RNA therapeutics for regenerative medicine.

It is estimated that millions of people around the world experience various types of tissue injuries every year. Regenerative medicine was born and developed for understanding and application with the aim of replacing affected organs or some cells. The research, manufacture, production, and distribution of RNA in cells have acted as a basic foundation for the development and testing of therapies and treatments that are widely applied in different fields of medicine. Vaccines against COVID-19 are considered one of the brilliant and outstanding successes of RNA therapeutics research. With the characteristics of bio-derived RNA therapeutics, the mechanism of rapid implementation, safe production, and flexibility to create proteins depending on actual requirements. Based on the advantages above in this review, we discuss RNA therapeutics for regenerative medicine, and the types of RNA therapies currently being used for regenerative medicine. The relationship between disease and regenerative medicine is currently being studied or tested in RNA therapeutics. We have also covered the mechanisms of action of RNA therapy for regenerative medicine and some of the limitations in our current understanding of the effects of RNA therapy in this area. Additionally, we have also covered developing RNA therapeutics for regenerative medicine, focusing on RNA therapeutics for regenerative medicine. As a final point, we discuss potential applications for therapeutics for regenerative medicine in the future, as well as their mechanisms.

Ultrahigh frequency transcutaneous electrical nerve stimulation for neuropathic pain alleviation and neuromodulation.

A challenging complication in patients with peripheral compressive neuropathy is neuropathic pain. Excessive neuroinflammation at the injury site worsens neuropathic pain and impairs function. Currently, non-invasive modulation techniques like transcutaneous electrical nerve stimulation (TENS) have shown therapeutic promise with positive results. However, the underlying regulatory molecular mechanism for pain relief remains complex and unexplored. This study aimed to validate the therapeutic effect of ultrahigh frequency (UHF)-TENS in chronic constriction injury of the rat sciatic nerve. Alleviation of mechanical allodynia was achieved through the application of UHF-TENS, lasting for 3 days after one session of therapy and 4 days after two sessions, without causing additional damage to the myelinated axon structure. The entire tissue collection schedule was divided into four time points: nerve exposure surgery, 7 days after nerve ligation, and 1 and 5 days after one session of UHF therapy. Significant reductions in pain-related neuropeptides, MEK, c-Myc, c-FOS, COX2, and substance P, were observed in the injured DRG neurons after UHF therapy. RNA sequencing of differential gene expression in sensory neurons revealed significant downregulation in Cables, Pik3r1, Vps4b, Tlr7, and Ezh2 after UHF therapy, while upregulation was observed in Nfkbie and Cln3. UHF-TENS effectively and safely relieved neuropathic pain without causing further nerve damage. The decreased production of pain-related neuropeptides within the DRG provided the therapeutic benefit. Possible molecular mechanisms behind UHF-TENS may result from the modulation of the NF-κB complex, toll-like receptor-7, and phosphoinositide 3-kinase/Akt signaling pathways. These results suggest the neuromodulatory effects of UHF-TENS in rat sciatic nerve chronic constriction injury, including alleviation of neuropathic pain, amelioration of pain-related neuropeptides, and regulation of neuroinflammatory gene expression. In combination with the regulation of related neuroinflammatory genes, UHF-TENS could become a new modality for enhancing the treatment of neuropathic pain in the future.

RNA therapeutics for metabolic disorders.

The prevalence of metabolic disorders is increasing exponentially and has recently reached epidemic levels. Over the decades, a large number of therapeutic options have been proposed to manage these diseases but still show several limitations. In this circumstance, RNA therapeutics have rapidly emerged as a new hope for patients with metabolic diseases. 57 years have elapsed from the discovery of mRNA, a large number of RNA-based drug candidates have been evaluated for their therapeutic effectiveness and clinical safety under clinical studies. To date, there are seven RNA drugs for treating metabolic disorders receiving official approval and entering the global market. Their targets include hereditary transthyretin-mediated amyloidosis (hATTR), familial chylomicronemia syndrome, acute hepatic porphyria, primary hyperoxaluria type 1 and hypercholesterolemia, which are all related to liver proteins. All of these seven RNA drugs are antisense oligonucleotides (ASO) and small interfering RNA (siRNA). These two types of treatment are both based on oligonucleotides complementary to target RNA through Watson-Crick base-pairing, but their mechanisms of action include different nucleases. Such treatments show greatest potential among all types of RNA therapeutics due to consecutive achievements in chemical modifications. Another method, mRNA therapeutics also promise a brighter future for patients with a handful of drug candidates currently under development.

Adipose-derived stem cells modulate neuroinflammation and improve functional recovery in chronic constriction injury of the rat sciatic nerve.

Introduction: Compressive neuropathy, a common chronic traumatic injury of peripheral nerves, leads to variable impairment in sensory and motor function. Clinical symptoms persist in a significant portion of patients despite decompression, with muscle atrophy and persistent neuropathic pain affecting 10%-25% of cases. Excessive inflammation and immune cell infiltration in the injured nerve hinder axon regeneration and functional recovery. Although adipose-derived stem cells (ASCs) have demonstrated neural regeneration and immunomodulatory potential, their specific effects on compressive neuropathy are still unclear. Methods: We conducted modified CCI models on adult male Sprague-Dawley rats to induce irreversible neuropathic pain and muscle atrophy in the sciatic nerve. Intraneural ASC injection and nerve decompression were performed. Behavioral analysis, muscle examination, electrophysiological evaluation, and immunofluorescent examination of the injured nerve and associated DRG were conducted to explore axon regeneration, neuroinflammation, and the modulation of inflammatory gene expression. Transplanted ASCs were tracked to investigate potential beneficial mechanisms on the local nerve and DRG. Results: Persistent neuropathic pain was induced by chronic constriction of the rat sciatic nerve. Local ASC treatment has demonstrated robust beneficial outcomes, including the alleviation of mechanical allodynia, improvement of gait, regeneration of muscle fibers, and electrophysiological recovery. In addition, locally transplanted ASCs facilitated axon remyelination, alleviated neuroinflammation, and reduced inflammatory cell infiltration of the injured nerve and associated dorsal root ganglion (DRG). Trafficking of the transplanted ASC preserved viability and phenotype less than 7 days but contributed to robust immunomodulatory regulation of inflammatory gene expression in both the injured nerve and DRG. Discussion: Locally transplanted ASC on compressed nerve improve sensory and motor recoveries from irreversible chronic constriction injury of rat sciatic nerve via alleviation of both local and remote neuroinflammation, suggesting the promising role of adjuvant ASC therapies for clinical compressive neuropathy.

Physical processing for decellularized nerve xenograft in peripheral nerve regeneration.

In severe or complex cases of peripheral nerve injuries, autologous nerve grafts are the gold standard yielding promising results, but limited availability and donor site morbidity are some of its disadvantages. Although biological or synthetic substitutes are commonly used, clinical outcomes are inconsistent. Biomimetic alternatives derived from allogenic or xenogenic sources offer an attractive off-the-shelf supply, and the key to successful peripheral nerve regeneration focuses on an effective decellularization process. In addition to chemical and enzymatic decellularization protocols, physical processes might offer identical efficiency. In this comprehensive minireview, we summarize recent advances in the physical methods for decellularized nerve xenograft, focusing on the effects of cellular debris clearance and stability of the native architecture of a xenograft. Furthermore, we compare and summarize the advantages and disadvantages, indicating the future challenges and opportunities in developing multidisciplinary processes for decellularized nerve xenograft.

The Clinical Observation of Inflammation Theory for Depression: The Initiative of the Formosa Long COVID Multicenter Study (FOCuS).

There is growing evidence that the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with increased risks of psychiatric sequelae. Depression, anxiety, cognitive impairments, sleep disturbance, and fatigue during and after the acute phase of COVID-19 are prevalent, long-lasting, and exerting negative consequences on well-being and imposing a huge burden on healthcare systems and society. This current review presented timely updates of clinical research findings, particularly focusing on the pathogenetic mechanisms underlying the neuropsychiatric sequelae, and identified potential key targets for developing effective treatment strategies for long COVID. In addition, we introduced the Formosa Long COVID Multicenter Study (FOCuS), which aims to apply the inflammation theory to the pathogenesis and the psychosocial and nutrition treatments of post-COVID depression and anxiety.

Arsenic compounds activate MAPK and inhibit Akt pathways to induce apoptosis in MA-10 mouse Leydig tumor cells.

Arsenic compounds have been applied treating acute promyelocytic 1eukemia and solid tumors with brief mechanism investigations. In fact, we have demonstrated that sodium arsenite plus dimethylarsenic acid could activate apoptosis in MA-10 mouse Leydig tumor cells by inducing caspase pathways. However, detail underlying mechanisms how caspase cascade is regulated remains elusive. Therefore, the apoptotic mechanism of sodium arsenite plus dimethylarsenic acid were examined in MA-10 cells in this study. Our results reveal that Fas/FasL protein expressions were stimulated by sodium arsenite plus dimethylarsenic acid in MA-10 cells. In addition, reactive oxygen species (ROS) generation, cytochrome C release, Bid truncation, and Bax translocation were induced in MA-10 cells by arsenic compounds. Moreover, activation of p38, JNK and ERK1/2, MAPK pathways was stimulated while Akt phosphorylated levels and Akt expression were decreased by sodium arsenite plus dimethylarsenic in MA-10 cells. In conclusion, sodium arsenite and dimethylarsenic acid did activate MAPK pathway plus ROS generation, but suppress Akt pathway, to modulate caspase pathway and then induce MA-10 cell apoptosis.

Training a Deep Contextualized Language Model for International Classification of Diseases, 10th Revision Classification via Federated Learning: Model Development and Validation Study.

BACKGROUND: The automatic coding of clinical text documents by using the International Classification of Diseases, 10th Revision (ICD-10) can be performed for statistical analyses and reimbursements. With the development of natural language processing models, new transformer architectures with attention mechanisms have outperformed previous models. Although multicenter training may increase a model's performance and external validity, the privacy of clinical documents should be protected. We used federated learning to train a model with multicenter data, without sharing data per se. OBJECTIVE: This study aims to train a classification model via federated learning for ICD-10 multilabel classification. METHODS: Text data from discharge notes in electronic medical records were collected from the following three medical centers: Far Eastern Memorial Hospital, National Taiwan University Hospital, and Taipei Veterans General Hospital. After comparing the performance of different variants of bidirectional encoder representations from transformers (BERT), PubMedBERT was chosen for the word embeddings. With regard to preprocessing, the nonalphanumeric characters were retained because the model's performance decreased after the removal of these characters. To explain the outputs of our model, we added a label attention mechanism to the model architecture. The model was trained with data from each of the three hospitals separately and via federated learning. The models trained via federated learning and the models trained with local data were compared on a testing set that was composed of data from the three hospitals. The micro F1 score was used to evaluate model performance across all 3 centers. RESULTS: The F1 scores of PubMedBERT, RoBERTa (Robustly Optimized BERT Pretraining Approach), ClinicalBERT, and BioBERT (BERT for Biomedical Text Mining) were 0.735, 0.692, 0.711, and 0.721, respectively. The F1 score of the model that retained nonalphanumeric characters was 0.8120, whereas the F1 score after removing these characters was 0.7875-a decrease of 0.0245 (3.11%). The F1 scores on the testing set were 0.6142, 0.4472, 0.5353, and 0.2522 for the federated learning, Far Eastern Memorial Hospital, National Taiwan University Hospital, and Taipei Veterans General Hospital models, respectively. The explainable predictions were displayed with highlighted input words via the label attention architecture. CONCLUSIONS: Federated learning was used to train the ICD-10 classification model on multicenter clinical text while protecting data privacy. The model's performance was better than that of models that were trained locally.

Autologous Platelet-Rich Growth Factor Reduces M1 Macrophages and Modulates Inflammatory Microenvironments to Promote Sciatic Nerve Regeneration.

The failure of peripheral nerve regeneration is often associated with the inability to generate a permissive molecular and cellular microenvironment for nerve repair. Autologous therapies, such as platelet-rich plasma (PRP) or its derivative platelet-rich growth factors (PRGF), may improve peripheral nerve regeneration via unknown mechanistic roles and actions in macrophage polarization. In the current study, we hypothesize that excessive and prolonged inflammation might result in the failure of pro-inflammatory M1 macrophage transit to anti-inflammatory M2 macrophages in large nerve defects. PRGF was used in vitro at the time the unpolarized macrophages (M0) macrophages were induced to M1 macrophages to observe if PRGF altered the secretion of cytokines and resulted in a phenotypic change. PRGF was also employed in the nerve conduit of a rat sciatic nerve transection model to identify alterations in macrophages that might influence excessive inflammation and nerve regeneration. PRGF administration reduced the mRNA expression of tumor necrosis factor-α (TNFα), interleukin-1ß (IL-1ß), and IL-6 in M0 macrophages. Increased CD206 substantiated the shift of pro-inflammatory cytokines to the M2 regenerative macrophage. Administration of PRGF in the nerve conduit after rat sciatic nerve transection promoted nerve regeneration by improving nerve gross morphology and its targeted gastrocnemius muscle mass. The regenerative markers were increased for regrown axons (protein gene product, PGP9.5), Schwann cells (S100ß), and myelin basic protein (MBP) after 6 weeks of injury. The decreased expression of TNFα, IL-1ß, IL-6, and CD68+ M1 macrophages indicated that the inflammatory microenvironments were reduced in the PRGF-treated nerve tissue. The increase in RECA-positive cells suggested the PRGF also promoted angiogenesis during nerve regeneration. Taken together, these results indicate the potential role and clinical implication of autologous PRGF in regulating inflammatory microenvironments via macrophage polarization after nerve transection.

Automatic International Classification of Diseases Coding System: Deep Contextualized Language Model With Rule-Based Approaches.

BACKGROUND: The tenth revision of the International Classification of Diseases (ICD-10) is widely used for epidemiological research and health management. The clinical modification (CM) and procedure coding system (PCS) of ICD-10 were developed to describe more clinical details with increasing diagnosis and procedure codes and applied in disease-related groups for reimbursement. The expansion of codes made the coding time-consuming and less accurate. The state-of-the-art model using deep contextual word embeddings was used for automatic multilabel text classification of ICD-10. In addition to input discharge diagnoses (DD), the performance can be improved by appropriate preprocessing methods for the text from other document types, such as medical history, comorbidity and complication, surgical method, and special examination. OBJECTIVE: This study aims to establish a contextual language model with rule-based preprocessing methods to develop the model for ICD-10 multilabel classification. METHODS: We retrieved electronic health records from a medical center. We first compared different word embedding methods. Second, we compared the preprocessing methods using the best-performing embeddings. We compared biomedical bidirectional encoder representations from transformers (BioBERT), clinical generalized autoregressive pretraining for language understanding (Clinical XLNet), label tree-based attention-aware deep model for high-performance extreme multilabel text classification (AttentionXLM), and word-to-vector (Word2Vec) to predict ICD-10-CM. To compare different preprocessing methods for ICD-10-CM, we included DD, medical history, and comorbidity and complication as inputs. We compared the performance of ICD-10-CM prediction using different preprocesses, including definition training, external cause code removal, number conversion, and combination code filtering. For the ICD-10 PCS, the model was trained using different combinations of DD, surgical method, and key words of special examination. The micro F1 score and the micro area under the receiver operating characteristic curve were used to compare the model's performance with that of different preprocessing methods. RESULTS: BioBERT had an F1 score of 0.701 and outperformed other models such as Clinical XLNet, AttentionXLM, and Word2Vec. For the ICD-10-CM, the model had an F1 score that significantly increased from 0.749 (95% CI 0.744-0.753) to 0.769 (95% CI 0.764-0.773) with the ICD-10 definition training, external cause code removal, number conversion, and combination code filter. For the ICD-10-PCS, the model had an F1 score that significantly increased from 0.670 (95% CI 0.663-0.678) to 0.726 (95% CI 0.719-0.732) with a combination of discharge diagnoses, surgical methods, and key words of special examination. With our preprocessing methods, the model had the highest area under the receiver operating characteristic curve of 0.853 (95% CI 0.849-0.855) and 0.831 (95% CI 0.827-0.834) for ICD-10-CM and ICD-10-PCS, respectively. CONCLUSIONS: The performance of our model with the pretrained contextualized language model and rule-based preprocessing method is better than that of the state-of-the-art model for ICD-10-CM or ICD-10-PCS. This study highlights the importance of rule-based preprocessing methods based on coder coding rules.

The Antimicrobial Effects of Bacterial Cellulose Produced by Komagataeibacter intermedius in Promoting Wound Healing in Diabetic Mice.

As a conventional medical dressing, medical gauze does not adequately protect complex and hard-to-heal diabetic wounds and is likely to permit bacterial entry and infections. Therefore, it is necessary to develop novel dressings to promote wound healing in diabetic patients. Komagataeibacter intermedius was used to produce unmodified bacterial cellulose, which is rarely applied directly to diabetic wounds. The produced cellulose was evaluated for wound recovery rate, level of inflammation, epidermal histopathology, and antimicrobial activities in treated wounds. Diabetic mices' wounds treated with bacterial cellulose healed 1.63 times faster than those treated with gauze; the values for the skin indicators in bacterial cellulose treated wounds were more significant than those treated with gauze. Bacterial cellulose was more effective than gauze in promoting tissue proliferation with more complete epidermal layers and the formation of compact collagen in the histological examination. Moreover, wounds treated with bacterial cellulose alone had less water and glucose content than those treated with gauze; this led to an increase of 6.82 times in antimicrobial protection, lower levels of TNF-α and IL-6 (39.6% and 83.2%), and higher levels of IL-10 (2.07 times) than in mice wounds treated with gauze. The results show that bacterial cellulose produced using K. intermedius beneficially affects diabetic wound healing and creates a hygienic microenvironment by preventing inflammation. We suggest that bacterial cellulose can replace medical gauze as a wound dressing for diabetic patients.

Investigation of Neuropathology after Nerve Release in Chronic Constriction Injury of Rat Sciatic Nerve.

Peripheral compressive neuropathy causes significant neuropathic pain, muscle weakness and prolong neuroinflammation. Surgical decompression remains the gold standard of treatment but the outcome is suboptimal with a high recurrence rate. From mechanical compression to chemical propagation of the local inflammatory signals, little is known about the distinct neuropathologic patterns and the genetic signatures after nerve decompression. In this study, controllable mechanical constriction forces over rat sciatic nerve induces irreversible sensorimotor dysfunction with sustained local neuroinflammation, even 4 weeks after nerve release. Significant gene upregulations are found in the dorsal root ganglia, regarding inflammatory, proapoptotic and neuropathic pain signals. Genetic profiling of neuroinflammation at the local injured nerve reveals persistent upregulation of multiple genes involving oxysterol metabolism, neuronal apoptosis, and proliferation after nerve release. Further validation of the independent roles of each signal pathway will contribute to molecular therapies for compressive neuropathy in the future.

A method to measure the extent of myocardial ischemia and steal with SPECT myocardial blood flow quantitation.

OBJECTIVE: We introduced a method to measure the extent of myocardial ischemia and steal with SPECT MBF quantitation. METHODS: Eighty-seven patients who received rest/Dipyridamole-stress 99mTc-Sestamibi (MIBI) dynamic SPECT scans and coronary angiography were included. Dynamic SPECT images were reconstructed with full physical corrections. The one-tissue kinetic model was utilized to quantify K1 and further converted to MBF with required corrections. Rest MBF, stress MBF and myocardial flow reserve (MFR) were converted to a flow status polar map by a flow diagram. Extents of 7 flow statuses were verified their cutoff points for detecting stenoses. The diagnostic performance (DP) was compared to that of MFR. RESULTS: Cutoff point of the extent to detect ≥ 50% stenosis was 3.01% for ischemia-steal status and 20.3% for the combined status of ischemia-steal and moderate. Using these criteria, sensitivity, specificity and accuracy to detect ≥ 50% stenosis were (80%, 75%, 79%) and (86%, 68%, 80%) for ≥ 70% stenosis. The DP was superior to that of MFR < 2.0 criterion (≥ 50%: 70%, 63%, 69%; ≥ 70%: 73%, 61%, 69%) (all p < 0.015). CONCLUSION: SPECT MBF quantitation integrated with the flow diagram can measure the extent of myocardial ischemia and steal which appeared more accurate to detect angiographic stenoses than the single MFR parameter.

The association between denture self-satisfaction rates and OHRQoL - a follow-up study.

BACKGROUD: The objectives of this study were to try to identify the key dimension in satisfaction from the combination of satisfaction clusters, and its effect on the change of OHRQoL(Oral Health-related Quality of Life) of elderly denture users. METHODS: This follow-up study was conducted in subjects aged 65 years and over. All participants (n = 2128) completed questionnaires before and approximately 6 months after receiving complete denture. Information obtained by questionnaire included demographic characteristics, patients' self-satisfaction rate and OHRQoL. The 6 satisfaction dimensions (including speaking, stability, esthetic, chewing, doctor and general dimensions) were classified as 5 cluster groups, which is the group of not at all satisfied in all dimensions (NAS); only satisfied with doctor and general dimensions(SDG); moderate satisfaction group(MS); quite satisfied group(QS); the highly satisfied group(HS) by an analysis of PCA (Principle component analysis) and CA (cluster analysis). Multiple linear regression was adapted to estimate the association between satisfaction and the responsiveness of OHIP-7T (Oral Health Impact Profile). RESULTS: When compared to the cluster "NAS", the greatest improvement of OHRQoL after treatment was found in the group "HS" (ß = 7.31(6.26-8.36), followed by group "QS" (ß = 4.71(3.54-5.87)), group "MS" (ß = 4.33(2.92-5.74)) and group "SDG" (ß = 3.25(2.10-4.41)). An increasing trend was detected in patient-rating satisfaction and OHRQoL. The satisfaction cluster group is an important factor of OHRQoL after adjusting for other confounders. CONCLUSION: Psychological-related aspects is the greatest impacting dimension on OHRQoL among denture wearers in Taiwan elderly. Better communication from the dental professional team with denture patients would improve their OHRQoL.

Dermoid cyst with secretion of CA 19-9 detected by 18F-FDG PET/CT: A case report.

INTRODUCTION: Carbohydrate antigen 19-9 (CA 19-9) is a tumor glycolipid, frequently elevated in the serum of patients due to malignancies from gastrointestinal organs; in particular, the pancreas. This carbohydrate antigen is also expressed in benign diseases. PATIENT CONCERNS: A case of a 27-year-old female who has an unknown origin CA 19-9 elevation for 2 years. DIAGNOSIS: After the left ovarian cystectomy and microscopic examination, the final diagnosis is a dermoid cyst. The dermoid cyst shows increased F-fluorodeoxyglucose (F-FDG) uptake in the F-FDG positron emission tomography (PET)/computed tomography (CT) study. INTERVENTION AND OUTCOMES: The laparoscopic oophorocystectomy was performed. It was observed that the patient's CA 19-9 level returned to normal after the surgery 6 months later. This showed that the dermoid cyst was responsible for the abnormal CA 19-9 level. CONCLUSION: In this case, we can learn that the F-FDG PET/CT scan has potential use in patients with unknown origin of elevation CA 19-9.

Efficient Prodrug Activator Gene Therapy by Retroviral Replicating Vectors Prolongs Survival in an Immune-Competent Intracerebral Glioma Model.

Prodrug activator gene therapy mediated by murine leukemia virus (MLV)-based retroviral replicating vectors (RRV) was previously shown to be highly effective in killing glioma cells both in culture and in vivo. To avoid receptor interference and enable dual vector co-infection with MLV-RRV, we have developed another RRV based on gibbon ape leukemia virus (GALV) that also shows robust replicative spread in a wide variety of tumor cells. We evaluated the potential of GALV-based RRV as a cancer therapeutic agent by incorporating yeast cytosine deaminase (CD) and E. coli nitroreductase (NTR) prodrug activator genes into the vector. The expression of CD and NTR genes from GALV-RRV achieved highly efficient delivery of these prodrug activator genes to RG-2 glioma cells, resulting in enhanced cytotoxicity after administering their respective prodrugs 5-fluorocytosine and CB1954 in vitro. In an immune-competent intracerebral RG-2 glioma model, GALV-mediated CD and NTR gene therapy both significantly suppressed tumor growth with CB1954 administration after a single injection of vector supernatant. However, NTR showed greater potency than CD, with control animals receiving GALV-NTR vector alone (i.e., without CB1954 prodrug) showing extensive tumor growth with a median survival time of 17.5 days, while animals receiving GALV-NTR and CB1954 showed significantly prolonged survival with a median survival time of 30 days. In conclusion, GALV-RRV enabled high-efficiency gene transfer and persistent expression of NTR, resulting in efficient cell killing, suppression of tumor growth, and prolonged survival upon CB1954 administration. This validates the use of therapeutic strategies employing this prodrug activator gene to arm GALV-RRV, and opens the door to the possibility of future combination gene therapy with CD-armed MLV-RRV, as the latter vector is currently being evaluated in clinical trials.

Determination of multiresidue analysis of ß-agonists in muscle and viscera using liquid chromatograph/tandem mass spectrometry with Quick, Easy, Cheap, Effective, Rugged, and Safe methodologies.

The official analytical method of the Taiwan Food and Drug Administration, Ministry of Health and Welfare for testing for veterinary drug residues in foods is the multiresidue analysis of ß-agonists. Samples are pretreated through liquid-liquid extraction and solid-phase extraction. This method is time consuming and requires the intensive use of solvents. To improve analytical efficiency and reduce costs, our study incorporated QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) techniques to establish a new method of multiresidue analysis of ß-agonists in animal muscle and viscera. The pretreatment time was shortened and solvent usage was minimized. The modified analysis was conducted using liquid chromatography/tandem mass spectrometry (LC-MS/MS) and quantification was performed using multiple reaction monitoring. The results demonstrated that the correlation coefficients of the tissue calibration curve were higher than 0.99 and the limit of quantification (LOQ) was 1 ppb. The average recoveries in spiked samples varied from 70% to 120%, and the relative difference between duplicated analysis results was lower than 10%. On the basis of the results, the proposed method was concluded to be an appropriate procedure for determining the presence of ß-agonists, and demonstrated the advantages of high recovery rates in spiked samples, high precision, reduced analysis time and solvent usage, and lower costs.

The impact of DPP-4 inhibitors on long-term survival among diabetic patients after first acute myocardial infarction.

BACKGROUND: Previous studies regarding the cardioprotective effects of dipeptidyl peptidase 4 (DPP-4) inhibitors have not provided sufficient evidence of a relationship between DPP-4 inhibition and actual cardiovascular outcomes. This study aimed to evaluate the impact of DPP-4 inhibitors on the survival of diabetic patients after first acute myocardial infarction (AMI). METHODS: This was a nationwide, propensity score-matched, case-control study of 186,112 first AMI patients, 72,924 of whom had diabetes. A propensity score, one-to-one matching technique was used to match 2672 controls to 2672 patients in the DPP-4 inhibitor group for analysis. Controls were matched based on gender, age, and a history of hypertension, dyslipidemia, diabetes, peripheral vascular disease, heart failure, cerebrovascular accident, end-stage renal disease, chronic obstructive pulmonary disease, and percutaneous coronary intervention. RESULTS: DPP-4 inhibitors improve the overall 3-year survival rate (log rank P < 0.0001), whether male or female. Cox proportional hazard regression showed DPP-4 inhibitor is beneficial in diabetes patients after AMI (HR = 0.86; 95% CI 0.78-0.95), especially in those patients with hypertension (HR = 0.87; 95% CI 0.78-0.97; P = 0.0103) and cerebrovascular disease (HR = 0.83; 95% CI 0.72-0.97; P = 0.018), but without dyslipidemia (HR = 0.78; 95% CI 0.67-0.92; P = 0.0029), without peripheral vascular disease (HR = 0.86; 95% CI 0.78-0.96; P = 0.0047), without heart failure (HR = 0.84; 95% CI 0.73-0.96; P = 0.0106), without end stage renal disease (HR = 0.86; 95% CI 0.77-0.95; P = 0.0035), and without chronic obstructive pulmonary disease (HR = 0.87; 95% CI 0.78-0.97; P = 0.0096). CONCLUSIONS: DPP-4 inhibitor therapy improved long-term survival in diabetic patients after first AMI, regardless of gender.

Noninvasive Nuclear SPECT Myocardial Blood Flow Quantitation to Guide Management for Coronary Artery Disease.

Recently, myocardial blood flow quantitation with dynamic SPECT has been validated to enhance the detection of multivessel coronary artery disease (CAD) and conclude equivocal SPECT myocardial perfusion study. This advance opened an important clinical application to utilize the tool in guiding CAD management for area where myocardial perfusion tracers for PET are unavailable or unaffordable. We present a clinical patient with ongoing recursive angina who underwent multiple nuclear stress tests for a sequence of CAD evaluation in 26 months and demonstrated that SPECT myocardial blood flow quantitation properly guided CAD management to warrant patient outcome.