Efficacy and safety of self-administered acupressure on symptoms, quality of life and nasal mucosal function in patients with perennial allergic rhinitis: study protocol for a randomized controlled exploratory trial.

INTRODUCTION: Allergic rhinitis is a global health problem that can potentially be managed through acupressure. Our clinical observations have identified Allergic Rhinitis Acupressure Therapeutic (ARAT) as a novel acupressure treatment acting on specific acupoints, which may enhance the effectiveness of acupressure. Therefore, we propose a three-arm randomized controlled trial will be conducted to investigate the efficacy and safety of ARAT for perennial allergic rhinitis (PAR). METHODS/DESIGN: In this trial, eligible 111 participants diagnosed with PAR will be randomly assigned to one of three groups: the ARAT group, the non-specific acupoints group, or the blank control group. The primary outcome will be the change in the total nasal symptom score, and the secondary outcomes will include: 1) changes in the scores of the standard version of Rhinoconjunctivitis Quality of Life Questionnaire (RQLQs); 2) acoustic rhinometry and anterior rhinomanometry; 3) changes in the scores of relief medication usage; 4) incidence of adverse events. Additionally, we will measure and compare the changes in cytokine levels (IL-5, IL-13, IFN-γ, and TSLP) in nasal secretions. The RQLQs and primary outcomes will be assessed at the beginning, middle, and end stages of the treatment period, with monthly follow-ups conducted over a total of three months. The secondary outcomes and biomarkers in nasal secretions will be measured at the beginning and end of the treatment period. Any adverse events or need for rescue medication will be carefully noted and recorded. DISCUSSION: This study may produce a new acupressure treatment prescription that is easy to learn, more targeted, and adaptable. This trial represents the first clinical investigation comparing ARAT treatment for PAR with the non-specific acupoints group and blank control group. Our data is expected to provide evidence demonstrating the safety and efficacy of ARAT for PAR patients, while also exploring the functional mechanism underlying ARAT treatment, moreover, the results offer valuable insights for healthcare professionals in managing PAR symptoms. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2300072292. Registered on June 08, 2023.

Corrigendum: Neural mechanism underlies CYLD modulation of morphology and synaptic function of medium spiny neurons in dorsolateral striatum.

[This corrects the article DOI: 10.3389/fnmol.2023.1107355.].

Deubiquitinase CYLD regulates excitatory synaptic transmission and short-term plasticity in the hippocampus.

The fate of proteins is determined by the addition of various forms of polyubiquitin during ubiquitin-mediated proteasomal degradation. Cylindromatosis (CYLD), a K63-specific deubiquitinase, is enriched in postsynaptic density fractions of the rodent central nervous system (CNS), but the synaptic role of CYLD in the CNS is poorly understand. Here we show that CYLD deficiency (Cyld-/-) results in reduced intrinsic hippocampal neuronal firing, a decrease in the frequency of spontaneous excitatory postsynaptic currents and a decrease in the amplitude of field excitatory postsynaptic potentials. Moreover, Cyld-/- hippocampus shows downregulated levels of presynaptic vesicular glutamate transporter 1 (vGlut1) and upregulated levels of postsynaptic GluA1, a subunit of the AMPA receptor, together with an altered paired-pulse ratio (PPR). We also found increased activation of astrocytes and microglia in the hippocampus of Cyld-/- mice. The present study suggests a critical role for CYLD in mediating hippocampal neuronal and synaptic activity.

Neural mechanism underlies CYLD modulation of morphology and synaptic function of medium spiny neurons in dorsolateral striatum.

Although the deubiquitinase cylindromatosis (CYLD), an abundant protein in the postsynaptic density fraction, plays a crucial role in mediating the synaptic activity of the striatum, the precise molecular mechanism remains largely unclear. Here, using a Cyld-knockout mouse model, we demonstrate that CYLD regulates dorsolateral striatum (DLS) neuronal morphology, firing activity, excitatory synaptic transmission, and plasticity of striatal medium spiny neurons via, likely, interaction with glutamate receptor 1 (GluA1) and glutamate receptor 2 (GluA2), two key subunits of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs). CYLD deficiency reduces levels of GluA1 and GluA2 surface protein and increases K63-linked ubiquitination, resulting in functional impairments both in AMPAR-mediated excitatory postsynaptic currents and in AMPAR-dependent long-term depression. The results demonstrate a functional association of CYLD with AMPAR activity, which strengthens our understanding of the role of CYLD in striatal neuronal activity.

Oxygen Glucose Deprivation Induced Prosurvival Autophagy Is Insufficient to Rescue Endothelial Function.

Endothelial dysfunction, referring to a disturbance in the vascular homeostasis, has been implicated in many disease conditions including ischemic/reperfusion injury and atherosclerosis. Endothelial mitochondria have been increasingly recognized as a regulator of calcium homeostasis which has implications in the execution of diverse cellular events and energy production. The mitochondrial calcium uniporter complex through which calcium enters the mitochondria is composed of several proteins, including the pore-forming subunit MCU and its regulators MCUR1, MICU1, and MICU2. Mitochondrial calcium overload leads to opening of MPTP (mitochondrial permeability transition pore) and results in apoptotic cell death. Whereas, blockage of calcium entry into the mitochondria results in reduced ATP production thereby activates AMPK-mediated pro-survival autophagy. Here, we investigated the expression of mitochondrial calcium uniporter complex components (MCU, MCUR1, MICU1, and MICU2), induction of autophagy and apoptotic cell death in endothelial cells in response to oxygen-glucose deprivation. Human pulmonary microvascular endothelial cells (HPMVECs) were subjected to oxygen-glucose deprivation (OGD) at 3-h timepoints up to 12 h. Interestingly, except MCUR1 which was significantly downregulated, all other components of the uniporter (MCU, MICU1, and MICU2) remained unchanged. MCUR1 downregulation has been shown to activate AMPK mediated pro-survival autophagy. Similarly, MCUR1 downregulation in response to OGD resulted in AMPK phosphorylation and LC3 processing indicating the activation of pro-survival autophagy. Despite the activation of autophagy, OGD induced Caspase-mediated apoptotic cell death. Blockade of autophagy did not reduce OGD-induced apoptotic cell death whereas serum starvation conferred enough cellular and functional protection. In conclusion, the autophagic flux induced by MCUR1 downregulation in response to OGD is insufficient in protecting endothelial cells from undergoing apoptotic cell death and requires enhancement of autophagic flux by additional means such as serum starvation.

Mitochondrial Dysfunction in Age-Related Metabolic Disorders.

Aging is a natural biological process in living organisms characterized by receding bioenergetics. Mitochondria are crucial for cellular bioenergetics and thus an important contributor to age-related energetics deterioration. In addition, mitochondria play a major role in calcium signaling, redox homeostasis, and thermogenesis making this organelle a major cellular component that dictates the fate of a cell. To maintain its quantity and quality, mitochondria undergo multiple processes such as fission, fusion, and mitophagy to eliminate or replace damaged mitochondria. While this bioenergetics machinery is properly protected, the functional decline associated with age and age-related metabolic diseases is mostly a result of failure in such protective mechanisms. In addition, metabolic by-products like reactive oxygen species also aid in this destructive pathway. Mitochondrial dysfunction has always been thought to be associated with diseases. Moreover, studies in recent years have pointed out that aging contributes to the decay of mitochondrial health by promoting imbalances in key mitochondrial-regulated pathways. Hence, it is crucial to understand the nexus of mitochondrial dysfunction in age-related diseases. This review focuses on various aspects of basic mitochondrial biology and its status in aging and age-related metabolic diseases.

Differential effects of citalopram on sleep-deprivation-induced depressive-like behavior and memory impairments in mice.

Recently there is increasing concern over the association between sleep deprivation (S-Dep) and depression. Mounting evidence suggests that S-Dep might be a risk factor for depression. However, underlying molecular mechanism remains elusive and currently there is no effective therapy to negate the effects of S-Dep. In this study, we aimed to examine whether subchronic treatment of citalopram (CTM), an antidepressant, can attenuate the negative effects of S-Dep in mice. Three-month-old C57BL/6J mice were divided into control, S-Dep, CTM control and CTM + S-Dep groups. CTM and CTM + S-Dep group treated with citalopram for 5 consecutive days at a dose of 10 mg/kg per day before experimental procedure. S-Dep and CTM + S-Dep group mice were sleep deprived for 24 h using an automated treadmill method. Our results revealed that S-Dep animals displayed an increased depressive-like behavior in forced swim, tail suspension and sucrose preference test and anxiety-like behavior in the open field and elevated plus maze, as well as disrupted spatial memory in Morris water maze. Western blotting analysis revealed that S-Dep caused reductions in the levels of the plasticity- and memory-related signaling molecules i.e. pCaMKII and pCREB in the hippocampus. Moreover, S-Dep animals showed synaptic plasticity deficits in the Schaffer collateral pathway. Interestingly, subchronic CTM treatment prevented S-Dep-induced decrease in pCaMKII and pCREB levels in the hippocampus. Furthermore, CTM treatment prevented S-Dep-induced deficits in synaptic plasticity, spatial memory, depressive-like behavior in sucrose preference test and anxiety-like behavior in open field test but not in force swim, tail suspension and elevated plus maze test. This data suggests differential effects of CTM on S-Dep-associated behavioral alterations and cognitive impairments.

Total cranial vault remodeling for isolated sagittal synostosis: part I. Postoperative cranial suture patency.

BACKGROUND: Total vault reconstruction addresses all phenotypic aspects of scaphocephaly. The clinical implications of remodeling across open cranial sutures, however, remain unclear. The purpose of this study was to assess patency of unaffected sutures following total vault remodeling for isolated sagittal synostosis. METHODS: The authors reviewed routine postoperative computed tomographic scans of patients who underwent total vault remodeling for isolated sagittal synostosis between 2004 and 2008. Sutural patency was scored by a single reviewer as follows: 0 = closed, 1 = partial, and 2 = open. Individual suture scores were tallied for a total sutural patency score. Computed tomographic scans were stratified by postoperative time and craniofacial surgeon. RESULTS: Forty-two patients met the inclusion criteria. Individual sutural closure rates were 42.6, 38.3, 74.5, and 74.5 percent for right coronal, left coronal, right lambdoidal, and left lambdoidal sutures, respectively. Lambdoidal sutures had a significantly higher rate of closure than coronal sutures (OR(Closure), 4.3; 95 percent CI, 2.3 to 8.0; p < 0.001); lambdoidal patency significantly changed over time (χ2 = 9.9, p = 0.04). Across craniofacial surgeons, coronal and lambdoidal patency were equivalent. The total sutural patency score did not significantly correlate with postoperative time, surgical age, preoperative cephalic index, or craniofacial surgeon. CONCLUSIONS: Total vault remodeling for isolated sagittal synostosis results in a high degree of secondary craniosynostosis. Lambdoidal sutures are especially prone to closure, with their patency diminishing over time. At this time, radiographic fusion of adjacent sutures following surgery has not been related to any difference in head shape. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Comparison of readers' detection of right-sided and left-sided breast cancers and microcalcifications.

INTRODUCTION: Aim of this study was to determine if there is a statistically and clinically significant difference in diagnostic performance (cancer diagnosis) and perceptual performance (microcalcification detection) when detecting left-sided or right-sided breast cancers and microcalcifications. METHODS: Eight radiologist readers (8-20 years experience in radiology, five current BreastScreen readers) read a set of 100 digital mammograms (23/100 had proven malignancies and 52/100 had confirmed microcalcifications) for three reads (random case order in each read). The same mammograms were presented on two reads, serving as the baseline reads. The data from these reads were used to calculate intra-observer variability (presented in an earlier study). The experimental read consisted of left-right mirror images of the original mammograms. In each read, the radiologists were requested to 'clear' or 'call-back' cases and to indicate if any microcalcifications (benign and malignant) were present on the mammograms. Reading conditions were standardised. RESULTS: Comparison of intra-reader performance difference for left-sided versus right-sided breast cancers and microcalcifications with intra-observer variability for breast cancer diagnosis and microcalcification detection, respectively, revealed no clinically significant difference between left-sided and right-sided detections. Per-case analysis showed more left-sided breast cancers and microcalcifications correctly detected. This left-right difference in detection did not reach statistical significance, P-value of 0.28 for cancer diagnosis and 0.74 for microcalcification detection. CONCLUSION: There is no statistically or clinically significant difference between left-sided and right-sided breast cancer diagnosis and microcalcification detection in a group of experienced radiologists. Individual reading patterns do not affect detection rates of left-sided and right-sided cancers and microcalcifications.

Intrareader variability in mammographic diagnostic and perceptual performance amongst experienced radiologists in Australia.

INTRODUCTION: The purpose of this study was, for a group of experienced radiologists, to identify the magnitude of and statistical significance of intrareader variability in mammographic diagnostic performance or cancer diagnosis and mammographic perceptual performance or microcalcification detection. METHODS: Eight radiologist readers (8-30 years experience in radiology, five current BreastScreen readers) read a set of 100 digital mammograms on two separate reads with random case orders. Twenty-three of the 100 had proven malignancies, and 52 of the 100 had confirmed microcalcifications. The same mammograms were presented for both reads. The radiologists were requested to clear or call back cases and to indicate if any benign and malignant microcalcifications were present on the mammograms. Reading conditions were standardised. RESULTS: Intrareader variability in accuracy was demonstrated to be between 0% and 6% for the diagnostic task of breast cancer diagnosis and between 0% and 16% for the perceptual task of microcalcification detection. Intrareader agreement in the group of readers was high; between 75% and 93% (κ=0.36-0.72) for cancer diagnosis and between 77.5% and 93% (κ=0.17-0.77) for microcalcification detection. There was no correlation between reader's experience in radiology or being a BreastScreen reader and level of intrareader variability in cancer diagnosis and microcalcification detection. CONCLUSION: There exists intrareader variability in diagnostic and perceptual performance. Despite this variability, intrareader agreement remains high.

Comparison of 3MP medical-grade to 1MP office-grade LCD monitors in mammographic diagnostic and perceptual performance.

INTRODUCTION: Picture archiving and communication systems images designed to be viewed on high-resolution medical-grade monitors are routinely viewed on office-grade monitors on the wards or at home. This study aimed to determine whether a statistically significant difference in diagnostic (cancer detection) and perceptual (microcalcification detection) performance exists between 3MP grade and 1MP office-grade monitors. METHODS: 3MP Dome medical-grade liquid crystal display (LCD) monitors (Planar, Beaverton, OR, USA) were compared to 1MP Dell office-grade LCD monitors (Dell Inc, Round Rock, TX, USA). Eight radiologists (reader experience 8-30 years) read the same set of 100 mammograms (23/100 with proven cancers and 52/100 with microcalcifications) presented in random order on three occasions separated by two time intervals of 12 weeks. Reads 1 and 3 utilised 3MP monitors and formed the baseline read. Read 2 utilised 1MP monitors and constituted the experimental read. Reading conditions were standardised. Readers were aware of which monitors they were using. Multivariate logistic regression analysis (to account for reader variability and monitor impact) was performed to assess for statistical significance. RESULTS: At α = 5%, confidence intervals analysis comparing the measured parameters between 1MP to 3MP monitors demonstrated no statistically significant difference in diagnostic and perceptual performance for the reader group. In cancer detection (the diagnostic task), reader accuracy remained high irrespective of monitor type. Regression analysis comparing performance with 1MP against 3MP monitors found P values of 0.693 and 0.324 for diagnostic and perceptual performance, respectively. CONCLUSION: There were no statistically and clinically significant differences between 3MP and 1MP monitors in mammographic diagnostic and perceptual performance. Comparable performance may be due to compensatory behaviour by readers.

[Isolation of a wild-type virulent phage of Helicobacter pylori and its simulated treatments of gastrointestinal Hp in vitro].

OBJECTIVE: To isolate the wild-type virulent phage of Helicobacter pylori (Hp) and simulate the treatments in vitro to investigate the methods for oral Hp-assisted penetration of the phage through the gastric barrier and offspring phage release for infection and treatment of gastrointestinal Hp. METHODS: The Hp strain was cultured with the candle cylinder method and the virulent phage was isolated by single plate or double plate experiment. A simulated gastric juice was applied and the bactericidal effect of the phage was tested with double flats experiment. RESULTS: After a 1.5-h treatment in simulated gastric juice, the orally derived Hp-borne phage was still capable of forming plaques while the control phage was not. CONCLUSION: The oral Hp can help the phage resist the gastric juice and then infect the gastrointestinal Hp.