Outcomes of a Double-Cup Construct to Treat Paprosky 3A and 3B Acetabular Defects at a Mean of 39 Months.

BACKGROUND: Modular reconstruction systems based on porous tantalum (PT) prosthetic components have been increasingly used for the treatment of complex acetabular bone defects in revision total hip arthroplasty. We report a novel technique that applies a revision cup as a "super-augment" to form a "double-cup" construct for Paprosky type III defects. METHODS: A retrospective review was conducted on revision total hip arthroplasty cases, comparing those treated with double-cup constructs (DC group, n = 48) to those treated with PT shells and augments (PT group, n = 48). All procedures were performed at the same institute between 2017 and 2022. Clinical outcome evaluation utilized the Harris Hip Score, Oxford Hip Score, and the 36-Item Short Form Survey. Preoperative and postoperative radiographic assessments measured hip center of rotation (COR) position and leg length discrepancy. Additionally, postoperative complications and implant survivorship were monitored during the follow-up period. RESULTS: The clinical outcomes improved substantially in both groups, which showed no significant difference in the Harris Hip Score (P = .786), the Oxford Hip Score (P = .570), and the 36-Item Short Form Survey (P = .691). Compared to the PT group, the reconstruction COR was significantly closer to the anatomic COR (vertical distance: 2.630 versus 7.355 mm, P = .0034; horizontal distance: 1.881 versus -6.413 mm, P < .0001) in Paprosky 3B type defects. Additionally, postoperative leg length discrepancy was less in the DC group (-8.252 versus -1.821 mm, P = .0008). Dislocation was the main complication in the DC group, and only 1 patient received re-revision due to repeated dislocation. The cumulative survival rate of the DC group (100%; 95% confidence interval 100) was better than the PT group (83.4%; 95% confidence interval 70.5 to 98.6) when re-revisions for aseptic loosening were the endpoint (P = .046). CONCLUSIONS: The DC is a reliable revision technique for the reconstruction of Paprosky type III bone defects. Although dislocation remains challenging, the biomechanically superior restoration achieved by this technique lowers the risk of aseptic loosening.

DNA vaccines targeting amyloid-ß oligomer ameliorate cognitive deficits of aged APP/PS1/tau triple-transgenic mouse models of Alzheimer's disease.

The amyloid-ß (Aß) oligomer, rather than the Aß monomer, is considered to be the primary initiator of Alzheimer's disease. It was hypothesized that p(Aß3-10)10-MT, the recombinant Aß3-10 gene vaccine of the Aß oligomer has the potential to treat Alzheimer's disease. In this study, we intramuscularly injected the p(Aß3-10)10-MT vaccine into the left hindlimb of APP/PS1/tau triple-transgenic mice, which are a model for Alzheimer's disease. Our results showed that the p(Aß3-10)10-MT vaccine effectively reduced Aß oligomer levels and plaque deposition in the cerebral cortex and hippocampus, decreased the levels tau protein variants, reduced synaptic loss, protected synaptic function, reduced neuron loss, and ameliorated memory impairment without causing any cerebral hemorrhaging. Therefore, this novel DNA vaccine, which is safe and highly effective in mouse models of Alzheimer's disease, holds a lot of promise for the treatment of Alzheimer's disease in humans.

Potential therapeutic target genes for systemic lupus erythematosus: a bioinformatics analysis.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease involving multiple organs. However, the underlying etiology and mechanisms remain unclear. This study was performed to identify potential therapeutic targets for SLE using bioinformatics methods. First, 584 differentially expressed genes were identified based on the GSE61635 dataset. Tissue-specific analyses, enrichment analyses, and Protein-Protein interaction network were successively conducted. Furthermore, ELISA was performed to confirm the expression levels of key genes in the control and SLE blood samples. The findings revealed that tissue-specific expression of markers of the hematological system (25.5%, 28/110) varied significantly. CCL2, MMP9, and RSAD2 expression was markedly increased in the SLE samples compared with controls. In conclusion, the identified key genes (CCL2, MMP9, and RSAD2) may act as possible therapeutic targets for the treatment of SLE.

Development of light response and GABAergic excitation-to-inhibition switch in zebrafish retinal ganglion cells.

The zebrafish retina has been an important model for studying morphological development of neural circuits in vivo. However, its functional development is not yet well understood. To investigate the functional development of zebrafish retina, we developed an in vivo patch-clamp whole-cell recording technique in intact zebrafish larvae. We first examined the developmental profile of light-evoked responses (LERs) in retinal ganglion cells (RGCs) from 2 to 9 days post-fertilization (dpf). Unstable LERs were first observed at 2.5 dpf. By 4 dpf, RGCs exhibited reliable light responses. As the GABAergic system is critical for retinal development, we then performed in vivo gramicidin perforated-patch whole-cell recording to characterize the developmental change of GABAergic action in RGCs. The reversal potential of GABA-induced currents (E(GABA)) in RGCs gradually shifted from depolarized to hyperpolarized levels during 2-4 dpf and the excitation-to-inhibition (E-I) switch of GABAergic action occurred at around 2.5 dpf when RGCs became light sensitive. Meanwhile, GABAergic transmission upstream to RGCs also became inhibitory by 2.5 dpf. Furthermore, down-regulation of the K(+)/Cl() co-transporter (KCC2) by the morpholino oligonucleotide-based knockdown approach, which shifted RGC E(GABA) towards a more depolarized level and thus delayed the E-I switch by one day, postponed the appearance of RGC LERs by one day. In addition, RGCs exhibited correlated giant inward current (GICs) during 2.5-3.5 dpf. The period of GICs was shifted to 3-4.5 dpf by KCC2 knockdown. Taken together, the GABAergic E-I switch occurs coincidently with the emergence of light responses and GICs in zebrafish RGCs, and may contribute to the functional development of retinal circuits.

[Study of early pathological changes and axonal injury of optic nerve in experimental allergic encephalomyelitis mouse].

OBJECTIVE: To observe the early pathological changes and myelin axonal injury of optic nerve during the different stage in EAE mouse, which can provide the theoretical evidence for further therapy. METHODS: It was an experimental study. EAE was induced with synthetic peptides that represent aa 35 to 55 (MOG35-55) by immunizing C57BL/6 mouse; To observe the pathological change of optic nerve in normal group, EAE group post-immunization 7, 11, 15, 19 d by morphology; The expression of ß-APP proteins marked axonal injury and normal myelin proteins CNPase in normal group, EAE group optic nerve after immunization 7, 11, 15, 19 d were detected by immunohistochemistry. RESULTS: More and more serious inflammation occurred in the optic nerve of EAE group after immunization 7, 11, 15, 19 d; The expression of CNPase proteins in the optic nerve of EAE group decreased post-immunization 11 d, so are in 15 d, 19 d, and the expression of ß-APP proteins in the optic nerve of EAE group increased significantly from 7 d to 19 d post-immunization. CONCLUSION: Inflammation in optic nerve of EAE mouse differ from early stage to peak stage after EAE induction; Axonal damage existing in the optic nerve of EAE mouse is independent on demyelination.

Aspirin Use on Incident Dementia and Mild Cognitive Decline: A Systematic Review and Meta-Analysis.

Background: More people with cognitive dysfunction and dementia also fall into the category of high vascular risk, for which aspirin is one of the most frequently used drugs. However, previous studies reporting that aspirin buffers against mild cognitive decline (MCI) and dementia remain controversial. We thus conducted an updated systematic review and meta-analysis to evaluate the association of aspirin use with the risk of MCI and dementia in older adults. Methods: Data sources from PubMed, Embase, Web of Science, and the Cochrane Database for randomized controlled trails (RCTs) and cohort studies (published between January 1, 2000 and April 11, 2020). Relative risks (RRs) and 95% confidence intervals (95% CIs) were used to pool data on the occurrence of dementia and MCI with random-effects models. Results: Of 3,193 identified articles, 15 studies (12 cohort studies and three RCTs) were eligible and were included in our analysis, which involved a total of 100,909 participants without cognitive dysfunctions or dementia at baseline. In pooled cohort studies, aspirin use did not reduce the incidence of MCI and dementia (the pooled RR = 0.97; 95% CI = 0.85-1.11; I for heterogeneity 2 = 65%) compared with non-users. However, low-dose aspirin (75-100 mg/day) was associated with a decreased likelihood of developing dementia or MCI (the pooled RR = 0.75; 95% CI = 0.63-0.9; I for heterogeneity 2 = 50.5%). This association existed in studies including all-cause dementia (the pooled RR = 0.82; 95% CI = 0.71-0.96) and Alzheimer's disease (AD) (the pooled RR = 0.54; 95% CI = 0.33-0.89), but not in MCI (the pooled RR = 0.58; 95% CI = 0.31-1.08). In RCTs, low-dose aspirin use was not significantly associated with less prevalence of dementia or MCI (RR = 0.94; 95% CI = 0.84-1.05; I for heterogeneity 2 = 0.0%). Conclusions: In cohort studies, we found that low-dose aspirin use had a higher likelihood of reducing the incidence of dementia, which was not supported by RCTs. The evidence was insufficient to fully evaluate the effect of aspirin on cognitive function and dementia. Well-designed studies and innovative approaches are therefore needed to clarify whether the use of aspirin improves cognitive function and reduces the risk of dementia.

3­N­Butyphthalide improves learning and memory in rats with vascular cognitive impairment by activating the SIRT1/BDNF pathway.

Vascular cognitive impairment (VCI) is a type of cerebral vascular disorder that leads to learning and memory decline. VCI models can be induced by chronic cerebral hypoperfusion via permanent bilateral common carotid artery occlusion. 3­N­Butylphthalide (NBP) is a neuroprotective drug used for the treatment of ischemic cerebrovascular diseases. Silent information regulator 1 (SIRT1) plays an important role in memory formation and cognitive performance, and its abnormal reduction is associated with cognitive dysfunction in neurodegenerative diseases. Brain­derived neurotrophic factor (BDNF) is a neurotrophic factor that plays critical roles in promoting neuronal growth and injury repair. The present study was performed to investigate the effects and the underlying mechanism of NBP on learning deficits in a rat model of VCI. Rats were divided into a control group, model group, low­NBP­dose group (30 mg/kg/day), high­NBP­dose group (60 mg/kg/day), NBP + SIRT1 inhibitor group and NBP + BDNF inhibitor group. Rats were then subjected to Morris water maze and T­maze tests, which identified that NBP treatment significantly attenuated memory impairments in VCI rats. Molecular examination indicated that SIRT1 and BDNF expression levels in the hippocampus were increased by NBP treatment. However, NBP failed to ameliorate cognitive function after inhibition of the SIRT1/BDNF signaling pathway. In addition, NBP in combination with a SIRT1 inhibitor suppressed BDNF protein expression, but inhibition of BDNF did not inhibit SIRT1 protein expression in rats with VCI. The present results suggested that the neuroprotective effects of NBP on learning deficits in a rat model of VCI may be via regulation of the SIRT1/BDNF signaling pathway, in which SIRT1 may be the upstream signaling molecule. Therefore, the SIRT1/BDNF pathway could be a potential therapeutic target for VCI.

Cytokine Profiling in Chinese SLE Patients: Correlations with Renal Dysfunction.

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic, systemic autoimmune disease that commonly causes kidney damage. Therefore, we measured plasma levels of cytokines that may be related to renal dysfunction in SLE patients. METHODS: To explore the differences between SLE patients with renal dysfunction and healthy volunteers, the levels of cytokines in plasma were screened using a human cytokine antibody array. Then, we chose fourteen of the elevated cytokines for verification with an expanded sample size by a human magnetic Luminex assay. Plasma samples were isolated from SLE patients (n = 72) and healthy volunteers (n = 8). RESULTS: Cytokine antibody array data showed elevated plasma cytokines in SLE patients with renal dysfunction compared with healthy volunteers. By using the human magnetic Luminex assay, we found that plasma levels of CHI3L1, GDF-15, IGFBP-2, MIF, ST2, TFF3, and uPAR were significantly higher in SLE patients than in healthy volunteers. Plasma levels of CXCL4 were significantly lower in the active group than in the inactive group, and plasma levels of CHI3L1, IGFBP-2, MIF, and MPO were significantly higher in the active group than in the inactive group. We also analyzed the correlation between plasma cytokine levels and the SLEDAI-2K, and our results showed that the plasma levels of the fourteen selected cytokines were weakly correlated or not correlated with the SLEDAI-2K. We further analyzed the correlation between cytokines and renal dysfunction. Plasma levels of GDF-15 and TFF3 were highly positively correlated with serum creatinine levels and 24-hour urine protein levels. CONCLUSION: Our data suggest that plasma levels of GDF-15 and TFF3 are potential renal dysfunction markers in SLE patients, but plasma levels of these cytokines are not correlated with the SLEDAI-2K. Further study is warranted to determine how these cytokines regulate inflammatory responses and renal dysfunction in SLE.

Müller Glial Cells Participate in Retinal Waves via Glutamate Transporters and AMPA Receptors.

Retinal waves, the spontaneous patterned neural activities propagating among developing retinal ganglion cells (RGCs), instruct the activity-dependent refinement of visuotopic maps. Although it is known that the wave is initiated successively by amacrine cells and bipolar cells, the behavior and function of glia in retinal waves remain unclear. Using multiple in vivo methods in larval zebrafish, we found that Müller glial cells (MGCs) display wave-like spontaneous activities, which start at MGC processes within the inner plexiform layer, vertically spread to their somata and endfeet, and horizontally propagate into neighboring MGCs. MGC waves depend on glutamatergic signaling derived from bipolar cells. Moreover, MGCs express both glia-specific glutamate transporters and the AMPA subtype of glutamate receptors. The AMPA receptors mediate MGC calcium activities during retinal waves, whereas the glutamate transporters modulate the occurrence of retinal waves. Thus, MGCs can sense and regulate retinal waves via AMPA receptors and glutamate transporters, respectively.

The Serotonergic Raphe Promote Sleep in Zebrafish and Mice.

The role of serotonin (5-HT) in sleep is controversial: early studies suggested a sleep-promoting role, but eventually the paradigm shifted toward a wake-promoting function for the serotonergic raphe. Here, we provide evidence from zebrafish and mice that the raphe are critical for the initiation and maintenance of sleep. In zebrafish, genetic ablation of 5-HT production by the raphe reduces sleep, sleep depth, and the homeostatic response to sleep deprivation. Pharmacological inhibition or ablation of the raphe reduces sleep, while optogenetic stimulation increases sleep. Similarly, in mice, ablation of the raphe increases wakefulness and impairs the homeostatic response to sleep deprivation, whereas tonic optogenetic stimulation at a rate similar to baseline activity induces sleep. Interestingly, burst optogenetic stimulation induces wakefulness in accordance with previously described burst activity of the raphe during arousing stimuli. These results indicate that the serotonergic system promotes sleep in both diurnal zebrafish and nocturnal rodents. VIDEO ABSTRACT.

Rheumatoid arthritis and risk of anxiety: a meta-analysis of cohort studies.

OBJECTIVES: Rheumatoid arthritis (RA) may increase the risk of anxiety, but results from prior studies have no consensus. Our study aimed to evaluate the relationship between RA and incident anxiety by using a quantitative meta-analysis. METHODS: A number of databases were used to gather relevant information; they included PubMed, EMBASE, and Web of Science, with the publication date of articles limited up to July 23, 2018. To evaluate their association, an odds ratio (OR) with 95% confidence interval (CI) was used. The random-effects model played a crucial role in calculating the pooled odds ratio, while subgroup analyses and sensitivity analyses were also performed. RESULTS: A total of 10 studies, including 6201 cases of anxiety and 139,875 participants, met our inclusion criteria for this meta-analysis. All individuals were without anxiety at baseline. The follow-up period ranged from 1.0 to 9.2 years. Overall, the quantitative meta-analysis suggested that subjects with RA were associated with a significantly increased risk of anxiety incidence (OR, 1.20; 95% CI, 1.03-1.39) than those without. CONCLUSION: Results of this meta-analysis indicate that individuals with RA may confer an increased risk for the development of anxiety. Future studies should explore whether clinical manifestations of RA are modifiable risk factors for anxiety.

Absence of associative motor learning and impaired time perception in a rare case of complete cerebellar agenesis.

Primary cerebellar agenesis (PCA), a brain disease where the cerebellum does not develop, is an extremely rare congenital disease with only eleven living cases reported thus far. Studies of the PCA case will thus provide valuable insights into the necessity of cerebellar development for controlling and modulating cognitive functions of the brain. In this follow-up study, we further investigated the performance of associative learning and time perception of a 26-year-old female complete PCA case. We assessed whether delayed eyeblink conditioning (EBC), which represents prototypical associative motor learning function of the cerebellum, could be partially compensated by the extracerebellar brain regions in complete absence of the cerebellum. We also assessed whether the cerebellum, a critical brain region for millisecond-range interval timing, is essential for perception of the second-range time interval. Twelve neurotypical age-matched individuals were used as controls. We found that although the complete PCA patient had only mild to moderate motor deficits, she was unable to perform the delayed EBC even after 1-week of extensive training. Additionally, the PCA patient also performed poorly during time reproduction experiments in which she overproduced the millisecond-range time intervals, while underproduced the second-range time intervals. The PCA patient also failed to perform the temporal eyeblink conditioning with a 5 s fixed interval as the conditioned stimulus. These results indicate that the cerebellum is indispensable for associative motor learning and involved in timing of sub-second intervals, as well as in the perception of second-range intervals.

The Locus Coeruleus Modulates Intravenous General Anesthesia of Zebrafish via a Cooperative Mechanism.

How general anesthesia causes loss of consciousness has been a mystery for decades. It is generally thought that arousal-related brain nuclei, including the locus coeruleus (LC), are involved. Here, by monitoring locomotion behaviors and neural activities, we developed a larval zebrafish model for studying general anesthesia induced by propofol and etomidate, two commonly used intravenous anesthetics. Local lesion of LC neurons via two-photon laser-based ablation or genetic depletion of norepinephrine (NE; a neuromodulator released by LC neurons) via CRISPR/Cas9-based mutation of dopamine-ß-hydroxylase (dbh) accelerates induction into and retards emergence from general anesthesia. Mechanistically, in vivo whole-cell recording revealed that both anesthetics suppress LC neurons' activity through a cooperative mechanism, inhibiting presynaptic excitatory inputs and inducing GABAA receptor-mediated hyperpolarization of these neurons. Thus, our study indicates that the LC-NE system plays a modulatory role in both induction of and emergence from intravenous general anesthesia.

Atrial Natriuretic Peptide: A Potential Early Therapy for the Prevention of Multiple Organ Dysfunction Syndrome Following Severe Trauma.

Trauma remains a tremendous medical burden partly because of increased expenditure for the management of multiple organ dysfunction syndrome (MODS) developed during hospital stay. The intestinal barrier injury continues to be a second insult resulting in MODS which currently lacks efficient strategies for prevention. Recent studies have uncovered multi-organ protective benefits of atrial natriuretic peptide (ANP) in cardiovascular disease. However, the role of ANP in the prevention of MODS following severe trauma has not been understood. In our laboratory study, 1-h infusion of exogenous ANP during hemorrhagic shock following severe trauma induced high-level expression of endogenous serum ANP after 24 h, this effect was related to the improved level of functional biomarkers in multiple organs. Such phenomenon has not been found in other laboratories. A thorough literature review consequently was performed to uncover the potential mechanisms, to appraise therapy safety, and to propose uncertainties. In severe trauma, short-term exogenous ANP therapy during hemorrhagic shock may promote sustained endogenous expression of ANP from intestinal epithelium through activating a positive feedback loop mechanism involving phospholipase C-γ1 and reactive oxygen species crosstalk. This feedback loop may prevent MODS through multiple signaling pathways. Administration of ANP during hemorrhagic shock is thought to be safe. Further studies are required to confirm our proposed mechanisms and to investigate the dose, duration, and timing of ANP therapy in severe trauma.

In Vivo Whole-Cell Patch-Clamp Recording in the Zebrafish Brain.

Zebrafish (Danio rerio) is a newly emerged vertebrate animal model with a conserved gross architecture of the brain and a rich repertoire of behaviors. Due to the optical transparency and structural simplicity of its brain, larval zebrafish has become an ideal in vivo model for dissecting neural mechanisms of brain functions at a whole-brain scale based on a strategy that spans scales from synapses, neurons, and circuits to behaviors. Whole-cell patch-clamp recording is an indispensable approach for studying synaptic and circuit mechanisms of brain functions. Due to the small size of neurons in the zebrafish brain, it is challenging to get whole-cell recordings from these cells. Here, we describe a protocol for obtaining in vivo whole-cell patch-clamp recordings from neurons in larval zebrafish.

Stereotyped initiation of retinal waves by bipolar cells via presynaptic NMDA autoreceptors.

Glutamatergic retinal waves, the spontaneous patterned neural activities propagating among developing retinal ganglion cells (RGCs), instruct the activity-dependent refinement of visuotopic maps. However, its initiation and underlying mechanism remain largely elusive. Here using larval zebrafish and multiple in vivo approaches, we discover that bipolar cells (BCs) are responsible for the generation of glutamatergic retinal waves. The wave originates from BC axon terminals (ATs) and propagates laterally to nearby BCs and vertically to downstream RGCs and the optic tectum. Its initiation is triggered by the activation of and consequent glutamate release from BC ATs, and is mediated by the N-methyl-D-aspartate subtype of glutamate receptors (NMDARs) expressed at these ATs. Intercellular asymmetry of NMDAR expression at BC ATs enables the preferential initiation of waves at the temporal retina, where BC ATs express more NMDARs. Thus, our findings indicate that glutamatergic retinal waves are initiated by BCs through a presynaptic NMDA autoreceptor-dependent process.

Positive selection rather than relaxation of functional constraint drives the evolution of vision during chicken domestication.

As noted by Darwin, chickens have the greatest phenotypic diversity of all birds, but an interesting evolutionary difference between domestic chickens and their wild ancestor, the Red Junglefowl, is their comparatively weaker vision. Existing theories suggest that diminished visual prowess among domestic chickens reflect changes driven by the relaxation of functional constraints on vision, but the evidence identifying the underlying genetic mechanisms responsible for this change has not been definitively characterized. Here, a genome-wide analysis of the domestic chicken and Red Junglefowl genomes showed significant enrichment for positively selected genes involved in the development of vision. There were significant differences between domestic chickens and their wild ancestors regarding the level of mRNA expression for these genes in the retina. Numerous additional genes involved in the development of vision also showed significant differences in mRNA expression between domestic chickens and their wild ancestors, particularly for genes associated with phototransduction and photoreceptor development, such as RHO (rhodopsin), GUCA1A, PDE6B and NR2E3. Finally, we characterized the potential role of the VIT gene in vision, which experienced positive selection and downregulated expression in the retina of the village chicken. Overall, our results suggest that positive selection, rather than relaxation of purifying selection, contributed to the evolution of vision in domestic chickens. The progenitors of domestic chickens harboring weaker vision may have showed a reduced fear response and vigilance, making them easier to be unconsciously selected and/or domesticated.

KCC2-dependent subcellular E(Cl) difference of ON-OFF retinal ganglion cells in larval zebrafish.

Subcellular difference in the reversal potential of Cl(-) (ECl) has been found in many types of neurons. As local ECl largely determines the action of nearby GABAergic/glycinergic synapses, subcellular ECl difference can effectively regulate neuronal computation. The ON-OFF retinal ganglion cell (RGC) processes both ON and OFF visual signals via its ON and OFF dendrites, respectively. It is thus interesting to investigate whether the ON and OFF dendrites of single RGCs exhibit different local ECl. Here, using in vivo gramicidin-perforated patch recording in larval zebrafish ON-OFF RGCs, we examine local ECl at the ON and OFF dendrites, and soma through measuring light-evoked ON and OFF inhibitory responses, and GABA-induced response at the soma, respectively. We find there are subcellular ECl differences between the soma and dendrite, as well as between the ON and OFF dendrites of single RGCs. These somato-dendritic and inter-dendritic ECl differences are dependent on the Cl(-) extruder, K(+)/Cl(-) co-transporter (KCC2), because they are largely diminished by down-regulating kcc2 expression with morpholino oligonucleotides (MOs) or by blocking KCC2 function with furosemide. Thus, our findings indicate that there exists KCC2-dependent ECl difference between the ON and OFF dendrites of individual ON-OFF RGCs that may differentially affect visual processing in the ON and OFF pathways.