Effect of Fenofibrate on Progression of Diabetic Retinopathy.

BACKGROUND: Findings from cardiovascular outcome trials suggest that fenofibrate therapy may reduce the progression of diabetic retinopathy. METHODS: We recruited and followed adults with nonreferable diabetic retinopathy or maculopathy using the national Diabetic Eye Screening (DES) program in Scotland. We randomly assigned participants to receive 145-mg fenofibrate tablets or placebo (taken daily or, in those with impaired renal function, on alternate days). The primary outcome was a composite of developing referable diabetic retinopathy or maculopathy (based on Scotland's DES grading scheme) or treatment (intravitreal injection, retinal laser, vitrectomy) for retinopathy or maculopathy. RESULTS: A total of 1151 participants were randomly assigned to treatment. During a median of 4.0 years, progression to referable diabetic retinopathy or maculopathy, or treatment thereof, occurred in 131 (22.7%) of 576 participants in the fenofibrate group and 168 (29.2%) of 575 in the placebo group (hazard ratio, 0.73; 95% confidence interval [CI], 0.58 to 0.91; P=0.006). In the fenofibrate group compared with the placebo group, the frequencies for any progression of retinopathy or maculopathy were 185 (32.1%) vs. 231 (40.2%); hazard ratio, 0.74; 95% CI, 0.61 to 0.90 and for the development of macular edema were 22 (3.8%) vs. 43 (7.5%); hazard ratio, 0.50; 95% CI, 0.30 to 0.84. Seventeen (3.0%) participants assigned fenofibrate and 28 (4.9%) assigned placebo were given treatment for retinopathy (hazard ratio, 0.58; 95% CI, 0.31 to 1.06). There was no effect on visual function, quality of life, or visual acuity. Trial-averaged estimated glomerular filtration rate was 7.9 (95% CI, 6.8 to 9.1) ml/min/1.73 m2 lower in participants in the fenofibrate group compared with the placebo group. Serious adverse events occurred in 208 (36.1%) participants allocated fenofibrate and 204 (35.5%) participants allocated placebo. CONCLUSIONS: Fenofibrate reduced progression of diabetic retinopathy compared with placebo among participants with early retinal changes. (Funded by the National Institute for Health and Care Research; ClinicalTrials.gov number, NCT03439345; ISRCTN number, ISRCTN15073006.).

The First Genetic Characterization of the SPRN Gene in Pekin Ducks (Anas platyrhynchos domesticus).

Prion diseases are fatal neurodegenerative disorders characterized by an accumulation of misfolded prion protein (PrPSc) in brain tissues. The shadow of prion protein (Sho) encoded by the shadow of prion protein gene (SPRN) is involved in prion disease progress. The interaction between Sho and PrP accelerates the PrPSc conversion rate while the SPRN gene polymorphisms have been associated with prion disease susceptibility in several species. Until now, the SPRN gene has not been investigated in ducks. We identified the duck SPRN gene sequence and investigated the genetic polymorphisms of 184 Pekin ducks. We compared the duck SPRN nucleotide sequence and the duck Sho protein amino acid sequence with those of several other species. Finally, we predicted the duck Sho protein structure and the effects of non-synonymous single nucleotide polymorphisms (SNPs) using computational programs. We were the first to report the Pekin duck SPRN gene sequence. The duck Sho protein sequence showed 100% identity compared with the chicken Sho protein sequence. We found 27 novel SNPs in the duck SPRN gene. Four amino acid substitutions were predicted to affect the hydrogen bond distribution in the duck Sho protein structure. Although MutPred2 and SNPs&GO predicted that all non-synonymous polymorphisms were neutral or benign, SIFT predicted that four variants, A22T, G49D, A68T, and M105I, were deleterious. To the best of our knowledge, this is the first report about the genetic and structural characteristics of the duck SPRN gene.

Novel polymorphisms and genetic studies of the shadow of prion protein gene (SPRN) in pheasants.

Background: Prion diseases in mammals are caused by the structural conversion of the natural prion protein (PrPC) to a pathogenic isoform, the "scrapie form of prion protein (PrPSc)." Several studies reported that the shadow of prion protein (Sho), encoded by the shadow of prion protein gene (SPRN), is involved in prion disease development by accelerating the conformational conversion of PrPC to PrPSc. Until now, genetic polymorphisms of the SPRN gene and the protein structure of Sho related to fragility to prion disease have not been investigated in pheasants, which are a species of poultry. Methods: Here, we identified the SPRN gene sequence by polymerase chain reaction (PCR) and compared the SPRN gene and Sho protein sequences among various prion disease-susceptible and -resistant species to identify the distinctive genetic features of pheasant Sho using Clustal Omega. In addition, we investigated genetic polymorphisms of the SPRN gene in pheasants and analyzed genotype, allele, and haplotype frequencies, as well as linkage disequilibrium among the genetic polymorphisms. Furthermore, we used in silico programs, namely Mutpred2, MUpro and AMYCO, to investigate the effect of non-synonymous single nucleotide polymorphisms (SNPs). Finally, the predicted secondary and tertiary structures of Sho proteins from various species were analyzed by Alphafold2. Results: In the present study, we reported pheasant SPRN gene sequences for the first time and identified a total of 14 novel SNPs, including 7 non-synonymous and 4 synonymous SNPs. In addition, the pheasant Sho protein sequence showed 100% identity with the chicken Sho protein sequence. Furthermore, amino acid substitutions were predicted to affect the hydrogen bond distribution in the 3D structure of the pheasant Sho protein. Conclusion: To the best of our knowledge, this is the first report of the genetic and structural features of the pheasant SPRN gene.

Diabetic Retinopathy and Quality of Life: A Systematic Review and Meta-Analysis.

Importance: The association between diabetic retinopathy (DR) and quality of life (QoL) has not been thoroughly investigated. Objective: To investigate the association between DR and both vision-related QoL (VRQoL) and general health-related QoL (HRQoL). Data Sources: MEDLINE, EBSCO, Embase, and Web of Science were searched from their inception to April 2022. Study Selection: Studies included adults with DR and a measure of QoL. Data Extraction and Synthesis: Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Two assumption-free meta-analyses were conducted. Analysis 1 included studies with participants without DR as the referent group to which QoL scores of participants with DR, grouped according to DR severity, were compared. Analysis 2 included all studies with participants with DR and a measure of QoL. QoL scores were pooled within categories of DR severity, and comparisons were made between these categories. Main Outcome and Measures: QoL measured using HRQoL and VRQoL scales. Results: A total of 93 articles were included: 79 in the meta-analyses and 14 in the narrative results. VRQoL was recorded in 54 studies, HRQoL in 26, and both in 13 studies. The most commonly used scales were the National Eye Institute 25-item Visual Function Questionnaire (VFQ-25) (n = 49) for VRQoL and the Short Form (SF) Health Survey (n = 18) for HRQoL. Thirty-five studies reported VFQ-25 composite scores. Analysis 1 consisted of 8 studies including 1138 participants with DR and 347 participants without DR. Compared with participants without DR, the composite VFQ-25 score was 3.8 (95% CI, 1.0-6.7) points lower in those with non-vision-threatening DR (NVTDR), 12.5 (95% CI, 8.5-16.5) lower in those with any DR, and 25.1 (95% CI, 22.8-27.2) lower in VTDR (P < .001 for trend). Analysis 2 consisted of 35 studies including 6351 participants with DR. The pooled mean VFQ-25 composite score was 91.8 (95% CI, 91.0-92.7) for participants with NVTDR, 77.6 (95% CI, 76.9-78.3) for any DR, and 73.2 (95% CI, 72.6-73.7) for VTDR (P < .001 for trend). HRQoL scores had weak or no associations with NVTDR and strong associations with VTDR. Conclusions and Relevance: This study found that VRQoL declined with the presence and severity of DR. Interventions to reduce progression of DR at both early and more advanced stages could improve VRQoL.

No Association between SARS-CoV-2 Infection and the Polymorphism of the Toll-like Receptor 7 (TLR7) Gene in Female Population.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a single-stranded RNA virus. Toll-like receptor 7 (TLR7) recognizes single-stranded RNA viruses. The TLR7 gene plays a critical role in the human innate and adaptive immune response to SARS-CoV-2 infections. Genetic factors probably affect SARS-CoV-2 infection susceptibility. In the current study, our aim was to search for genetic variations associated with COVID-19 patients in the TLR7 gene of a Korean population. We designed five gene-specific primers to cover the coding region of the human TLR7 gene. Using amplicon sequencing, we screened the genetic polymorphisms in the coding region of the TLR7 gene in COVID-19 patients and healthy controls. The genotype frequencies, allele frequencies, and Hardy-Weinberg equilibrium (HWE) were examined. We identified a low-frequency synonymous single nucleotide polymorphism (SNP) (rs864058) in the coding region of the TLR7 gene. There were no significant differences in the genotype or allele frequencies of the TLR7 rs864058 polymorphism between COVID-19 female patients and healthy controls (p = 1.0). In conclusion, TLR7 (rs864058) polymorphism is low frequency in Korean populations and is not associated with SARS-CoV-2 infection.

Potential Therapeutic Use of Stem Cells for Prion Diseases.

Prion diseases are neurodegenerative disorders that are progressive, incurable, and deadly. The prion consists of PrPSc, the misfolded pathogenic isoform of the cellular prion protein (PrPC). PrPC is involved in a variety of physiological functions, including cellular proliferation, adhesion, differentiation, and neural development. Prion protein is expressed on the membrane surface of a variety of stem cells (SCs), where it plays an important role in the pluripotency and self-renewal matrix, as well as in SC differentiation. SCs have been found to multiply the pathogenic form of the prion protein, implying their potential as an in vitro model for prion diseases. Furthermore, due to their capability to self-renew, differentiate, immunomodulate, and regenerate tissue, SCs are prospective cell treatments in many neurodegenerative conditions, including prion diseases. Regenerative medicine has become a new revolution in disease treatment in recent years, particularly with the introduction of SC therapy. Here, we review the data demonstrating prion diseases' biology and molecular mechanism. SC biology, therapeutic potential, and its role in understanding prion disease mechanisms are highlighted. Moreover, we summarize preclinical studies that use SCs in prion diseases.

Age Related Senescence, Apoptosis, and Inflammation Profiles in Periodontal Ligament Cells from Canine Teeth.

OBJECTIVE: The periapical tissues, including periodontal ligament cells (PDLCs) play an important role in repairing the surrounding tissue of the teeth. A decrease in the regenerative potentiality of resident stem cells (PDLCs) has been suggested to be attributed to the decline of pulp regeneration. Therefore, examining the functional changes in periodontal tissue and cells that occur during the aging process is necessary. METHODS: The changes in the cementum extract (CE) and PDLCs isolated from young and aged dog teeth were evaluated. PDLCs growth rate, senescence markers, p16 and p21, and proinflammatory cytokines, IL-6, IL-1ß, and TNF-α, were analyzed by RT-PCR. Bax, an apoptosis marker, Bcl-2, a marker for cell survival, and IL-6 were examined by Western blot analyses to detect their variance expression in the CE. RESULTS: Our results demonstrated that aged PDLCs exhibit a low growth rate and an increased expression of p16; however, no change has been demonstrated in the expression of p21. The chronic inflammatory molecules, IL-6 and TNF-α, were significantly upregulated compared to young PDLCs. Western blot analyses showed decreased expression of Bcl-2 in the CE of the aged tooth (p < 0.001). CONCLUSION: Taken together, aging influences the functional changes of PDLCs and CE and increases senescence, chronic inflammation, and apoptosis markers. As a result, donor age is a key factor influencing the utilization of PDLCs for tooth regeneration.

Comparative histological analysis of the skin for forensic investigation of some animal species.

Macroscopical and histological analysis of the skin is fundamental in both human and veterinary forensic investigations. However, databases of differential skin histology of various animal species are rare. The aim of the present study is to identify species-specific differential histological features of the skin that could be used in forensic investigations including animal identification. For this purpose, skin specimens were collected from the neck region of various farm animals including buffalo, cow, camel, sheep, goat, dog, and donkey, and were processed for histological analysis. Our comparative analysis revealed specific histological features in the skin that could differentiate between the studied animal species. The epidermis layer of the skin was very thick in buffalo, intermediate in cow, sheep, goat, dog, and donkey, but very thin in camel. The papillomatous epidermis was very frequent in buffalo, but very rare in cow. In the dermis layer of the skin, four structures were located which showed differential features between the studied animal species: the papillary layer, which was thick in buffalo, camel, sheep, dog, and donkey but thin in cow and goat. The sweat glands, which were few in buffalo, cow, goat, and dog, but numerous and deeply located in the dermis of sheep; they were individually located in all studied animals except in camel and donkey they were arranged in clusters. The hair follicles were characteristic for the skin of sheep as they were present at two different levels in the dermis with simple and compound hair follicles. The sebaceous glands were large and multi-lobular in buffalo, but small and uni-lobular in cow and camel. The hypodermis layer of the skin was very thick in sheep and goat in contrast to all other analyzed animals. In conclusion, the present study provides comprehensive information on the differential histological features of the skin of seven different domestic animal species that could be used as a key in forensic investigations.

A Constitutional Mismatch Repair Deficiency Syndrome Presented With an Advanced Rectal Cancer in a Juvenile Female: A Case Report and Literature Review.

The constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and challenging condition with a poor prognosis. It results from biallelic mismatch repair gene mutations and leads to multiorgan cancers. Therefore, we report the first case of advanced juvenile rectal cancer related to CMMRD syndrome in the Gulf region. She is a 13-year-old female, born to non-consanguineous parents with a positive family history of malignancy, presented with an eight-month history of a retractable bulging anal mass associated with diarrhea mixed with blood and constitutional symptoms. She was cachectic with café au lait spots all over her body. Upon investigation, she was found to have invasive rectal adenocarcinoma. The case was started on neoadjuvant chemoradiotherapy in addition to genetic testing which showed a homozygous pathogenic variant in PMS2, indicating CMMRD syndrome. The patient underwent pre-operative post-neoadjuvant reassessment followed by laparoscopic total proctocolectomy with ileal J-pouch creation and ileoanal anastomosis with temporary diverting loop ileostomy which later on was reversed with no complications or recurrence. The family declined to continue the adjuvant therapy but accepted the surveillance programs and genetic testing. Unusual or late presentation secondary to a very rare syndrome like CMMRD is a major challenge to clinicians, hence a high index of suspicion and proper utilization of genetics programs might be the best available solutions.

Treatment strategies for meniscal lesions: from past to prospective therapeutics.

Menisci play an important role in the biomechanics of knee joint function, including loading transmission, joint lubrication, prevention of soft tissue impingement during motion and joint stability. Meniscal repair presents a challenge due to a lack of vascularization that limits the healing capacity of meniscal tissue. In this review, the authors aimed to untangle the available treatment options for repairing meniscal tears. Various surgical procedures have been developed to treat meniscal tears; however, clinical outcomes are limited. Consequently, numerous researchers have focused on different treatments such as the application of exogenous and/or autologous growth factors, scaffolds including tissue-derived matrix, cell-based therapy and miRNA-210. The authors present current and prospective treatment strategies for meniscal lesions.

One of the most common knee injuries, especially in athletes, is a meniscal tear. There are two wedge-shaped pieces of fibrocartilage that act as shock absorbers between the thighbone and shinbone (menisci). The menisci help to transmit weight from one bone to another and play an important role in knee stability. The challenge for researchers and clinicians is to repair meniscal injuries, despite the lack of vascularization. The authors discuss the available approaches for repairing meniscal tears. Non surgical and surgical procedures are reviewed, clarifying their clinical outcomes. Other approaches to tissue engineering are also discussed. Using the patient's cells may be a potential strategy to repair meniscal injuries and improve the durability of the knee joint.

A 66-Year-Old Man Presenting with Port-Site Metastatic Gastric Adenocarcinoma 4 Years After Laparoscopic Resection of a Rectal Adenocarcinoma.

BACKGROUND There is a recognized association between synchronous and metachronous colorectal and gastric adenocarcinoma. This report describes a 66-year-old man presenting with port-site metastatic gastric adenocarcinoma 4 years after laparoscopic resection of a rectal adenocarcinoma. CASE REPORT A 66-year-old male rectal cancer survivor presented to the clinic with a painless mass at the previous laparoscopic anterior resection port site. Physical examination revealed a soft port-site mass measuring 5×4 cm. Abdominal CT revealed enlargement of the right rectus abdominis muscle and thickening of the gastric fundus. A biopsy of the right abdominal wall mass revealed metastatic adenocarcinoma. Immunohistochemistry (IHC) testing was positive for cytokeratin 7 (CK7) and CDx2 and negative for cytokeratin 20 (CK20). The possible primary malignancy was upper gastrointestinal, and it was less likely to be colorectal in origin. Subsequently, the upper endoscopy revealed a friable, erythematous gastric mucosa. Biopsy revealed an invasive moderately differentiated gastric adenocarcinoma with positive IHC for CK7 and CDx2 and negative for CK20. The rectal adenocarcinoma pathology slides were reviewed, and IHC testing showed negative CK7 and positive CK20. Patient was known to have multiple comorbidities with poor functional status. The tumor board decision was made to manage him palliatively with best supportive care for the diagnosis of metastatic gastric cancer. CONCLUSIONS This report has presented a case of possible metachronous gastric adenocarcinoma with port-site metastasis following resection of a rectal adenocarcinoma. Clinicians should be aware of the association between synchronous and metachronous colorectal and gastric adenocarcinoma and the challenges associated with the diagnosis.

Effects of Normal Synovial Fluid and Interferon Gamma on Chondrogenic Capability and Immunomodulatory Potential Respectively on Equine Mesenchymal Stem Cells.

Synovial fluid contains cytokines, growth factors and resident mesenchymal stem cells (MSCs). The present study aimed to (1) determine the effects of autologous and allogeneic synovial fluid on viability, proliferation and chondrogenesis of equine bone marrow MSCs (BMMSCs) and (2) compare the immunomodulatory properties of equine synovial fluid MSCs (SFMSCs) and BMMSCs after stimulation with interferon gamma (INF-γ). To meet the first aim of the study, the proliferation and viability of MSCs were evaluated by MTS and calcein AM staining assays. To induce chondrogenesis, MSCs were cultured in a medium containing TGF-ß1 or different concentrations of synovial fluid. To meet the second aim, SFMSCs and BMMSCs were stimulated with IFN-γ. The concentration of indoleamine-2,3-dioxygenase (IDO) and nitric oxide (NO) were examined. Our results show that MSCs cultured in autologous or allogeneic synovial fluid could maintain proliferation and viability activities. Synovial fluid affected chondrocyte differentiation significantly, as indicated by increased glycosaminoglycan contents, compared to the chondrogenic medium containing 5 ng/mL TGF-ß1. After culturing with IFN-γ, the conditioned media of both BMMSCs and SFMSCs showed increased concentrations of IDO, but not NO. Stimulating MSCs with synovial fluid or IFN-γ could enhance chondrogenesis and anti-inflammatory activity, respectively, suggesting that the joint environment is suitable for chondrogenesis.

Characterization of stable hypoxia-preconditioned dental pulp stem cells compared with mobilized dental pulp stem cells for application for pulp regenerative therapy.

BACKGROUND: Dental pulp stem cells (DPSCs) have been developed as a potential source of mesenchymal stem cells (MSCs) for regeneration of dental pulp and other tissues. However, further strategies to isolate highly functional DPSCs beyond the colony-forming methods are required. We have demonstrated the safety and efficacy of DPSCs isolated by G-CSF-induced mobilization and cultured under normoxia (mobilized DPSCs, MDPSCs) for pulp regeneration. The device for isolation of MDPSCs, however, is not cost-effective and requires a prolonged cell culture period. It is well known that MSCs cultured under hypoxic-preconditions improved MSC proliferation activity and stemness. Therefore, in this investigation, we attempted to improve the clinical utility of DPSCs by hypoxia-preconditioned DPSCs (hpDPSCs) compared with MDPSCs to improve the potential clinical utility for pulp regeneration in endodontic dentistry. METHODS: Colony-forming DPSCs were isolated and preconditioned with hypoxia in a stable closed cultured system and compared with MDPSCs isolated from the individual dog teeth. We examined the proliferation rate, migration potential, anti-apoptotic activity, and gene expression of the stem cell markers and angiogenic/neurotrophic factors. Trophic effects of the conditioned medium (CM) were also evaluated. In addition, the expression of immunomodulatory molecules upon stimulation with IFN-γ was investigated. The pulp regenerative potential and transplantation safety of hpDPSCs were further assessed in pulpectomized teeth in dogs by histological and immunohistochemical analyses and by chemistry of the blood and urine tests. RESULTS: hpDPSCs demonstrated higher proliferation rate and expression of a major regulator of oxygen homeostasis, HIF-1α, and a stem cell marker, CXCR-4. The direct migratory activity of hpDPSCs in response to G-CSF was significantly higher than MDPSCs. The CM of hpDPSCs stimulated neurite extension. However, there were no changes in angiogenic, migration, and anti-apoptotic activities compared with the CM of MDPSCs. The expression of immunomodulatory gene, PTGE was significantly upregulated by IFN gamma in hpDPSCs compared with MDPSCs. However, no difference in nitric oxide was observed. The regenerated pulp tissue was quantitatively and qualitatively similar in hpDPSC transplants compared with MDPSC transplants in dog teeth. There was no evidence of toxicity or adverse events of the hpDPSC transplantation. CONCLUSIONS: These results demonstrated that the efficacy of hpDPSCs for pulp regeneration was identical, although hpDPSCs improved stem cell properties compared to MDPSCs, suggesting their potential clinical utility for pulp regeneration.

Effects of p-Cresol on Senescence, Survival, Inflammation, and Odontoblast Differentiation in Canine Dental Pulp Stem Cells.

Aging, defined by a decrease in the physical and functional integrity of the tissues, leads to age-associated degenerative diseases. There is a relation between aged dental pulp and the senescence of dental pulp stem cells (DPSCs). Therefore, it is important to investigate the molecular processes underlying the senescence of DPSCs to elucidate the dental pulp aging mechanisms. p-Cresol (PC), a uremic toxin, is strongly related to cellular senescence. Here, age-related phenotypic changes including senescence, apoptosis, inflammation, and declining odontoblast differentiation in PC-treated canine DPSCs were investigated. Under the PC condition, cellular senescence was induced by decreased proliferation capacity and increased cell size, senescence-associated ß-galactosidase (SA-ß-gal) activity, and senescence markers p21, IL-1ß, IL-8, and p53. Exposure to PC could stimulate inflammation by the increased expression of IL-6 and cause the distraction of the cell cycle by the increased level of Bax protein and decreased Bcl-2. The levels of odontoblast differentiation markers, dentin sialophosphoprotein (DSPP), dentin matrix protein 1, and osterix, were decreased. Consistent with those findings, the alizarin red staining, alkaline phosphatase, and DSPP protein level were decreased during the odontoblast differentiation process. Taken together, these findings indicate that PC could induce cellular senescence in DPSCs, which may demonstrate the changes in aging dental pulp.

Pulp Regeneration: Current Approaches, Challenges, and Novel Rejuvenating Strategies for an Aging Population.

We showed the safety and efficacy of pulp regenerative therapy by the autologous transplantation of mobilized dental pulp stem cells with granulocyte colony-stimulating factor in a pilot clinical study of young and middle-aged pulpectomized teeth. An experimental study in dogs further demonstrated an age-dependent decline in the amount of regenerated pulp tissue. In our society, in which people will soon live beyond 100 years, this therapy should be efficacious for contributing to the functional survival and endurance of the tooth not only for pulpectomized young teeth but also for aged teeth with periapical disease. However, there are 2 challenges: 1 is enhancing pulp regeneration in aged teeth, and another is complete disinfection before cell transplantation. Thus, this review presents trypsin pretreatment for the former and a novel irrigant, nanobubbles with antibacterial nanopolymers, for the latter, thus demonstrating potential utility for pulp regenerative therapy in aged teeth with periapical disease.

Congenital isolated in-situ liver malrotation: very rare presentation. case report.

Liver anomalies are uncommon. We are reporting a case of 27 years old male admitted as a case of biliary pancreatitis. Upon hospitalization work-up, MRCP was done reveling incidentally in situ liver malrotation which was confirmed intraoperatively. It is very rare anomaly.

Treatment of Pulpectomized Teeth With Trypsin Prior to Transplantation of Mobilized Dental Pulp Stem Cells Enhances Pulp Regeneration in Aged Dogs.

There is an age-dependent decline of pulp regeneration, due to the decline of migration, proliferation, and cell survival of resident stem cells. Trypsin is a proteolytic enzyme clinically used for tissue repair. Here, we investigated the effects of trypsin pretreatment of pulpectomized teeth prior to cell transplantation on pulp regeneration in aged dogs. The amount of regenerated pulp was significantly higher in trypsin-pretreated teeth compared to untreated teeth. Trypsin pretreatment increased the number of cells attached to the dentinal wall that differentiated into odontoblast-like cells. The trypsin receptor, PAR2, was higher in vitro expression in the periodontal ligament cells (PDLCs) from aged dogs compared to those from young. The direct effects of trypsin on aged PDLCs were increased expression of genes related to immunomodulation, cell survival, and extracellular matrix degradation. To examine the indirect effects on microenvironment, highly extracted proteins from aged cementum were identified by proteomic analyses. Western blotting demonstrated that significantly increased fibronectin was released by the trypsin treatment of aged cementum compared to young cementum. The aged cementum extract (CE) and dentin extract (DE) by trypsin treatment increased angiogenesis, neurite extension and migration activities as elicited by fibronectin. Furthermore, the DE significantly increased the mRNA expression of immunomodulatory factors and pulp markers in the aged DPSCs. These results demonstrated the effects of trypsin on the microenvironment in addition to the resident cells including PDLCs in the aged teeth. In conclusion, the potential utility of trypsin pretreatment to stimulate pulp regeneration in aged teeth and the underlying mechanisms were demonstrated.

Care-pathways for patients presenting to emergency ambulance services with self-harm: national survey.

BACKGROUND: Self-harm is among the top five causes of acute hospital admissions and ambulance clinicians are often the first point of contact. However, the Emergency Department (ED) may not be the most appropriate place of care and little is known about the existence or nature of alternative pathways available to UK ambulance services. This survey describes the current management pathways used by ambulance services for patients who have self-harmed. METHODS: A structured questionnaire was sent to all UK ambulance services by email and followed up by telephone in 2018. Three independent researchers (two clinical) coded responses which were analysed thematically. RESULTS: All 13 UK ambulance services responded to the survey: nine by email and four by telephone interview. Two services reported a service-wide protocol for managing people presenting with self-harm, with referral to mental health crisis team available as an alternative to conveyance to ED, following on-scene psychosocial assessment. Four services reported local pathways for managing mental health patients which included care of patients who had self-harmed. Four services reported being in the process of developing pathways for managing mental health patients. Six services reported no service-wide nor local pathways for managing self-harm patients. No robust evaluation of new care models was reported. CONCLUSION: Practice in ambulance services in the UK is variable, with a minority having a specific clinical pathway for managing self-harm, with an option to avoid ED. New pathways for patients who have self-harmed must be evaluated in terms of safety, clinical and cost-effectiveness.

Immunomodulation and Regeneration Properties of Dental Pulp Stem Cells: A Potential Therapy to Treat Coronavirus Disease 2019.

The coronavirus disease 2019 (COVID-19) pandemic, originating from Wuhan, China, is known to cause severe acute respiratory symptoms. The occurrence of a cytokine storm in the lungs is a critical step in the disease pathogenesis, as it causes pathological lesions, pulmonary edema, and acute respiratory distress syndrome, potentially resulting in death. Currently, there is no effective treatment that targets the cytokine storm and helps regenerate the damaged tissue. Mesenchymal stem cells (MSCs) are known to act as anti-inflammatory/immunomodulatory candidates and activate endogenous regeneration. As a result, MSC therapy is a potential treatment approach for COVID-19. Intravenous injection of clinical-grade MSCs into COVID-19 patients can induce an immunomodulatory response along with improved lung function. Dental pulp stem cells (DPSCs) are considered a potential source of MSCs for immunomodulation, tissue regeneration, and clinical application. Although some current clinical trials have treated COVID-19 patients with DPSCs, this therapy has not been approved. Here, we review the potential use of DPSCs and their significance in the development of a therapy for COVID-19.

Two Histologically Different Primary Malignancies: Synchronous Obstructive Descending Colon Adenocarcinoma and Appendicular Carcinoid Tumor.

BACKGROUND Synchronous primary tumors are defined as 2 or more different histological tumors discovered in one patient at the same time or within a period of 6 months. Colorectal cancer is one of the most common cancers in the United States. Inversely, synchronous colorectal cancer and carcinoid tumors are rare. Carcinoid tumors can be classified into functioning and non-functioning tumors. Carcinoid tumors are steadily increasing in incidence. There is only 1 case reported in the literature as synchronous colorectal cancer and appendicular carcinoid. The difficulty is to manage 2 different types of malignancies at the same time. An optimal medical or chemotherapy strategy is needed. CASE REPORT A 29-year-old woman presented to the emergency room carrying with her computerized tomography (CT) abdomen and pelvic images showing bowel obstruction. Investigations confirmed an obstructing descending colon mass. She underwent colonoscopic stenting as emergency treatment with multiple biopsies. The pathology report came back positive for adenocarcinoma, and we planned to proceed with surgery. Intraoperatively, she was found to have an appendicular mass. The surgical team decided to proceed with laparoscopic-assisted subtotal colectomy. The postoperative course was uneventful, with no complications. The patient was discharged on postoperative day 6 in stable condition. CONCLUSIONS Synchronous colorectal cancer and carcinoid tumors are rare malignancies. The challenge is to find an optimal medical or chemotherapy strategy to manage both malignancies.