negative organisms, such as Salmonella and Neisseria, we have examined the relative roles of lipopolysaccharide (LPS) structure and capsule in determining binding and conclude that the LPS is of major importance. Our results from studies with several clinically relevant organisms also show that MBL binding detected by flow cytometry leads to measurable activation of purified C4, suggesting that the bound lectin is capable of initiating opsonophagocytosis and/or bacterial lysis. There is an increasing literature suggesting that MBL deficiency, which mainly results from three relatively common single point mutations in exon 1 of the gene, predisposes both to infection by extracellular pathogens and to autoimmune disease. In addition, the protein also modulates disease severity, at least in part through a complex, dose‐dependent influence on cytokine production. The mechanisms and signalling pathways involved in such processes remain to be elucidated.
We thank the Medical Research Council, the Wellcome Trust and Action Research for their support. Research at the Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust benefits from R&D funding received from the NHS Executive. We thank David Smithson for graphic design of the figures.
The influence of the innate immune protein mannose-binding lectin (MBL) on the response of human phagocytes to Neisseria meningitidis was investigated. MBL increased the association of killed ...meningococci with neutrophils, monocytes, and macrophages by increasing the proportion of cells that recognized bacteria. MBL down-regulated the normal change in expression of the leukocyte adhesion molecules CD11b and CD62L. In an ex vivo model, the addition of MBL to the blood of MBL-deficient donors influenced the production of monocyte-derived inflammatory cytokines. The addition of high concentrations of MBL (>6 μg/mL) profoundly decreased the production of interleukin (IL)–6, IL-1β, and tumor necrosis factor–α by monocytes in response to meningococci, whereas lower concentrations enhanced the production of IL-6 and IL-1β. These results suggest that MBL not only is involved in complement activation but also is a potent regulator of inflammatory pathways and, as such, may affect the severity of meningococcal disease
Antibody drugs are widely used in cancer therapy, but conditions to maximize tumor penetration and efficacy have yet to be fully elucidated. In this study, we investigated the impact of antibody ...binding affinity on tumor targeting and penetration with affinity variants that recognize the same epitope. Specifically, we compared four derivatives of the C6.5 monoclonal antibody (mAb), which recognizes the same HER2 epitope (monovalent K(D) values ranging from 270 to 0.56 nmol/L). Moderate affinity was associated with the highest tumor accumulation at 24 and 120 hours after intravenous injection, whereas high affinity was found to produce the lowest tumor accumulation. Highest affinity mAbs were confined to the perivascular space of tumors with an average penetration of 20.4 ± 7.5 μm from tumor blood vessels. Conversely, lowest affinity mAbs exhibited a broader distribution pattern with an average penetration of 84.8 ± 12.8 μm. In vitro internalization assays revealed that antibody internalization and catabolism generally increased with affinity, plateauing once the rate of HER2 internalization exceeded the rate of antibody dissociation. Effects of internalization and catabolism on tumor targeting were further examined using antibodies of moderate (C6.5) or high-affinity (trastuzumab), labeled with residualizing ((111)In-labeled) or nonresidualizing ((125)I-labeled) radioisotopes. Significant amounts of antibody of both affinities were degraded by tumors in vivo. Furthermore, moderate- to high-affinity mAbs targeting the same HER2 epitope with monovalent affinity above 23 nmol/L had equal tumor accumulation of residualizing radiolabel over 120 hours. Results indicated equal tumor exposure, suggesting that mAb penetration and retention in tumors reflected affinity-based differences in tumor catabolism. Together, these results suggest that high-density, rapidly internalizing antigens subject high-affinity antibodies to greater internalization and degradation, thereby limiting their penetration of tumors. In contrast, lower-affinity antibodies penetrate tumors more effectively when rates of antibody-antigen dissociation are higher than those of antigen internalization. Together, our findings offer insights into how to optimize the ability of therapeutic antibodies to penetrate tumors.
Acquired copper deficiency presents with a spastic gait and sensory ataxia. Spinal cord magnetic resonance imaging (MRI) in patients with copper deficiency myelopathy may show increased T2 signal, ...most commonly in the dorsal midline cervical and thoracic cord. These imaging findings may be reversible with normalization of serum copper. The clinical and imaging picture is very similar to the subacute combined degeneration seen in patients with vitamin B12 deficiency. Neuroradiologists should consider this possibility when a long segment of symmetric dorsal spinal cord T2-hyperintensity is identified.
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