A clinical study of the local injection of a freshly manufactured 35 kDa hyaluronan fragment for treating chronic wounds.

This study manufactured a 35 kDa hyaluronan fragment (HA35) by enzymatically degrading high-molecular-weight HA using hyaluronidase PH20 derived from bovine testis. The research then examined the therapeutic efficacy of locally administered, tissue-permeable HA35 in alleviating chronic wounds and their associated neuropathic pain. For 20 patients with nonhealing wounds and associated pain lasting over three months, 100 mg of HA35 was injected daily into the healthy skin surrounding the chronic wound for 10 days. Self-assessments before and after treatment indicated that HA35 significantly enhanced wound healing. This was evidenced by the formation of fresh granulation tissue on the wounds (p < 0.0001); reduced darkness, redness, dryness, and damage in the skin surrounding the wounds (p < 0.0001), and a decrease in wound size (p < 0.001). Remarkably, HA35 injections alleviated pain associated with chronic wounds within 24 hours (p < 0.0001). It can be concluded that the low-molecular-weight hyaluronan fragment HA35 potentially enhances the immune response and angiogenesis during wound healing.

Night and Day, Why Radiologists Need Play.

What is play and why does it matter for radiologists? Play can take many forms in the workplace, including organic, managed, task-related, diversionary, and resistive forms of play, and play may also take the form of authentic self-expression and creation. In this review article, we will discuss the benefits of play including improved problem solving, gaining perspective, and stress reduction, and also provide low-tech and high-tech examples of beneficial play for the radiology team in work and personal contexts.

Characterization, Bioactivity, and Biodistribution of 35 kDa Hyaluronan Fragment.

It has been reported that hyaluronic acid (HA) with a 35 kDa molecular weight (HA35) acts biologically to protect tissue from injury, but its biological properties are not yet fully characterized. This study aimed to evaluate the cellular effects and biodistribution of HA35 compared to HA with a 1600 kDa molecular weight (HA1600). We assessed the effects of HA35 and HA1600 on cell migration, NO and ROS generation, and gene expression in cultured macrophages, microglia, and lymphocytes. HA35 was separately radiolabeled with 99mTc and 125I and administered to C57BL/6J mice for in vivo biodistribution imaging. In vitro studies indicated that HA35 and HA1600 similarly enhanced cell migration through HA receptor binding mechanisms, reduced the generation of NO and ROS, and upregulated gene expression profiles related to cell signaling pathways in immune cells. HA35 showed a more pronounced effect in regulating a broader range of genes in macrophages and microglia than HA1600. Upon intradermal or intravenous administration, radiolabeled HA35 rapidly accumulated in the liver, spleen, and lymph nodes. In conclusion, HA35 not only exhibits effects on cellular bioactivity comparable to those of HA1600 but also exerts biological effects on a broader range of immune cell gene expression. The findings herein offer valuable insights for further research into the therapeutic potential of HA35 in inflammation-mediated tissue injury.

Seeing a Talking Face Matters: Gaze Behavior and the Auditory-Visual Speech Benefit in Adults' Cortical Tracking of Infant-directed Speech.

In face-to-face conversations, listeners gather visual speech information from a speaker's talking face that enhances their perception of the incoming auditory speech signal. This auditory-visual (AV) speech benefit is evident even in quiet environments but is stronger in situations that require greater listening effort such as when the speech signal itself deviates from listeners' expectations. One example is infant-directed speech (IDS) presented to adults. IDS has exaggerated acoustic properties that are easily discriminable from adult-directed speech (ADS). Although IDS is a speech register that adults typically use with infants, no previous neurophysiological study has directly examined whether adult listeners process IDS differently from ADS. To address this, the current study simultaneously recorded EEG and eye-tracking data from adult participants as they were presented with auditory-only (AO), visual-only, and AV recordings of IDS and ADS. Eye-tracking data were recorded because looking behavior to the speaker's eyes and mouth modulates the extent of AV speech benefit experienced. Analyses of cortical tracking accuracy revealed that cortical tracking of the speech envelope was significant in AO and AV modalities for IDS and ADS. However, the AV speech benefit [i.e., AV > (A + V)] was only present for IDS trials. Gaze behavior analyses indicated differences in looking behavior during IDS and ADS trials. Surprisingly, looking behavior to the speaker's eyes and mouth was not correlated with cortical tracking accuracy. Additional exploratory analyses indicated that attention to the whole display was negatively correlated with cortical tracking accuracy of AO and visual-only trials in IDS. Our results underscore the nuances involved in the relationship between neurophysiological AV speech benefit and looking behavior.

Anti-Inflammatory Effects of the 35kDa Hyaluronic Acid Fragment (B-HA/HA35).

Background: Hyaluronic acid (HA) and HA fragments interact with a variety of human body receptors and are involved in the regulation of various physiological functions and leukocyte trafficking in the body. Accordingly, the development of an injectable HA fragment with good tissue permeability, the identification of its indications, and molecular mechanisms are of great significance for its clinical application. The previous studies showed that the clinical effects of injectable 35kDa B-HA result from B-HA binding to multiple receptors in different cells, tissues, and organs. This study lays the foundation for further studies on the comprehensive clinical effects of injectable B-HA. Methods: We elaborated on the production process, bioactivity assay, efficacy analyses, and safety evaluation of an injectable novel HA fragment with an average molecular weight of 35 kDa (35 kDa B-HA), produced by recombinant human hyaluronidase PH20 digestion. Results: The results showed that 35 kDa B-HA induced human erythrocyte aggregation (rouleaux formation) and accelerated erythrocyte sedimentation rates through the CD44 receptor. B-HA application and injection treatment significantly promoted the removal of mononuclear cells from the site of inflammation and into the lymphatic circulation. At a low concentration, 35 kDa B-HA inhibited production of reactive oxygen species and tumor necrosis factor by neutrophils; at a higher concentration, 35 kDa B-HA promoted the migration of monocytes. Furthermore, 35 kDa B-HA significantly inhibited the migration of neutrophils with or without lipopolysaccharide treatment, suggesting that in local tissues, higher concentrations of 35 kDa B-HA have antiinflammatory effects. After 99mTc radiolabeled 35 kDa B-HA was intravenously injected into mice, it quickly entered into the spleen, liver, lungs, kidneys and other organs through the blood circulation. Conclusion: This study demonstrated that the HA fragment B-HA has good tissue permeability and antiinflammatory effects, laying a theoretical foundation for further clinical studies.

Seeing a talking face matters: Infants' segmentation of continuous auditory-visual speech.

Visual speech cues from a speaker's talking face aid speech segmentation in adults, but despite the importance of speech segmentation in language acquisition, little is known about the possible influence of visual speech on infants' speech segmentation. Here, to investigate whether there is facilitation of speech segmentation by visual information, two groups of English-learning 7-month-old infants were presented with continuous speech passages, one group with auditory-only (AO) speech and the other with auditory-visual (AV) speech. Additionally, the possible relation between infants' relative attention to the speaker's mouth versus eye regions and their segmentation performance was examined. Both the AO and the AV groups of infants successfully segmented words from the continuous speech stream, but segmentation performance persisted for longer for infants in the AV group. Interestingly, while AV group infants showed no significant relation between the relative amount of time spent fixating the speaker's mouth versus eyes and word segmentation, their attention to the mouth was greater than that of AO group infants, especially early in test trials. The results are discussed in relation to the possible pathways through which visual speech cues aid speech perception.

Regional differences of tachykinin effects on smooth muscle and pacemaker potentials of the stomach, duodenum, ileum and colon of an emetic model, the house musk shrews.

BACKGROUND AND AIMS: The contractile effects of tachykinins on the gastrointestinal tract are well-known, but how they modulate slow-waves, particularly in species capable of emesis, remains largely unknown. We aimed to elucidate the effects of tachykinins on myoelectric and contractile activity of isolated gastrointestinal tissues of the Suncus murinus. METHODS: The effects of substance P (SP), neurokinin (NK)A, NKB and selective NK1 (CP122,721, CP99,994), NK2 (SR48,968, GR159,897) and NK3 (SB218,795, SB222,200) receptor antagonists on isolated stomach, duodenum, ileum and colon segments were studied. Mechanical contractile activity was recorded using isometric force displacement transducers. Electrical pacemaker activity was recorded using a microelectrode array. RESULTS: Compared with NKA, SP induced larger contractions in stomach tissue and smaller contractions in intestinal segments, where oscillation magnitudes increased in intestinal segments, but not the stomach. CP122,721 and GR159,897 inhibited electrical field stimulation-induced contractions of the stomach, ileum and colon. NKB and NK3 had minor effects on contractile activity. The inhibitory potencies of SP and NKA on the peristaltic frequency of the colon and ileum, respectively, were correlated with those on electrical pacemaker frequency. SP, NKA and NKB inhibited pacemaker activity of the duodenum and ileum, but increased that of the stomach and colon. SP elicited a dose-dependent contradictive pacemaker frequency response in the colon. CONCLUSION: This study revealed distinct effects of tachykinins on the mechanical and electrical properties of the stomach and colon vs. the proximal intestine, providing a unique aspect on neuromuscular correlation in terms of the effects of tachykinin on peristaltic and pacemaker activity in gastrointestinal-related symptoms.

Adjunctive endoscopic clip marking enhances non-operative management of massive lower gastrointestinal bleeding.

BACKGROUNDS: Massive lower gastrointestinal bleeding (LGB) is common especially in elderly patients. Controversy in the approach to management stems from location of bleeding and morbidity of surgery. Colonic diverticula disease (CD) is the leading cause of painless haematochezia and haemodynamic instability. METHODS: The use of a novel technique of endoscopic pre-marking (EPM) with radiopaque metal clips to localize is described. EPM guided superselective active transarterial embolization (A-TAE) when active vascular blush was seen. When no active contrast extravasation was seen, EPM also guided prophylactic superselective transarterial embolization (P-TAE). RESULTS: From May 2004 to December 2021, there were 36 patients with massive LGB from diverticular disease encompassing 44 separate bleeding episodes. Spontaneous haemostasis was observed in 18.2% (8/44). The overall success rate in non-operative management was 83.3% (30/36) patients. Three patients proceeded for emergency surgery. Of the 36 patients, six patients had documented EPM followed by TAE due to recurrent bleed in the same episode. A-TAE was performed in two patients. P-TAE was performed in the four patients without active contrast extravasation. Initial haemostasis was successful in five out of six patients. One patient failed embolization and proceeded to emergency surgery. Three months later, one patient encountered late rebleeding and was scheduled for elective colectomy. None of the six developed intestinal infarction from embolization. The 30-day mortality was 0%. CONCLUSION: A consistent approach to LGB and defined protocol of endoscopic haemostasis, with routine EPM and embolization, has the potential to mitigate the morbidity and mortality in this group of vulnerable patients.

Enhanced safety and efficacy of protease-regulated CAR-T cell receptors.

Regulatable CAR platforms could circumvent toxicities associated with CAR-T therapy, but existing systems have shortcomings including leakiness and attenuated activity. Here, we present SNIP CARs, a protease-based platform for regulating CAR activity using an FDA-approved small molecule. Design iterations yielded CAR-T cells that manifest full functional capacity with drug and no leaky activity in the absence of drug. In numerous models, SNIP CAR-T cells were more potent than constitutive CAR-T cells and showed diminished T cell exhaustion and greater stemness. In a ROR1-based CAR lethality model, drug cessation following toxicity onset reversed toxicity, thereby credentialing the platform as a safety switch. In the same model, reduced drug dosing opened a therapeutic window that resulted in tumor eradication in the absence of toxicity. SNIP CARs enable remote tuning of CAR activity, which provides solutions to safety and efficacy barriers that are currently limiting progress in using CAR-T cells to treat solid tumors.

Involvement of TRPV1 and TRPA1 in the modulation of pacemaker potentials in the mouse ileum.

BACKGROUND: The roles of transient receptor potential cation channel, subfamily V, member 1 (TRPV1) and subfamily A, member 1 (TRPA1) in mechanisms of gastrointestinal motility are complex. This study aimed to clarify the effects of several TRPV1 and TRPA1 ligands on the electrical potentials generated by pacemaker cells in the mouse-isolated ileum. METHOD: The pacemaker potentials of ileal segments of mice were recorded extracellularly using a 60-channel microelectrode array. The dominant frequencies, average waveform periods and propagation velocities were quantified. The effects of TRPV1 and TRPA1 agonist and antagonist were compared with the baseline recordings. RESULTS: The electrophysiological recordings showed that capsaicin (30 µM to 3 mM), resiniferatoxin (300 µM), capsazepine (100-300 µM), allyl isothiocyanate (300 µM), isovelleral (300 µM), icilin (300 µM), A-967,079 (10 µM), AP18 (20 µM) and HC-030,031 (50 µM) significantly reduced the pacemaker frequency and increased the waveform period relative to the baseline. Conversely, ruthenium red (300 µM) significantly increased the pacemaker frequency and reduced the waveform period. Capsaicin (3 mM) and AP18 (20 µM) also significantly reduced the propagation velocity. However, all tested antagonists failed to inhibit the effects of agonists. AMG9810 (300 µM), but not A-967,079 (300 µM), significantly inhibited the increases in pacemaker frequency caused by increased temperatures. CONCLUSION: Our findings suggest that TRPV1 and TRPA1 play a minor role in regulating pacemaker potentials and that at non-specific actions at other TRP and ion channels most likely contributed to the overall effects on the electrophysiological recordings that we observed.

The peptide symporter SLC15a4 is essential for the development of systemic lupus erythematosus in murine models.

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease representing a serious unmet medical need. The disease is associated with the loss of self-tolerance and exaggerated B cell activation, resulting in autoantibody production and the formation of immune complexes that accumulate in the kidney, causing glomerulonephritis. TLR7, an important mediator of the innate immune response, drives the expression of type-1 interferon (IFN), which leads to expression of type-1 IFN induced genes and aggravates lupus pathology. Because the lysosomal peptide symporter slc15a4 is critically required for type-1 interferon production by pDC, and for certain B cell functions in response to TLR7 and TLR9 signals, we considered it as a potential target for pharmacological intervention in SLE. We deleted the slc15a4 gene in C57BL/6, NZB, and NZW mice and found that pristane-challenged slc15a4-/- mice in the C57BL/6 background and lupus prone slc15a4-/- NZB/W F1 mice were both completely protected from lupus like disease. In the NZB/W F1 model, protection persisted even when disease development was accelerated with an adenovirus encoding IFNα, emphasizing a broad role of slc15a4 in disease initiation. Our results establish a non-redundant function of slc15a4 in regulating both innate and adaptive components of the immune response in SLE pathobiology and suggest that it may be an attractive drug target.

CHEDDA syndrome: a case report and review of the literature for this newly described entity.

Congenital hypotonia, epilepsy, developmental delay, and digital anomalies (CHEDDA) is a recently identified neurodevelopmental syndrome which has only 8 reported cases to date since its existence was proposed in 2007. We report a case of CHEDDA syndrome identified in a newborn female with congenital anomalies including Pierre-Robin sequence, arthrogryposis, craniosynostosis, cleft palate, and cardiac abnormalities who subsequently developed epilepsy at 1 month of life. Diagnosis was identified by whole-exome sequencing identifying mutations in a conserved histidine-rich motif within the gene Atrophin-1. Radiologic findings of cerebral atrophy, hypoplasia of the cerebellum, and thinning of the corpus callosum were identified in this patient, consistent with other reported cases. Given the rarity of this condition, we report this case and its findings to increase awareness of CHEDDA syndrome as a possible underlying diagnosis for neonates who present with this constellation of symptoms and radiologic findings.

Food Allergy Management at School in the Era of Immunotherapy.

PURPOSE OF REVIEW: Food allergy is increasing in prevalence, and management focuses on strict avoidance of known allergens and appropriately treating reactions. Any reaction has the potential to result in anaphylaxis, which can be fatal. Children spend a significant amount of time in the childcare or school setting, and interactions between families, school personnel, and clinicians are important to ensure the health and safety of children with allergies and asthma. RECENT FINDINGS: This review examines current food allergy guidelines and legislation, an assessment of allergen-free schools, the importance of written anaphylaxis action plans, training and education of school personnel, emerging treatment options, and the social implications of having food allergies. As the clinical use and research into food allergen immunotherapy continues to expand, an additional level of education and management is required of school personnel and caregivers. Food allergy has both medical and social implications, which are magnified in the school setting.

Multiplex Solid-Phase Melt Curve Analysis for the Point-of-Care Detection of HIV-1 Drug Resistance.

A point-of-care HIV-1 genotypic resistance assay that could be performed during a clinic visit would enable care providers to make informed treatment decisions for patients starting therapy or experiencing virologic failure on therapy. The main challenge for such an assay is the genetic variability at and surrounding each drug-resistance mutation (DRM). We analyzed a database of diverse global HIV sequences and used thermodynamic simulations to design an array of surface-bound oligonucleotide probe sets with each set sharing distinct 5' and 3' flanking sequences but having different centrally located nucleotides complementary to six codons at HIV-1 DRM reverse transcriptase position 103: AAA, AAC, AAG, AAT, AGA, and AGC. We then performed in vitro experiments using 80-mer oligonucleotides and PCR-amplified DNA from clinical plasma HIV-1 samples and culture supernatants that contained subtype A, B, C, D, CRF01_AE, and CRF02_AG viruses. Multiplexed solid-phase melt curve analysis discriminated perfectly among each of the six reported reverse transcriptase position 103 codons in both 80-mers and clinical samples. The sensitivity and specificity for detecting targets that contained AAC mixed with targets that contained AAA were >98% when AAC was present at a proportion of ≥10%. Multiplexed solid-phase melt curve analysis is a promising approach for developing point-of-care assays to distinguish between different codons in genetically variable regions such as those surrounding HIV-1 DRMs.

Mitochondrial Function in Astrocytes Is Essential for Normal Emergence from Anesthesia in Mice.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: In mice, restriction of loss of the mitochondrial complex I gene Ndufs4 to glutamatergic neurons confers a profound hypersensitivity to volatile anesthetics.Astrocytes are crucial to glutamatergic synapse functioning during excitatory transmission. WHAT THIS ARTICLE TELLS US THAT IS NEW: In a tamoxifen-activated astrocyte-specific Ndufs4(KO) mouse, the induction EC50s for tail clamp in both isoflurane and halothane were similar between the control and astrocyte-specific Ndufs4(KO) mice at 3 weeks after 4-hydroxy tamoxifen injection. However, the emergent concentrations in both anesthetics for the astrocyte-specific Ndufs4(KO) mice were half that of the controls.Similarly, the induction EC50s for loss of righting reflex were similar between the control and astrocyte-specific Ndufs4(KO) mice; concentrations for regain of righting reflex in both anesthetics for the astrocyte-specific Ndufs4(KO) mice were much less than the control.Thus, mitochondrial complex I function within astrocytes is essential for normal emergence from anesthesia. BACKGROUND: In mice, restriction of loss of the mitochondrial complex I gene Ndufs4 to glutamatergic neurons confers a profound hypersensitivity to volatile anesthetics similar to that seen with global genetic knockout of Ndufs4. Astrocytes are crucial to glutamatergic synapse functioning during excitatory transmission. Therefore, the authors examined the role of astrocytes in the anesthetic hypersensitivity of Ndufs4(KO). METHODS: A tamoxifen-activated astrocyte-specific Ndufs4(KO) mouse was constructed. The specificity of the astrocyte-specific inducible model was confirmed by using the green fluorescent protein reporter line Ai6. Approximately 120 astrocyte-specific knockout and control mice were used for the experiments. Mice were anesthetized with varying concentrations of isoflurane or halothane; loss of righting reflex and response to a tail clamp were determined and quantified as the induction and emergence EC50s. Because norepinephrine has been implicated in emergence from anesthesia and astrocytes respond to norepinephrine to release gliotransmitters, the authors measured norepinephrine levels in the brains of control and knockout Ndufs4 animals. RESULTS: The induction EC50s for tail clamp in both isoflurane and halothane were similar between the control and astrocyte-specific Ndufs4(KO) mice at 3 weeks after 4-hydroxy tamoxifen injection (induction concentration, EC50(ind)-isoflurane: control = 1.27 ± 0.12, astrocyte-specific knockout = 1.21 ± 0.18, P = 0.495; halothane: control = 1.28 ± 0.05, astrocyte-specific knockout = 1.20 ± 0.05, P = 0.017). However, the emergent concentrations in both anesthetics for the astrocyte-specific Ndufs4(KO) mice were less than the controls for tail clamp; (emergence concentration, EC50(em)-isoflurane: control = 1.18 ± 0.10, astrocyte-specific knockout = 0.67 ± 0.11, P < 0.0001; halothane: control = 1.08 ± 0.09, astrocyte-specific knockout = 0.59 ± 0.12, P < 0.0001). The induction EC50s for loss of righting reflex were also similar between the control and astrocyte-specific Ndufs4(KO) mice (EC50(ind)-isoflurane: control = 1.02 ± 0.10, astrocyte-specific knockout = 0.97 ± 0.06, P = 0.264; halothane: control = 1.03 ± 0.05, astrocyte-specific knockout = 0.99 ± 0.08, P = 0.207). The emergent concentrations for loss of righting reflex in both anesthetics for the astrocyte-specific Ndufs4(KO) mice were less than the control (EC50(em)-isoflurane: control = 1.0 ± 0.07, astrocyte-specific knockout = 0.62 ± 0.12, P < 0.0001; halothane: control = 1.0 ± 0.04, astrocyte-specific KO = 0.64 ± 0.09, P < 0.0001); N ≥ 6 for control and astrocyte-specific Ndufs4(KO) mice. For all tests, similar results were seen at 7 weeks after 4-hydroxy tamoxifen injection. The total norepinephrine content of the brain in global or astrocyte-specific Ndufs4(KO) mice was unchanged compared to control mice. CONCLUSIONS: The only phenotype of the astrocyte-specific Ndufs4(KO) mouse was a specific impairment in emergence from volatile anesthetic-induced general anesthesia. The authors conclude that normal mitochondrial function within astrocytes is essential for emergence from anesthesia.

Patients with chronic rhinosinusitis and obstructive sleep apnea have increased paroxysmal limb movement.

BACKGROUND: Patients with chronic rhinosinusitis (CRS) frequently experience sleep disruption and are at a higher than normal risk for obstructive sleep apnea (OSA). The purpose of this study was to determine how CRS affects polysomnography findings and sleep-related breathing in OSA. METHODS: A cohort study was performed that included 107 adult patients with CRS and comorbid OSA (CRS+OSA group) and 137 patients with OSA and without CRS as the control group. An electronic medical records database was used to identify eligible subjects. Comorbid conditions and polysomnography data were compared between the two groups by using logistic and linear regression analyses. RESULTS: A total of 246 patients were included: 107 patients in the CRS+OSA group and 137 patients with OSA and without CRS in the control group. After adjusting for demographic factors, the patients in the CRS+OSA group had a lower body mass index (BMI) and higher age at the time of diagnosis of OSA (p < 0.001). The patients in the CRS+OSA group had higher odds of having asthma and eczema. There was an increase in the periodic limb movement (PLM) index in the CRS+OSA group. Apnea and hypopnea indices were similar in the two groups. CONCLUSION: Patients with CRS developed OSA at a lower BMI; patients CRS and OSA had similar sleep-related breathing patterns but higher risks for PLMs compared with patients with OSA and without CRS.