Comparison of 16S rRNA gene sequencing microbiota among children with serological IgE-mediated food hypersensitivity.

BACKGROUND: We hypothesized that specific food hypersensitivity (FH) in children is linked to specific gut microbiota. The aim of our study was to quantify and evaluate differences in gut microbial composition among children with different IgE-mediated FH. METHODS: Children (n = 81) aged 18 to 36 months were enrolled, fecal samples of 57 children with FH and 24 healthy children were evaluated using next-generation sequencing. Individual microbial diversity and composition were analyzed via targeting the 16 S rRNA gene hypervariable V3-V5 regions. RESULTS: Children with IgE-mediated FH (in milk, egg white, soy) had significantly lower gut microbiota diversity and richness than healthy children. Children with IgE-mediated FH exhibited relatively high abundances of Firmicutes and relative underrepresentation of the phylum Bacteroidetes. We observed significant increases in relative abundances of Ruminococcaceae, Clostridiaceae, and Erysipelotrichaceae (p < 0.01, compared to control) in children with milk hypersensitivity and of Clostridiaceae and Erysipelotrichaceae (p < 0.01) in children with peanut hypersensitivity. We also found significant increases in the numbers of Clostridiaceae, Lachnospiraceae and Pasteurellaceae (p < 0.01) in children with egg white hypersensitivity. CONCLUSIONS: These findings identify early evidence of different gut microbiota development/ differentiation in children with food hypersensitivity. Specific food hypersensitivities may be associated with compositional changes in intestinal microbiota. IMPACT: These findings identify early evidence of different gut microbiota development/differentiation in children with food hypersensitivity. We built a gut microbial profile that could identify toddlers at risk for food hypersensitivity. Children with enriched Firmicutes (phylum) with partial different families may be associated with food hypersensitivity. Enriched family Clostridiaceae, Ruminococcaceae, Lachnospiraceae, or Erysipelotrichaceae in gut microbiota may be associated with specific food hypersensitivities (such as milk, egg white, peanut) in children.

A dynamic approach to support outbreak management using reinforcement learning and semi-connected SEIQR models.

BACKGROUND: Containment measures slowed the spread of COVID-19 but led to a global economic crisis. We establish a reinforcement learning (RL) algorithm that balances disease control and economic activities. METHODS: To train the RL agent, we design an RL environment with 4 semi-connected regions to represent the COVID-19 epidemic in Tokyo, Osaka, Okinawa, and Hokkaido, Japan. Every region is governed by a Susceptible-Exposed-Infected-Quarantined-Removed (SEIQR) model and has a transport hub to connect with other regions. The allocation of the synthetic population and inter-regional traveling is determined by population-weighted density. The agent learns the best policy from interacting with the RL environment, which involves obtaining daily observations, performing actions on individual movement and screening, and receiving feedback from the reward function. After training, we implement the agent into RL environments describing the actual epidemic waves of the four regions to observe the agent's performance. RESULTS: For all epidemic waves covered by our study, the trained agent reduces the peak number of infectious cases and shortens the epidemics (from 165 to 35 cases and 148 to 131 days for the 5th wave). The agent is generally strict on screening but easy on movement, except for Okinawa, where the agent is easy on both actions. Action timing analyses indicate that restriction on movement is elevated when the number of exposed or infectious cases remains high or infectious cases increase rapidly, and stringency on screening is eased when the number of exposed or infectious cases drops quickly or to a regional low. For Okinawa, action on screening is tightened when the number of exposed or infectious cases increases rapidly. CONCLUSIONS: Our experiments exhibit the potential of the RL in assisting policy-making and how the semi-connected SEIQR models establish an interactive environment for imitating cross-regional human flows.

Unlocking the Secrets Behind Advanced Artificial Intelligence Language Models in Deidentifying Chinese-English Mixed Clinical Text: Development and Validation Study.

BACKGROUND: The widespread use of electronic health records in the clinical and biomedical fields makes the removal of protected health information (PHI) essential to maintain privacy. However, a significant portion of information is recorded in unstructured textual forms, posing a challenge for deidentification. In multilingual countries, medical records could be written in a mixture of more than one language, referred to as code mixing. Most current clinical natural language processing techniques are designed for monolingual text, and there is a need to address the deidentification of code-mixed text. OBJECTIVE: The aim of this study was to investigate the effectiveness and underlying mechanism of fine-tuned pretrained language models (PLMs) in identifying PHI in the code-mixed context. Additionally, we aimed to evaluate the potential of prompting large language models (LLMs) for recognizing PHI in a zero-shot manner. METHODS: We compiled the first clinical code-mixed deidentification data set consisting of text written in Chinese and English. We explored the effectiveness of fine-tuned PLMs for recognizing PHI in code-mixed content, with a focus on whether PLMs exploit naming regularity and mention coverage to achieve superior performance, by probing the developed models' outputs to examine their decision-making process. Furthermore, we investigated the potential of prompt-based in-context learning of LLMs for recognizing PHI in code-mixed text. RESULTS: The developed methods were evaluated on a code-mixed deidentification corpus of 1700 discharge summaries. We observed that different PHI types had preferences in their occurrences within the different types of language-mixed sentences, and PLMs could effectively recognize PHI by exploiting the learned name regularity. However, the models may exhibit suboptimal results when regularity is weak or mentions contain unknown words that the representations cannot generate well. We also found that the availability of code-mixed training instances is essential for the model's performance. Furthermore, the LLM-based deidentification method was a feasible and appealing approach that can be controlled and enhanced through natural language prompts. CONCLUSIONS: The study contributes to understanding the underlying mechanism of PLMs in addressing the deidentification process in the code-mixed context and highlights the significance of incorporating code-mixed training instances into the model training phase. To support the advancement of research, we created a manipulated subset of the resynthesized data set available for research purposes. Based on the compiled data set, we found that the LLM-based deidentification method is a feasible approach, but carefully crafted prompts are essential to avoid unwanted output. However, the use of such methods in the hospital setting requires careful consideration of data security and privacy concerns. Further research could explore the augmentation of PLMs and LLMs with external knowledge to improve their strength in recognizing rare PHI.

The trends of pediatric duodenal ulcer and predictors of recurrence.

BACKGROUND: Duodenal ulcer (DU) causes various symptoms in children. The prevalence of Helicobacter pylori (Hp)-associated DU has been reducing in some regions, yet the updated trend in Taiwan is unknown. Risk factors of DU recurrence have not been comprehensively investigated in children. METHODS: This retrospective study included children diagnosed with DU to evaluate the demographics, symptoms, diagnostics, treatment, and outcomes. Specific populations (infant, surgery required) were sorted for subgroup analysis. Predictors of DU recurrence was analyzed in patients who received endoscopic follow-ups. RESULTS: A total of 488 children were included. Most patients were male (72.5%), school-aged (11.3 ± 4.8 years old), and with varied underlying diseases in one-fifth. The annual incidences were around 3-5%, with a declining trend of case numbers and the Hp-positive proportion. Hp infection, concurrent gastric ulcer, perforation, and mortality were noted in 32.7%, 16%, 1.6%, and 1% of patients. Patients with or without Hp infection showed different clinical features but similar outcomes. The characteristics of subpopulations were depicted respectively. Male sex, lower Hb level, and perforation were independent risk factors associated with recurrence. CONCLUSIONS: Hp-positive DU seems to wane. Patients with male sex, lower Hb level, or perforation at diagnosis carried a higher risk of recurrence, which may warrant active surveillance and endoscopic follow-up.

Clinical Features and Genetic Analysis of Taiwanese Primary Immunodeficiency Patients with Prolonged Diarrhea and Monogenetic Inflammatory Bowel Disease.

PURPOSE: Diarrhea lasting longer than 14 days which fails to respond to conventional management is defined as severe and protracted diarrhea and might overlap with inflammatory bowel disease (IBD). METHODS: The prevalence, associated pathogens, and prognosis of severe and protracted diarrhea without IBD (SD) and with monogenetic IBD (mono-IBD) in primary immunodeficiency patients (PID) were investigated in Taiwan. RESULTS: A total of 301 patients were enrolled between 2003 and 2022, with predominantly pediatric-onset PID. Of these, 24 PID patients developed the SD phenotype before prophylactic treatment, including Btk (six), IL2RG (four), WASP, CD40L, gp91 (three each), gp47, RAG1 (one each), CVID (two), and SCID (one) without identified mutations. The most detectable pathogens were pseudomonas and salmonella (six each), and all patients improved after approximately 2 weeks of antibiotic and/or IVIG treatments. Six (25.0%) mortalities without HSCT implementation were due to respiratory failure from interstitial pneumonia (3 SCID and 1 CGD), intracranial hemorrhage (WAS), and lymphoma (HIGM). In the mono-IBD group, seventeen patients with mutant TTC7A (2), FOXP3 (2), NEMO (2), XIAP (2), LRBA (1), TTC37 (3), IL10RA (1), STAT1 (1), ZAP70 (1), PIK3CD (1), and PIK3R1 (1) genes failed to respond to aggressive treatments. Nine mono-IBD patients with TTC7A (2), FOXP3 (2), NEMO (2), XIAP (2), and LRBA (1) mutations were fatal in the absence of HSCT. The mono-IBD group had a significantly earlier age of diarrhea onset (1.7 vs 33.3 months, p = 0.0056), a longer TPN duration (34.2 vs 7.0 months, p < 0.0001), a shorter follow-up period (41.6 vs 132.6 months, p = 0.007), and a higher mortality rate (58.9 vs 25.0%, p = 0.012) compared with the SD group. CONCLUSION: When compared to those with the SD phenotype, the mono-IBD patients had significant early-onset and poor responses to empiric antibiotics, IVIG, and steroids. Anti-inflammatory biologics and suitable HSCT still have the potential to control or even cure the mono-IBD phenotype.

Lightweight Deep Neural Network Embedded with Stochastic Variational Inference Loss Function for Fast Detection of Human Postures.

Fusing object detection techniques and stochastic variational inference, we proposed a new scheme for lightweight neural network models, which could simultaneously reduce model sizes and raise the inference speed. This technique was then applied in fast human posture identification. The integer-arithmetic-only algorithm and the feature pyramid network were adopted to reduce the computational complexity in training and to capture features of small objects, respectively. Features of sequential human motion frames (i.e., the centroid coordinates of bounding boxes) were extracted by the self-attention mechanism. With the techniques of Bayesian neural network and stochastic variational inference, human postures could be promptly classified by fast resolving of the Gaussian mixture model for human posture classification. The model took instant centroid features as inputs and indicated possible human postures in the probabilistic maps. Our model had better overall performance than the baseline model ResNet in mean average precision (32.5 vs. 34.6), inference speed (27 vs. 48 milliseconds), and model size (46.2 vs. 227.8 MB). The model could also alert a suspected human falling event about 0.66 s in advance.

Primary endoscopic variceal ligation reduced acute variceal bleeding events but not long-term mortality in pediatric-onset portal hypertension.

BACKGROUND/PURPOSE: Esophageal variceal bleeding (EVB) is a medical emergency in patients with portal hypertension (PHT). However, studies on the long-term outcomes of prophylactic endoscopic variceal ligation (EVL) in pediatric-onset PHT are lacking. METHODS: Between 1999 and 2020, patients who received EVL in the Electronic Report System of the Pediatric Endoscopy Unit were included in this retrospective study. EVL was classified as primary prophylaxis when it was performed for esophageal varices (EVs) without previous bleeding. If it was implemented in acute EVB, the subsequent EVL was classified as secondary prophylaxis. RESULTS: Fifty-eight patients aged 10 months to 33 years with 31 males were included. Thirty-eight patients were classified as primary prophylaxis group, and twenty, secondary prophylaxis group. The primary prophylaxis group experienced fewer 5-year EVB events than the secondary prophylaxis group (cumulative risk: 14.4% versus 32.4%). Still, it didn't significantly affect overall survival and biliary atresia transplant-free survival. Long-term mortality was significantly associated with higher serum direct bilirubin levels (≥0.55 mg/dL) and lower albumin levels (≤2.54 mg/dL) at the first EVL. Aspartate aminotransferase-to-platelet ratio index (APRI) with a cut-off value of 1.24 helped to predict EV presence at the initial esophagogastroduodenoscopy (EGD) (AUROC = 0.762, sensitivity 75.0%, and specificity 66.7%). CONCLUSION: Primary prophylactic EVL, despite reducing acute EVB, may not change overall survival and biliary atresia transplant-free survival. APRI > 1.24 may predict EV presence at the first EGD and help to schedule a surveillance EGD. Higher direct bilirubin and lower albumin levels at the first EVL may relate to long-term mortality.

Improvement in vocal-cord visualization with Trachway video intubating stylet using direct oxygen flow and effective analysis of the fraction of inspired oxygen: a bench study.

The Trachway video intubating stylet device facilitates the visualization of the airways of patients from the tip of an endotracheal tube (ETT) during intubation. The major limitations of Trachway are the restricted view due to secretions and the risk of a prolonged apnea during intubation. We conducted a bench study to verify the performance of an alternative, easily applicable airway device that allows better visualization of trackways during Trachway-assisted intubation and prevents the detrimental effects of apnea-related hypoxia. We conducted a bench study to thoroughly evaluate the oral-secretion-elimination ability of a newly designed oxygen delivery device (ODD) to improve vocal-cord visualization using the three commonly used ETT sizes (i.e., 7, 7.5, and 8 mm). Moreover, we measured the fraction of inspired oxygen (FiO2) under different, continuous oxygen-flow supplies (1-10 L/min) during intubation. Each condition was analyzed for a 2 min video-stylet-intubation period. The supplemental oxygen flow and FiO2 fraction achieved using our ODD were higher, and smaller ETTs exhibited better secretion elimination. The ODD, which can be easily coupled with Trachway stylets, enabled high-quality visualization during oxygen flows of 6-8 L/min, and higher FiO2 fractions were achieved at higher oxygen flow rates. The use of the ODD improved the visualization of the airways during video stylet-assisted intubations using the additional FiO2 supply. The ODD developed in this study improves the visualization of airways with Trachway stylets and enhances the safety of intubation.

Detection of pediatric hepatic steatosis through ultrasound backscattering analysis.

OBJECTIVES: Hepatic steatosis has become a considerable concern in the pediatric population. The objective of this study was to evaluate the feasibility of using ultrasound Nakagami imaging to produce a parametric image for analyzing the echo amplitude distribution to assess pediatric hepatic steatosis. METHODS: A total of 68 pediatric participants were enrolled in healthy control (n = 26) and study groups (n = 42). Raw data from ultrasound imaging were acquired for each participant analysis using AmCAD-US, a software approved by the US Food and Drug Administration for ultrasound Nakagami imaging. The Nakagami parameters were compared with the hepatic steatosis index (HSI) and the steatosis grade (G0: HSI < 30; G1: 30 ≤ HSI < 36; G2: 36 ≤ HSI < 41.6; G3: 41.6 ≤ HSI < 43; G4: HSI ≥ 43) using correlation analysis, one-way analysis of variance (ANOVA), and receiver operating characteristic (ROC) curve analysis. RESULTS: The Nakagami parameter increased from 0.53 ± 0.13 to 0.82 ± 0.05 with increasing severity of hepatic steatosis from G0 to G4 and were significantly different between the different grades of hepatic steatosis (p < .05). The areas under the ROC curves were 0.96, 0.92, 0.85, and 0.82 for diagnosing hepatic steatosis ≥ G1, ≥ G2, ≥ G3, and ≥ G4, respectively. CONCLUSIONS: The Nakagami parameter value quantifies changes in the echo amplitude distribution of ultrasound backscattered signals caused by fatty infiltration, providing a novel, noninvasive, and effective data analysis technique to detect pediatric hepatic steatosis. KEY POINTS: • Ultrasound Nakagami imaging enabled quantification of the echo amplitude distribution for tissue characterization. • The Nakagami parameter increased with the increasing severity of pediatric hepatic steatosis. • The Nakagami parameter demonstrated promising diagnostic performance in evaluating pediatric hepatic steatosis.

High initial bowel resection rate and very-early-onset inflammatory bowel disease - A challenge in a low-prevalence area.

BACKGROUND: Inflammatory bowel diseases (IBD) include ulcerative colitis (UC) and Crohn's disease (CD). The incidence in children and adolescents has risen since the 21st century globally, including Taiwan. The study aimed to disclose the characteristics and outcome of pediatric IBD (pIBD) patients in a tertiary center for the past two decades. METHODS: We retrospectively reviewed the charts of pIBD children from 2000 to 2018 in a tertiary center in Northern Taiwan. Demographics, presentations, diagnostic modalities, treatment, and outcomes were analyzed. RESULTS: A total of 38 cases were enrolled, including 27 CD and 11 UC patients. An almost 3-folds increase in incidence after 2010 was observed. Twelve cases (32%) were early-onset, and six of them (16%) were very-early-onset; four of them were detected with single-gene mutations [XIAP, TTC7A (2 siblings), and ZAP70]. Eleven CD patients (40.7%) received bowel resection at the onset, and another two (7.4%) had bowel resection years after the diagnosis. Initial bowel resection was associated with fibrostenotic/penetrating behavior, early-onset disease, and growth failure. CONCLUSION: This study demonstrated an increased incidence of pIBD in the past two decades in Taiwan, a low-prevalence region. The initial high bowel resection rate in CD was related to the fibrostenotic and/or penetrating behavior, younger age at diagnosis, and growth failure.

Computational Complexity Reduction of Neural Networks of Brain Tumor Image Segmentation by Introducing Fermi-Dirac Correction Functions.

Nowadays, deep learning methods with high structural complexity and flexibility inevitably lean on the computational capability of the hardware. A platform with high-performance GPUs and large amounts of memory could support neural networks having large numbers of layers and kernels. However, naively pursuing high-cost hardware would probably drag the technical development of deep learning methods. In the article, we thus establish a new preprocessing method to reduce the computational complexity of the neural networks. Inspired by the band theory of solids in physics, we map the image space into a noninteraction physical system isomorphically and then treat image voxels as particle-like clusters. Then, we reconstruct the Fermi-Dirac distribution to be a correction function for the normalization of the voxel intensity and as a filter of insignificant cluster components. The filtered clusters at the circumstance can delineate the morphological heterogeneity of the image voxels. We used the BraTS 2019 datasets and the dimensional fusion U-net for the algorithmic validation, and the proposed Fermi-Dirac correction function exhibited comparable performance to other employed preprocessing methods. By comparing to the conventional z-score normalization function and the Gamma correction function, the proposed algorithm can save at least 38% of computational time cost under a low-cost hardware architecture. Even though the correction function of global histogram equalization has the lowest computational time among the employed correction functions, the proposed Fermi-Dirac correction function exhibits better capabilities of image augmentation and segmentation.

A network approach to investigating the key microbes and stability of gut microbial communities in a mouse neuropathic pain model.

BACKGROUND: Neuropathic pain is an abnormally increased sensitivity to pain, especially from mechanical or thermal stimuli. To date, the current pharmacological treatments for neuropathic pain are still unsatisfactory. The gut microbiota reportedly plays important roles in inducing neuropathic pain, so probiotics have also been used to treat it. However, the underlying questions around the interactions in and stability of the gut microbiota in a spared nerve injury-induced neuropathic pain model and the key microbes (i.e., the microbes that play critical roles) involved have not been answered. We collected 66 fecal samples over 2 weeks (three mice and 11 time points in spared nerve injury-induced neuropathic pain and Sham groups). The 16S rRNA gene was polymerase chain reaction amplified, sequenced on a MiSeq platform, and analyzed using a MOTHUR- UPARSE pipeline. RESULTS: Here we show that spared nerve injury-induced neuropathic pain alters gut microbial diversity in mice. We successfully constructed reliable microbial interaction networks using the Metagenomic Microbial Interaction Simulator (MetaMIS) and analyzed these networks based on 177,147 simulations. Interestingly, at a higher resolution, our results showed that spared nerve injury-induced neuropathic pain altered both the stability of the microbial community and the key microbes in a gut micro-ecosystem. Oscillospira, which was classified as a low-abundance and core microbe, was identified as the key microbe in the Sham group, whereas Staphylococcus, classified as a rare and non-core microbe, was identified as the key microbe in the spared nerve injury-induced neuropathic pain group. CONCLUSIONS: In summary, our results provide novel experimental evidence that spared nerve injury-induced neuropathic pain reshapes gut microbial diversity, and alters the stability and key microbes in the gut.

IL-33-Responsive Group 2 Innate Lymphoid Cells Are Regulated by Female Sex Hormones in the Uterus.

Group 2 innate lymphoid cells (ILC2s) reside in multiple organs in the body, where they play roles in immunity, tissue homeostasis, and metabolic regulation. However, little is known about the regulatory mechanisms of ILC2s in different organs. Here, we identified ILC2s in the mouse uterus and found that they express cell surface molecules, including the IL-33 receptor, ST2, that are roughly comparable to those expressed by lung ILC2s. Both in vivo and in vitro treatment with IL-33 induced type 2 cytokine production in uterine ILC2s, suggesting that they respond to IL-33 in a manner similar to ILC2s in other organs. Importantly, uterine ILC2s were nearly absent in ovariectomized mice and were increased in wild-type mice by estrogen administration, whereas lung ILC2s were unaffected by both ovariectomy and estrogen administration. Likewise, a marked reduction in uterine ILC2s was observed in mice deficient in estrogen receptor α or estrogen receptor ß. Furthermore, uterine ILC2s highly expressed estrogen receptor α, and in vitro culture of isolated uterine ILC2s with 17ß-estradiol modified expression of a number of genes. Finally, an increased prevalence in neonatal mortality was observed in litters from dams lacking the IL-33 receptor, ST2. Taken together, our findings indicate that unlike lung IL2Cs, uterine ILC2s are regulated by female sex hormones, which may specialize them for specific physiological functions.

Topical tacrolimus and steroids modulate T cells in acute rejection of hand allotransplantation: Two case reports.

Acute rejection is not uncommon after vascularized composite allotransplantation. We reported the effects of adjunctive topical immunosuppressant with topical tacrolimus (Protopic®) and steroid cream (Clobetasol®) in the management of acute rejection in two hand transplantation patients. Case 1 is a 45-year-old male with distal forearm deficit 4 years ago and Case 2 is a 30-year-old male with a proximal forearm deficiency 2 years ago, respectively. Both of them suffered from occupational accident and received hand allotransplantation. Induction was performed with antithymocyte globulins and methylprednisolone. Maintenance therapy consisted of tacrolimus (FK506), mycophenolate mofetil, and prednisone. Both cases experienced acute rejection, which we treated with topical tacrolimus and Clobetasol for 2 weeks, combined with systemic immunosuppressant maintenance therapy without adding pulse-steroid therapy. Clinically, both cases recovered after adjunctive treatments. The skin biopsies showed significantly decreased perivascular lymphocyte infiltration after topical treatment. Immunohistochemical staining showed that CD3+ T-cells and CD20+ B-cells were suppressed in the recovery phase. FoxP3-positive regulatory T cells were increased after treatment. Topical tacrolimus and Clobetasol as an adjunctive treatment with maintenance systemic immunosuppressives may be useful to control acute rejection, which correlated with modulation of lymphocyte activation, especially T cells. The treatment needs further investigation with gaining more comparable data.

Association of maternal allergy with human milk soluble CD14 and fatty acids, and early childhood atopic dermatitis.

BACKGROUND: This study aimed to investigate whether maternal allergy is associated with soluble CD14 (sCD14) and fatty acid composition in different stages of lactation and the onset of atopic dermatitis (AD) in early childhood. METHODS: In total, 443 mother-child groups (445 children) were enrolled in the Prediction of Allergies in Taiwanese Children birth cohort study. Colostrum and mature milk at 2 months postpartum (2-month HM) were collected from lactating mothers. Information regarding parental allergy histories and physician-diagnosed atopic diseases was obtained using age-specific questionnaires (0-2 years). We compared sCD14 levels and the composition of 30 fatty acids in the colostrum and 2-month HM, respectively, between allergic and non-allergic mothers and between children with and without AD by the age of 2 years. RESULTS: In total, 185 (41.8%) mothers presented with allergies, and 154 (34.6%) children had physician-diagnosed AD by the age of 2 years. Both in the colostrum and 2-month HM of 289 lactating mothers, sCD14 levels were significantly lower in allergic mothers whose children presented with AD compared with children who did not (P = 0.015 and 0.044, respectively). Among the children with AD who were born to non-allergic mothers, sCD14 levels were lower. However, the result was not statistically significant (P = 0.376 and 0.264, respectively). Our data revealed the lack of associations between fatty acid composition and AD (P > 0.05). CONCLUSION: Decreased sCD14 levels in the colostrum and 2-month HM were associated with AD at 2 years of age, particularly among children born to mothers with allergies.

Bone infarction of the hip after hand allotransplantation: A case report.

Vascularized composite allotransplantation represents as an emerging field in reconstructive surgery. However, some complications can be associated with the procedure. The authors describe a case of bone infarctions of the bilateral hip joints following the first hand allotransplantation in Taiwan. A 45-year-old man who experienced a traumatic amputation of the distal third of his forearm received a hand transplantation from a brain-dead donor. Immunosuppression included antithymocyte globulins, and bolus methylprednisolone (Solu-Medrol) was used for the induction. The maintenance therapy protocol included systemic tacrolimus, mycophenolate mofetil, and prednisone. The patient discontinued the systemic steroid 15 months after surgery. Two episodes of acute rejections were observed at 105 and 810 days after surgery. These signs disappeared after pulse therapy with Solu-Medrol, titration with tacrolimus, and topical immunosuppressive creams (tacrolimus and clobetasol). However, the patient felt pain in both hips after long periods of standing 30 months after the transplantation. A pelvic radiograph and magnetic resonance imaging revealed avascular necrosis (AVN) in both hip joints. Because of the progressive worsening of the pain, the patient underwent a decompression surgery on the left hip involving a fibula bone graft. The patient underwent a right hip hemi-arthroplasty with a bipolar prosthesis 3 months later. The patient remained in good health without major complications. These findings indicate that systemic steroids and tacrolimus might be the major predisposing factors for the induction of AVN after hand allotransplantation.

Chronic Neuropathic Pain Protects the Heart from Ischemia-Reperfusion Injury.

The prevalence of chronic pain increases with age. The pain occurrence in the elderly ranges from 25% to 80% in different countries. Ischemic heart disease is also prevailing in the aged people. Restored blood flow quickly rescues myocardium but also causes ischemia-reperfusion (IR) injury. Brief episodes of ischemia at a distant organ could reduce the myocardial reperfusion injury. This is called remote ischemic preconditioning (RIPC) cardioprotection. Several circulating factors and neurogenic signals contribute to the cardioprotection by RIPC. Preinfarction angina, a form of chest pain, is associated with significant cardioprotection in myocardial infarction patients. Activation of peripheral nociception also induces cardioprotection against IR injury via neurogenic pathway. It is possible that angina also induces nociceptive signal pathway to provide cardioprotection. It is unclear whether pre-existing chronic pain will also have a cardioprotection effect. We recently reported chronic neuropathic pain attenuates cardiac IR injury in mice. ERK activation in anterior nucleus of paraventricular thalamus (PVA) is required for this remote cardioprotection. Direct activation of PVA neurons also provides cardioprotection against cardiac IR injury. Chronic neuropathic pain-induced cardioprotection requires activation of parasympathetic nerves. This review summarizes the potential interaction of chronic pain and cardiac IR injury.

Excavatolide-B Enhances Contextual Memory Retrieval via Repressing the Delayed Rectifier Potassium Current in the Hippocampus.

Memory retrieval dysfunction is a symptom of schizophrenia, autism spectrum disorder (ASD), and absence epilepsy (AE), as well as an early sign of Alzheimer's disease. To date, few drugs have been reported to enhance memory retrieval. Here, we found that a coral-derived natural product, excavatolide-B (Exc-B), enhances contextual memory retrieval in both wild-type and Cav3.2-/- mice via repressing the delayed rectifier potassium current, thus lowering the threshold for action potential initiation and enhancing induction of long-term potentiation (LTP). The human CACNA1H gene encodes a T-type calcium channel (Cav3.2), and its mutation is associated with schizophrenia, ASD, and AE, which are all characterized by abnormal memory function. Our previous publication demonstrated that Cav3.2-/- mice exhibit impaired contextual-associated memory retrieval, whilst their retrieval of spatial memory and auditory cued memory remain intact. The effect of Exc-B on enhancing the retrieval of context-associated memory provides a hope for novel drug development.

IL-33 dysregulates regulatory T cells and impairs established immunologic tolerance in the lungs.

BACKGROUND: Airway exposure to environmental antigens generally leads to immunologic tolerance. A fundamental question remains: Why is airway tolerance compromised in patients with allergic airway diseases? IL-33 promotes innate and adaptive type 2 immunity and might provide the answer to this question. OBJECTIVE: The goal of this study was to investigate the roles played by IL-33 in altering regulatory T (Treg) cells in the lungs and in affecting previously established airway immunologic tolerance. METHODS: We analyzed CD4+ forkhead box P3 (Foxp3)+ Treg cells that were isolated from the lungs of naive BALB/c mice and those treated with IL-33. Airway tolerance and allergen-induced airway inflammation models in mice were used to investigate how IL-33 affects established immunologic tolerance in vivo. RESULTS: CD4+Foxp3+ Treg cells in the lungs expressed the IL-33 receptor ST2. When exposed to IL-33, Treg cells upregulated their expression of the canonical TH2 transcription factor GATA3, as well as ST2, and produced type 2 cytokines. Treg cells lost their ability to suppress effector T cells in the presence of IL-33. Airway administration of IL-33 with an antigen impaired immunologic tolerance in the lungs that had been established by prior exposure to the antigen. Dysregulated Foxp3+ Treg cells with distinct characteristics of TH2 cells increased in the lungs of mice undergoing IL-33-dependent allergen-driven airway inflammation. CONCLUSIONS: IL-33 dysregulated lung Treg cells and impaired immunologic tolerance to inhaled antigens. Established airway tolerance might not be sustained in the presence of an innate immunologic stimulus, such as IL-33.

The type VI adenylyl cyclase protects cardiomyocytes from ß-adrenergic stress by a PKA/STAT3-dependent pathway.

BACKGROUND: The type VI adenylyl cyclase (AC6) is a main contributor of cAMP production in the heart. The amino acid (aa) sequence of AC6 is highly homologous to that of another major cardiac adenylyl cyclase, AC5, except for its N-terminus (AC6-N, aa 1-86). Activation of AC6, rather than AC5, produces cardioprotective effects against heart failure, while the underlying mechanism remains to be unveiled. Using an AC6-null (AC6-/-) mouse and a knockin mouse with AC6-N deletion (AC6 ΔN/ΔN), we aimed to investigate the cardioprotective mechanism of AC6 in the heart. METHODS: Western blot analysis and immunofluorescence staining were performed to determine the intracellular distribution of AC6, AC6-ΔN (a truncated AC6 lacking the first 86 amino acids), and STAT3 activation. Activities of AC6 and AC6-ΔN in the heart were assessed by cAMP assay. Apoptosis of cardiomyocytes were evaluated by the TUNEL assay and a propidium iodine-based survival assay. Fibrosis was examined by collagen staining. RESULTS: Immunofluorescence staining revealed that cardiac AC6 was mainly anchored on the sarcolemmal membranes, while AC6-ΔN was redistributed to the sarcoplasmic reticulum. AC6ΔN/ΔN and AC6-/- mice had more apoptotic myocytes and cardiac remodeling than WT mice in experimental models of isoproterenol (ISO)-induced myocardial injury. Adult cardiomyocytes isolated from AC6ΔN/ΔN or AC6-/- mice survived poorly after exposure to ISO, which produced no effect on WT cardiomyocytes under the condition tested. Importantly, ISO treatment induced cardiac STAT3 phosphorylation/activation in WT mice, but not in AC6ΔN/ΔN and AC6-/- mice. Pharmacological blockage of PKA-, Src-, or STAT3- pathway markedly reduced the survival of WT myocytes in the presence of ISO, but did not affect those of AC6ΔN/ΔN and AC6-/- myocytes, suggesting an important role of AC6 in mediating cardioprotective action through the activation of PKA-Src-STAT3-signaling. CONCLUSIONS: Collectively, AC6-N controls the anchorage of cardiac AC6 on the sarcolemmal membrane, which enables the coupling of AC6 with the pro-survival PKA-STAT3 pathway. Our findings may facilitate the development of novel therapies for heart failure.