Deletion of equilibrative nucleoside transporter 2 disturbs energy metabolism and exacerbates disease progression in an experimental model of Huntington's disease.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease, characterized by motor dysfunction and abnormal energy metabolism. Equilibrative nucleoside transporter 1 (ENT1) and ENT2 are the major nucleoside transporters in cellular plasma membrane of the brain. Yet, unlike ENT1 whose function has been better investigated in HD, the role of ENT2 in HD remains unclear. The present study aimed to investigate the impacts of ENT2 deletion on HD using a well-characterized mouse model (R6/2). Microarray analysis, quantitative real-time polymerase chain reaction, and immunostaining of ENT2 in postmortem human brain tissues were conducted. R6/2 mice with or without genetic deletion of ENT2 were generated. Motor functions, including rotarod performance and limb-clasping test, were examined at the age of 7 to 12 weeks. Biochemical changes were evaluated by immunofluorescence staining and immunoblotting at the age of 12 to 13 weeks. In regard to energy metabolism, levels of striatal metabolites were determined by liquid chromatography coupled with the fluorescence detector or quadrupole time-of-flight mass spectrometer. Mitochondrial bioenergetics was assessed by the Seahorse assay. The results showed that ENT2 protein was detected in the neurons and astrocytes of human brains and the levels in the postmortem brain tended to be higher in patients with HD. In mice, ENT2 deletion did not alter the phenotype of the non-HD controls. Yet, ENT2 deletion deteriorated motor function and increased the number of aggregated mutant huntingtin in the striatum of R6/2 mice. Notably, disturbed energy metabolism with decreased ATP level and increased AMP/ ATP ratio was observed in R6/2-Ent2-/- mice, compared with R6/2-Ent2+/+ mice, resulting in the activation of AMPK in the late disease stage. Furthermore, ENT2 deletion reduced the NAD+/NADH ratio and impaired mitochondrial respiration in the striatum of R6/2 mice. Taken together, these findings indicate the crucial role of ENT2 in energy homeostasis, in which ENT2 deletion further impairs mitochondrial bioenergetics and deteriorates motor function in R6/2 mice.

The Critical Role of Equilibrative Nucleoside Transporter-2 in Modulating Cerebral Damage and Vascular Dysfunction in Mice with Brain Ischemia-Reperfusion.

BACKGROUND: Cerebral vascular protection is critical for stroke treatment. Adenosine modulates vascular flow and exhibits neuroprotective effects, in which brain extracellular concentration of adenosine is dramatically increased during ischemic events and ischemia-reperfusion. Since the equilibrative nucleoside transporter-2 (Ent2) is important in regulating brain adenosine homeostasis, the present study aimed to investigate the role of Ent2 in mice with cerebral ischemia-reperfusion. METHODS: Cerebral ischemia-reperfusion injury was examined in mice with transient middle cerebral artery occlusion (tMCAO) for 90 minutes, followed by 24-hour reperfusion. Infarct volume, brain edema, neuroinflammation, microvascular structure, regional cerebral blood flow (rCBF), cerebral metabolic rate of oxygen (CMRO2), and the production of reactive oxygen species (ROS) were examined following the reperfusion. RESULTS: Ent2 deletion reduced the infarct volume, brain edema, and neuroinflammation in mice with cerebral ischemia-reperfusion. tMCAO-induced disruption of brain microvessels was ameliorated in Ent2-/- mice, with a reduced expression of matrix metalloproteinases-9 and aquaporin-4 proteins. Following the reperfusion, the rCBF of the wild-type (WT) mice was quickly restored to the baseline, whereas, in Ent2-/- mice, rCBF was slowly recovered initially, but was then higher than that in the WT mice at the later phase of reperfusion. The improved CMRO2 and reduced ROS level support the beneficial effects caused by the changes in the rCBF of Ent2-/- mice. Further studies showed that the protective effects of Ent2 deletion in mice with tMCAO involve adenosine receptor A2AR. CONCLUSIONS: Ent2 plays a critical role in modulating cerebral collateral circulation and ameliorating pathological events of brain ischemia and reperfusion injury.

Changes of blood-brain-barrier function and transfer of amyloid beta in rats with collagen-induced arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is characterized by synovial inflammation, cartilage damage, and systemic inflammation. RA is also associated with the occurrence of neuroinflammation and neurodegenerative diseases. In this study, the impacts of RA on the function of the blood-brain barrier (BBB) and the disposition of amyloid beta (Aß), including BBB transport and peripheral clearance of Aß, were investigated in rats with collagen-induced arthritis (CIA), an animal model with similarity to clinical and pathological features of human RA. METHODS: CIA was induced in female Lewis rats. In addition to neuroinflammation, the integrity and function of the BBB were examined. The expression of Aß-transporting proteins at brain blood vessels was measured. Blood-to-brain influx and plasma clearance of Aß were determined. RESULTS: Both microgliosis and astrogliosis were significantly increased in the brain of CIA rats, compared with controls. In terms of BBB function, the BBB permeability of sodium fluorescein, a marker compound for BBB integrity, was significantly increased in CIA rats. Moreover, increased expression of matrix metalloproteinase-3 (MMP-3) and MMP-9 and decreased expression of tight junction proteins, zonula occludens-1 (ZO-1) and occludin, were observed in brain microvessels of CIA rats. In related to BBB transport of Aß, protein expression of the receptor of advanced glycation end product (RAGE) and P-glycoprotein (P-gp) was significantly increased in brain microvessels of CIA rats. Notably, much higher expression of RAGE was identified at the arterioles of the hippocampus of CIA rats. Following an intravenous injection of human Aß, significant higher brain influx of Aß was observed in the hippocampus of CIA rats. CONCLUSIONS: Neuroinflammation and the changes of BBB function were observed in CIA rats. The increased RAGE expression at cerebral blood vessels and enhanced blood-to-brain influx of Aß indicate the imbalanced BBB clearance of Aß in RA.

Emerging roles of dysregulated adenosine homeostasis in brain disorders with a specific focus on neurodegenerative diseases.

In modern societies, with an increase in the older population, age-related neurodegenerative diseases have progressively become greater socioeconomic burdens. To date, despite the tremendous effort devoted to understanding neurodegenerative diseases in recent decades, treatment to delay disease progression is largely ineffective and is in urgent demand. The development of new strategies targeting these pathological features is a timely topic. It is important to note that most degenerative diseases are associated with the accumulation of specific misfolded proteins, which is facilitated by several common features of neurodegenerative diseases (including poor energy homeostasis and mitochondrial dysfunction). Adenosine is a purine nucleoside and neuromodulator in the brain. It is also an essential component of energy production pathways, cellular metabolism, and gene regulation in brain cells. The levels of intracellular and extracellular adenosine are thus tightly controlled by a handful of proteins (including adenosine metabolic enzymes and transporters) to maintain proper adenosine homeostasis. Notably, disruption of adenosine homeostasis in the brain under various pathophysiological conditions has been documented. In the past two decades, adenosine receptors (particularly A1 and A2A adenosine receptors) have been actively investigated as important drug targets in major degenerative diseases. Unfortunately, except for an A2A antagonist (istradefylline) administered as an adjuvant treatment with levodopa for Parkinson's disease, no effective drug based on adenosine receptors has been developed for neurodegenerative diseases. In this review, we summarize the emerging findings on proteins involved in the control of adenosine homeostasis in the brain and discuss the challenges and future prospects for the development of new therapeutic treatments for neurodegenerative diseases and their associated disorders based on the understanding of adenosine homeostasis.

Amelioration of lipopolysaccharide-induced memory impairment in equilibrative nucleoside transporter-2 knockout mice is accompanied by the changes in glutamatergic pathways.

Neuroinflammation has been implicated in cognitive deficits in neurological and neurodegenerative diseases. Lipopolysaccharide (LPS)-induced neuroinflammation and the breakdown of the blood-brain barrier can be attenuated in mice with equilibrative nucleoside transporter-2 (ENT2/Ent2) deletion. The present study was aimed to investigate the role of ENT2 in cognitive and neuronal functions under physiological and inflammatory conditions, in terms of behavioral performance and synaptic plasticity in saline- and LPS-treated Ent2 knockout (KO) mice and their wild-type (WT) littermate controls. Repeated administrations of LPS significantly impaired spatial memory formation in Morris water maze and hippocampal-dependent long-term potentiation (LTP) in WT mice. The LPS-treated WT mice exhibited significant synaptic and neuronal damage in the hippocampus. Notably, the LPS-induced impairment in spatial memory and LTP performance were attenuated in Ent2 KO mice, along with the preservation of neuronal survival. The beneficial effects were accompanied by the normalization of excessive extracellular glutamate and aberrant downstream signaling of glutamate receptor activation, including the upregulation of phosphorylated p38 mitogen-activated protein kinase and the downregulation of phosphorylated cyclic adenosine monophosphate-response element-binding protein. There was no significant difference in behavioral outcome and all tested parameters between these two genotypes under physiological condition. These results suggest that ENT2 plays an important role in regulating inflammation-associated cognitive decline and neuronal damage.

Deletion of equilibrative nucleoside transporter-2 protects against lipopolysaccharide-induced neuroinflammation and blood-brain barrier dysfunction in mice.

Neuroinflammation is a common pathological feature of many brain diseases and is a key mediator of blood-brain barrier (BBB) breakdown and neuropathogenesis. Adenosine is an endogenous immunomodulator, whose brain extracellular level is tightly controlled by equilibrative nucleoside transporters-1 (ENT1) and ENT2. This study was aimed to investigate the role of ENTs in the modulation of neuroinflammation and BBB function. The results showed that mRNA level of Ent2 was significantly more abundant than that of Ent1 in the brain (hippocampus, cerebral cortex, striatum, midbrain, and cerebellum) of wild-type (WT) mice. Ent2-/- mice displayed higher extracellular adenosine level in the hippocampus than their littermate controls. Repeated lipopolysaccharide (LPS) treatment induced microglia activation, astrogliosis and upregulation of proinflammatory cytokines, along with aberrant BBB phenotypes (including reduced tight junction protein expression, pericyte loss, and immunoglobulin G extravasation) and neuronal apoptosis in the hippocampus of WT mice. Notably, Ent2-/- mice displayed significant resistance to LPS-induced neuroinflammation, BBB breakdown, and neurotoxicity. These findings suggest that Ent2 is critical for the modulation of brain adenosine tone and deletion of Ent2 confers protection against LPS-induced neuroinflammation and neurovascular-associated injury.

Anti-inflammatory effects of powdered product of Bu Yang Huan Wu decoction: Possible role in protecting against Transient Focal Cerebral Ischemia.

Bu Yang Huan Wu decoction (BYHW) is a traditional Chinese medicine (TCM) that consists of several herbs and has been used in patients with ischemic stroke for centuries. Although powdered formula of BYHW has widely been prescribed in clinic nowadays, evidence-based effectiveness and mechanism of action of BYHW powdered product in stroke remain to be characterized. Adult male Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 90 min followed by reperfusion for 24 h (ischemia/reperfusion; I/R) or sham surgery. After I/R, the rats were then given low dose (0.5 g/kg) and high dose (2.5 g/kg) of BYHW or vehicle by oral gavage twice a day for seven consecutive days. The results showed that I/R induced obvious cerebral infarction and neurobehavioral defects, in parallel with histological aberrations and extensive signaling of proinflammatory cytokines, including tumor necrosis factor (TNF-α) and interleukin-6 (IL-6), in the stroke model. Post-I/R treatment with BYHW powdered product significantly reduced the infarct area and ameliorated neurofunctional defects in a dose-dependent manner. The dose dependence was associated with TNF-α downregulation and interleukin-10 (IL-10) induction. In summary, the present findings demonstrated that BYHW powdered product exhibited therapeutic efficacy for experimental stroke and a higher dose treatment may strengthen the effectiveness via inflammatory modulation.

Ultrasonographic Features of Trigger Finger in Patients With Hyperuricemia.

PURPOSE: The purpose of the current study was to compare demographic differences and ultrasonographic features in primary trigger finger and trigger finger in association with hyperuricemia. METHODS: Between October 2008 and February 2010, a prospective review of consecutive cases of 54 patients with trigger finger and hyperuricemia, 76 patients with a trigger finger without hyperuricemia, and 80 control cases were enrolled. The clinical results were analyzed by descriptive epidemiology, an ultrasonographic measurement of the thickness of A1 pulley, cross-sectional area of the flexor tendon and synovium. RESULTS: The middle finger was primarily affected, followed by the index and ring fingers in both trigger finger groups. The thickness of A1 pulley, cross-sectional area of the flexor tendon, and flexor tendon with synovium in trigger finger without hyperuricemia group were significantly larger than that in trigger finger with hyperuricemia and control groups. There was no significant difference between trigger finger with hyperuricemia and control groups. Double-contour sign and tophus were only observed in trigger finger with hyperuricemia group. CONCLUSIONS: Thickness of A1 pulley, cross-sectional area of the flexor tendon, and flexor tendon with synovium were significantly larger in trigger finger without hyperuricemia group. These findings were not evident in trigger finger with hyperuricemia group.

Prediction of local relapse and distant metastasis in patients with definitive chemoradiotherapy-treated cervical cancer by deep learning from [18F]-fluorodeoxyglucose positron emission tomography/computed tomography.

BACKGROUND: We designed a deep learning model for assessing 18F-FDG PET/CT for early prediction of local and distant failures for patients with locally advanced cervical cancer. METHODS: All 142 patients with cervical cancer underwent 18F-FDG PET/CT for pretreatment staging and received allocated treatment. To augment the amount of image data, each tumor was represented as 11 slice sets each of which contains 3 2D orthogonal slices to acquire a total of 1562 slice sets. In each round of k-fold cross-validation, a well-trained proposed model and a slice-based optimal threshold were derived from a training set and used to classify each slice set in the test set into the categories of with or without local or distant failure. The classification results of each tumor were aggregated to summarize a tumor-based prediction result. RESULTS: In total, 21 and 26 patients experienced local and distant failures, respectively. Regarding local recurrence, the tumor-based prediction result summarized from all test sets demonstrated that the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 71%, 93%, 63%, 95%, and 89%, respectively. The corresponding values for distant metastasis were 77%, 90%, 63%, 95%, and 87%, respectively. CONCLUSION: This is the first study to use deep learning model for assessing 18F-FDG PET/CT images which is capable of predicting treatment outcomes in cervical cancer patients. KEY POINTS: • This is the first study to use deep learning model for assessing 18 F-FDG PET/CT images which is capable of predicting treatment outcomes in cervical cancer patients. • All 142 patients with cervical cancer underwent 18 F-FDG PET/CT for pretreatment staging and received allocated treatment. To augment the amount of image data, each tumor was represented as 11 slice sets each of which contains 3 2D orthogonal slices to acquire a total of 1562 slice sets. • For local recurrence, all test sets demonstrated that the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 71%, 93%, 63%, 95%, and 89%, respectively. The corresponding values for distant metastasis were 77%, 90%, 63%, 95%, and 87%, respectively.

Synovial fluid biomarkers: association with chronic rotator cuff tear severity and pain.

BACKGROUND: We tested the hypothesis that biomarkers in the synovial fluid of the glenohumeral (shoulder) joint are correlated with visual analog scale (VAS) scores, functional scores, and ultrasound findings of chronic rotator cuff tear (RCT) severity. METHODS: We measured biomarkers in shoulder joint synovial fluid of 42 patients with partial-thickness (21), nonmassive full-thickness (10), and massive full-thickness (11) RCTs. Pain duration, tear severity, and VAS and functional scores were compared with interleukin (IL) 1ß, IL-6, matrix metalloproteinase (MMP) 1, and MMP-13 levels. RESULTS: Both MMP-1 and MMP-13 levels were significantly highest in the massive full-thickness group. MMP-13 levels were significantly different between groups, but proinflammatory cytokine IL-1ß and IL-6 levels were not. However, IL-1ß levels were significantly positively correlated with VAS (r = 0.66; P <.01) and functional scores (r = 0.61; P <.01), but IL-6, MMP-1, and MMP-13 levels were not. CONCLUSIONS: IL-1ß levels in shoulder synovial fluid correlated positively with shoulder pain and functional scores in patients with chronic RCTs. Both MMP-1 and MMP-13 levels were altered and increased with cuff tear severity.

The critical role of Nramp1 in degrading α-synuclein oligomers in microglia under iron overload condition.

Oligomeric α-synuclein is a key mediator in the pathogenesis of Parkinson's disease (PD) and is mainly cleared by autophagy-lysosomal pathway, whose dysfunction results in the accumulation and cell-to-cell transmission of α-synuclein. In this study, concomitant with the accumulation of iron and oligomeric α-synuclein, higher expression of a lysosomal iron transporter, natural resistance-associated macrophage protein-1 (Nramp1), was observed in microglia in post-mortem striatum of sporadic PD patients. Using Nramp1-deficient macrophage (RAW264.7) and microglial (BV-2) cells as in-vitro models, iron exposure significantly reduced the degradation rate of the administered human α-synuclein oligomers, which can be restored by the expression of the wild-type, but not mutant (D543N), Nramp1. Likewise, under iron overload condition, mice with functional Nramp1 (DBA/2 and C57BL/6 congenic mice carrying functional Nramp1) had a better ability to degrade infused human α-synuclein oligomers than mice with nonfunctional Nramp1 (C57BL/6) in the brain and microglia. The interplay between iron and Nramp1 exhibited parallel effects on the clearance of α-synuclein and the activity of lysosomal cathepsin D in vitro and in vivo. Collectively, these findings suggest that the function of Nramp1 contributes to microglial degradation of oligomeric α-synuclein under iron overload condition and may be implicated in the pathogenesis of PD.

Effects of lipopolysaccharide on the expression of plasma membrane monoamine transporter (PMAT) at the blood-brain barrier and its implications to the transport of neurotoxins.

Plasma membrane monoamine transporter (PMAT) is a polyspecific organic cation transporter that is highly expressed in the central nervous system. This study aimed to investigate the effect of lipopolysaccharide on PMAT expression at the blood-brain barrier and the interaction between PMAT and neurotoxins. As a result, PMAT mRNA was identified in brain microvessels (BMVs), brain microvascular endothelial cells (BMECs), astrocytes, and pericytes isolated from C57BL/6 mice and/or Wistar rats using RT-qPCR. The immunofluorescence staining confirmed the expression of PMAT protein in BMVs and striatum of C57BL/6 mice. Western blotting demonstrated its localization at the luminal and abluminal sides of BMECs. In C57BL/6 mice, PMAT protein was significantly increased in BMVs 24 h after an intraperitoneal injection of 3 mg/kg lipopolysaccharide. Lipopolysaccharide treatment also significantly increased PMAT expression in cerebral cortex and the striatum in a time-dependent manner, as well as the brain-to-plasma ratio of 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1-benzyl-TIQ). In isolated cells, lipopolysaccharide treatment significantly increased PMAT mRNA in brain astrocytes and the BMECs co-cultured with astrocytes. In addition to 1-methyl-4-phenylpyridinium, the kinetic study indicated that both 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 1-benzyl-TIQ are substrates of human PMAT. These findings suggest that inflammation can change PMAT expression at the blood-brain barrier, which may affect PMAT-mediated transport of neurotoxins. We demonstrated the expression of plasma membrane monoamine transporter (PMAT; mRNA or protein) at several subunits of the blood-brain barrier. Lipopolysaccharide treatment can significantly increase the expression of PMAT in vivo (in brain microvessels, cerebral cortex, and the striatum of C57BL/6 mice) and in vitro (in brain astrocytes and brain microvascular endothelial cells co-cultured with astrocytes). Lipopolysaccharide treatment also increased the brain-to-plasma ratio of 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1-benzyl-TIQ) in mice, where 1-benzyl-TIQ competitively inhibited 1-methyl-4-phenylpyridinium (MPP(+)) uptake in MDCK-human PMAT (hPMAT) cells and its uptake in MDCK-hPMAT is concentration dependent.

Effects of different dosage of dexamethasone on behavioral, electrophysiological, and histomorphological recovery in a chronic sciatic nerve compression model.

OBJECTIVE: To investigate the effects of different doses of topical dexamethasone (Dex) on sciatic nerves with simulated compressive neuropathy. METHODS: Thirty-two Wistar rats were divided into four groups of 8: Sham group: no compression of the sciatic nerve + no treatment; Saline: chronic compression of the left sciatic nerve for 4 weeks + saline; 0.8% Dex: chronic compression + 0.8 mg of Dex; 3.2% Dex: chronic compression + 3.2 mg of Dex. Two sponge strips soaked with saline or Dex were placed under and over the nerve for 30 min in both Dex groups. Mixed-nerve-elicited somatosensory evoked potentials (M-SSEPs) and compound muscle action potentials (CMAPs) were measured to verify the compressive neuropathy in post-treatment follow-up. Behavioral observations of thermal hyperalgesia tests were quantified before electrophysiological examinations. Treated and contralateral nerves were harvested for histomorphological analysis. RESULTS: M-SSEP and CMAP amplitudes significantly decreased and latencies were significantly prolonged on postcompression thermal hyperalgesia tests. Rats in both Dex groups showed significant improvement in both sensory and motor conductive values and in neurological function, as well as increased mean myelin diameter on the final histomorphological examination. For rats in the saline group, these parameters showed incomplete recovery compared with the Sham group and the precompression baseline. Moreover, the changes after Dex treatment were not dose-dependent. CONCLUSIONS: Topical Dex reversed electrophysiological, behavioral, and structural changes in chronically compressed sciatic nerves. Differences between the beneficial effects of high-dose and low-dose Dex were nonsignificant.

Ultrasonographically Guided Percutaneous Carpal Tunnel Release: Early Clinical Experiences and Outcomes.

PURPOSE: To present the technique and results of ultrasonographically guided percutaneous carpal tunnel release (PCTR) in a consecutive series of patients with carpal tunnel syndrome (CTS). METHODS: We used previously defined landmarks with the "safe zones," localization, estimated size, and extent of the transverse carpal ligament (TCL) for this prospective clinical study of 91 consecutive cases of carpal tunnel release treated with this technique. The follow-up consisted of 4 time points (1 week and 2, 6, and 12 months) and a final evaluation at an average of 22.5 months. RESULTS: The sensory disturbances disappeared in 76.8%, 93.4%, 100%, and 100% of the patients at 1 week and 2, 6, and 12 months postoperatively, respectively. Moderate pain was experienced in 24.2% of patients within 1 week, in 6.6% of patients within 2 months, and in 1.1% of patients within 12 months after the operation. In the final evaluation, 2 hands were graded as unsatisfactory: one hand had moderate wrist pain without sensory disturbance, and one hand had a recurrence 14 months after the operation. There were no intraoperative or postoperative complications. CONCLUSIONS: Ultrasonographically assisted PCTR is a safe and effective procedure, but it is technically demanding and requires substantial training to be proficient in its use. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Inflammation is present in de Quervain Disease--correlation study between biochemical and histopathological evaluation.

BACKGROUND: De Quervain disease is a stenosing condition of the sheath of the abductor pollicis longus and extensor pollicis brevis tendons at the radial styloid process. Previous studies consistently reported that the pathological change of this condition is thought to be primarily an extensor retinaculum thickened by fibrosis and angiogenesis instead of inflammation. Contradictorily, the conservative treatment for de Quervain disease is anti-inflammatory medication. The inflammatory response may be involved in this disease; however, there is no present study directly evidencing whether the inflammatory responses exist in de Quervain disease or not. The histopathology of de Quervain disease is yet to be elucidated clearly. PURPOSE: To grade all specimens in the different stages and characterize specific inflammatory cell and factors to examine whether inflammatory response is involved in de Quervain disease. METHODS: Retinaculum samples were collected from 13 patients with de Quervain disease after surgery. The specimens were evaluated histologically by collagen structure grading and immunohistochemically by quantifying the presence of neutrophil elastase, macrophages, cyclooxygenase, and vascular endothelium. RESULTS: Neutrophil elastase and cyclooxygenase occur in the de Quervain disease retinaculum and increased with the grade of collagen structure. After angiogenesis, macrophage infiltration occurs in the grade II matrix worse than grade III matrix. CONCLUSIONS: Inflammation is present in de Quervain disease. This study provides direct evidence for inflammatory cell and infiltration factors and offer valuable clues for specific pharmacological therapies for de Quervain disease.

The Estrogen Receptor-ß Expression in De Quervain's Disease.

Stenosing tenosynovitis of the first dorsal compartment of the wrist (a.k.a. de Quervain's disease) is common but how estrogen is involved is still unknown. We previously reported that inflammation was involved in the pathogenesis of this ailment. In the present study, we extended our investigation of estrogen receptor (ER)-ß expression to determine whether estrogen is involved in the pathogenesis of de Quervain's. Intraoperative retinaculum samples were collected from 16 patients with the ailment. Specimens were histologically graded by collagen structure and immunohistochemically evaluated by quantifying the expression of ER-ß, interleukin (IL)-1ß and IL-6 (inflammatory cytokines), cyclooxygenase (COX)-2 (an inflammatory enzyme), and vascular endothelial growth factor (VEGF), and Von Willebrand's factor (vWF). De Quervain's occurs primarily in women. The female:male ratio in our study was 7:1. We found that ER-ß expression in the retinaculum was positively correlated with disease grade and patient age. Additionally, disease severity was associated with inflammatory factors--IL-1ß and IL-6, COX-2, and VEGF and vWF in tenosynovial tissue. The greater the levels of ER-ß expression, tissue inflammation, and angiogenesis are, the more severe de Quervain's disease is. ER-ß might be a useful target for novel de Quervain's disease therapy.

Performance of ChatGPT on Stage 1 of the Taiwanese medical licensing exam.

Introduction: Since its release by OpenAI in November 2022, numerous studies have subjected ChatGPT to various tests to evaluate its performance in medical exams. The objective of this study is to evaluate ChatGPT's accuracy and logical reasoning across all 10 subjects featured in Stage 1 of Senior Professional and Technical Examinations for Medical Doctors (SPTEMD) in Taiwan, with questions that encompass both Chinese and English. Methods: In this study, we tested ChatGPT-4 to complete SPTEMD Stage 1. The model was presented with multiple-choice questions extracted from three separate tests conducted in February 2022, July 2022, and February 2023. These questions encompass 10 subjects, namely biochemistry and molecular biology, anatomy, embryology and developmental biology, histology, physiology, microbiology and immunology, parasitology, pharmacology, pathology, and public health. Subsequently, we analyzed the model's accuracy for each subject. Result: In all three tests, ChatGPT achieved scores surpassing the 60% passing threshold, resulting in an overall average score of 87.8%. Notably, its best performance was in biochemistry, where it garnered an average score of 93.8%. Conversely, the performance of the generative pre-trained transformer (GPT)-4 assistant on anatomy, parasitology, and embryology was not as good. In addition, its scores were highly variable in embryology and parasitology. Conclusion: ChatGPT has the potential to facilitate not only exam preparation but also improve the accessibility of medical education and support continuous education for medical professionals. In conclusion, this study has demonstrated ChatGPT's potential competence across various subjects within the SPTEMD Stage 1 and suggests that it could be a helpful tool for learning and exam preparation for medical students and professionals.

The use of ultrasound for monitoring reduction and ulnar nerve subluxation in pediatric humeral supracondylar fractures.

BACKGROUND: Traditional treatment for displaced humeral supracondylar fractures (SCFs) in children involves closed reduction (CR) under fluoroscopic guidance, percutaneous pinning, and immobilization with a long-arm cast. This study aims to explore the viability of using radiation-free ultrasound (US) for guiding CR and tracking ulnar nerve dynamics during medial pinning, contrasting the US method with the conventional cross pinning technique. MATERIALS AND METHODS: We assessed 70 children with acute displaced SCFs. The US group (n = 30) underwent US-guided reduction, whereas the traditional group (n = 40) underwent fluoroscopy-guided reduction. Both groups received percutaneous cross pinning and subsequent cast immobilization. Postoperative outcomes were compared between the two methods after a 6-month follow-up. In the US group, ultrasonography assessed fracture displacement distances before and after CR. The angle at which the ulnar nerve relocated to the cubital tunnel during elbow extension was documented using real-time US monitoring during medial pinning. RESULTS: The US group demonstrated improved reduction accuracy, increased range of motion, superior restoration of both Baumann and Humeroulnar angles, and a decreased incidence of malunions compared to the traditional group (all p < 0.05). The ultrasonographic measurement of fracture displacement was comparable with that of fluoroscopy (intraclass correlation coefficient > 0.90). In the US group, no ulnar nerve injury was noted, compared to 2.5 % in the traditional group, and real-time US observations revealed ulnar nerve hypermobility, with 53.3 % of patients exhibiting anterior ulnar nerve subluxation at 120° elbow flexion, 40 % at 90°, 16.7 % at 60°, and none at 30° flexion. CONCLUSION: Ultrasound is as reliable as fluoroscopy for evaluating fracture reductions. The use of intra-operative ultrasound significantly improves reduction accuracy and radiographic outcomes while reducing the risk of ulnar nerve injury.

Early prediction of distant metastasis in patients with uterine cervical cancer treated with definitive chemoradiotherapy by deep learning using pretreatment [ 18 F]fluorodeoxyglucose positron emission tomography/computed tomography.

OBJECTIVES: A deep learning (DL) model using image data from pretreatment [ 18 F]fluorodeoxyglucose ([ 18 F] FDG)-PET or computed tomography (CT) augmented with a novel imaging augmentation approach was developed for the early prediction of distant metastases in patients with locally advanced uterine cervical cancer. METHODS: This study used baseline [18F]FDG-PET/CT images of newly diagnosed uterine cervical cancer patients. Data from 186 to 25 patients were analyzed for training and validation cohort, respectively. All patients received chemoradiotherapy (CRT) and follow-up. PET and CT images were augmented by using three-dimensional techniques. The proposed model employed DL to predict distant metastases. Receiver operating characteristic (ROC) curve analysis was performed to measure the model's predictive performance. RESULTS: The area under the ROC curves of the training and validation cohorts were 0.818 and 0.830 for predicting distant metastasis, respectively. In the training cohort, the sensitivity, specificity, and accuracy were 80.0%, 78.0%, and 78.5%, whereas, the sensitivity, specificity, and accuracy for distant failure were 73.3%, 75.5%, and 75.2% in the validation cohort, respectively. CONCLUSION: Through the use of baseline [ 18 F]FDG-PET/CT images, the proposed DL model can predict the development of distant metastases for patients with locally advanced uterine cervical cancer treatment by CRT. External validation must be conducted to determine the model's predictive performance.

Sonographically assisted percutaneous removal of screws in dynamization of the interlocking intramedullary nail.

OBJECTIVES: Dynamization is a method of removing the interlocking screw(s) farthest from the fracture site for improving healing in femoral and tibial fractures that show delayed healing after static interlocking nailing. We describe a simple sonographically assisted technique for percutaneous dynamization of deep-seated impalpable screws. METHODS: Between March 2001 and March 2005, 20 dynamization procedures were completed using the developed technique under the diagnosis of delayed healing or a nonunion at a mean of 4.8 months after index surgery. After adequately positioning the involved leg, the transducer was placed on the area of the inlet of the screw. Longitudinal and transverse sonographically scanned sections, used to show the head of the screw, were then marked on the skin where the two sections intersected. After this precise marking, a small incision on the mark allowed insertion of the screwdriver and easy percutaneous removal of the screw using only local anesthesia for pain control. RESULTS: We removed 31 screws: 9 proximal femoral screws, 20 distal femoral screws, and 2 proximal tibial screws. The mean depth of the screws was 3.4 cm. The mean operation times were 1.6 minutes for the sonographic examination and 3.5 minutes for removal of one screw. No infections or morbidities were caused by the procedure. CONCLUSIONS: Sonography is an effective tool for localizing a locked screw and facilitates percutaneous removal of screws under only local anesthesia for dynamization. This method needs no special instruments and reduces the time needed for dissecting the tissue and locating the screw.