3714 research outputs found
Sort by
Modeling microbiota-associated human diseases: from minimal models to complex systems
No full textAlterations in the intestinal microbiota are associated with various human diseases of the digestive system, including obesity and its associated metabolic diseases, inflammatory bowel diseases (IBD), and colorectal cancer (CRC). All three diseases are characterized by modifications of the richness, composition, and metabolic functions of the human intestinal microbiota. Despite being multi-factorial diseases, studies in germ-free animal models have unarguably identified the intestinal microbiota as a causal driver of disease pathogenesis. However, for an increased mechanistic understanding of microbial signatures in human diseases, models require detailed refinement to closely mimic the human microbiota and reflect the complexity and range of dysbiosis observed in patients. The transplantation of human fecal microbiota into animal models represents a powerful tool for studying the causal and functional role of the dysbiotic human microbiome in a pathological context. While human microbiota-associated models were initially employed to study obesity, an increasing number of studies have applied this approach in the context of IBD and CRC over the past decade. In this review, we discuss different approaches that allow the functional validation of the bacterial contribution to human diseases, with emphasis on obesity and its associated metabolic diseases, IBD, and CRC. We discuss the utility of simple models, such as in vitro fermentation systems of the human microbiota and ex vivo intestinal organoids, as well as more complex whole organism models. Our focus here lies on human microbiota-associated mouse models in the context of all three diseases, as well as highlighting the advantages and limitations of this approach
Lower extremity amputation: the emerging role of targeted muscle reinnervation (TMR) and regenerative peripheral nerve interface (RPNI)
No full textLower extremity amputation is increasingly prevalent in the United States, with growing numbers of patients suffering from diabetes and peripheral vascular disease. Amputation has significant functional sequelae as more than half of patients are unable to ambulate at one year postoperatively. Improving mobility and decreasing chronic post-amputation pain can significantly improve the quality of life for these patients and reduce the cost burden on the healthcare system. Plastic and reconstructive surgery has been at the forefront of “reconstructive amputation”, in which nerve pedicles can be surgically guided to decrease painful neuroma formation as well as provide targets for myoelectric prosthesis use. We herein review post-amputation outcomes, epidemiology of chronic, post-amputation pain, and current treatments, including total muscle reinnervation and regenerative peripheral nerve interface, which are at the forefront of multidisciplinary treatment of lower extremity amputees
Surgical route and pathological risk factors in early cervical cancer - Node Zero (SURPEC-N0)
No full textAim: The aim of this study is to compare disease-free survival (DFS) and overall survival (OS) in patients with stage I cervical cancer (≤ 4cms, lymph node-negative) undergoing open radical hysterectomy (ORH) vs. minimally invasive radical hysterectomy (MIRH).Methods: All patients undergoing radical hysterectomy between January 2012-December 2018 from the largest tertiary referral cancer centre were included. A 1:1 propensity matching was done based on four independent prognostic factors to compare DFS and OS with the route of surgery. Results: One hundred and ninety-nine patients were included during the study period. The median age of the cohort was 50 years. The median follow-up of patients was 47 months. Following 1:1 propensity matching, a total of 174 patients were analysed for DFS and OS in ORH (n = 87) and MIRH (n = 87) groups. Protective measure was used in two-thirds of the patients during MIRH. Twenty-nine patients (16.7%) had recurrences. For the matched cohort (n = 174), the DFS at 36 and 60 months was 84.8% (78.1%-89.6%) and 81% (73.4%-86.6%) respectively and the OS was 96.5% (91.7%-98.5%) and 95.6% (90.3%-98%) respectively. There was no statistically significant difference in DFS or OS between ORH and MIRH. Conclusion: The present study showed no difference in oncological outcomes in MIRH compared to ORH. Retrospective audits on patient characteristics such as screening/vaccination history along with surgical technique/load and matching for crucial risk factors should be factored in future studies to eliminate the possible methodological errors
Prevention and management of peri-procedural TAVR complications
No full textTranscatheter aortic valve replacement (TAVR) is a safe and effective treatment strategy for severe aortic stenosis. However, peri-procedural complications can have a significant impact on acute and longer-term morbidity and mortality. Therefore, this review article provides a practical overview on how to prevent and manage the common and also rare but life-threatening peri-procedural TAVR complications
Targeting the complement system in pancreatic cancer drug resistance: a novel therapeutic approach
No full textPancreatic cancer is ranked as the fourth leading cause of cancer-related mortality and is predicted to become the second leading cause of cancer-related death by 2030. The cause of this high mortality rate is due to pancreatic ductal adenocarcinoma’s rapid progression and metastasis, and development of drug resistance. Today, cancer immunotherapy is becoming a strong candidate to not only treat various cancers but also to combat against chemoresistance. Studies have suggested that complement system pathways play an important role in cancer progression and chemoresistance, especially in pancreatic cancer. A recent report also suggested that several signaling pathways play an important role in causing chemoresistance in pancreatic cancer, major ones including nuclear factor kappa B, signal transducer and activator of transcription 3, c-mesenchymal-epithelial transition factor, and phosphoinositide-3-kinase/protein kinase B. In addition, it has also been proven that the complement system has a very active role in establishing the tumor microenvironment, which would aid in promoting tumorigenesis, progression, metastasis, and recurrence. Interestingly, it has been shown that the downstream products of the complement system directly upregulate inflammatory mediators, which in turn activate these chemo-resistant pathways. Therefore, targeting complement pathways could be an innovative approach to combat against pancreatic cancer drugs resistance. In this review, we have discussed the role of complement system pathways in pancreatic cancer drug resistance and a special focus on the complement as a therapeutic target in pancreatic cancer
In vitro modeling of the complex retinal condition age-related macular degeneration
No full textAim: To model a complex retinal disease such as age-related macular degeneration (AMD) in vitro, we aimed to combine genetic and environmental risk factors in a retinal pigment epithelium (RPE) cell culture model generated via induced pluripotent stem cells (iPSCs) from subjects with an extremely high and an extremely low genetic disease risk. As an external stimulus, we chose defined oxidative stress conditions.Methods: Patients were genotyped for known AMD-associated genetic variants and their individual genetic risk score (GRS) was calculated defining individual iPSC-RPE cell lines which reflect the extreme ends of the genetic risk for AMD. Sodium iodate (NaIO3, SI) was used to induce oxidative stress and cellular responses were followed by analyzing nuclear factor erythroid 2-related factor 2 (NRF2) pathway activation by mRNA and protein expression.Results: We present a collection of eight iPSC-RPE cell lines, with four each harboring an extreme low or an extreme high GRS for AMD. RPE identity was verified structurally and functionally. We found that 24 and 72 h of SI treatment induced a significant upregulation of NRF2 response genes HMOX1 and NQO1, without showing cytotoxic effects or negatively influencing RPE cell integrity. High- vs. low-risk cell lines revealed similar first line defenses in oxidative stress response mediated through the NRF2 pathway.Conclusion: Delineating the NRF2-mediated oxidative stress response was sought in iPSC-RPE cell lines with maximally divergent genetic AMD risk profiles. Under the specific stress conditions chosen, our data indicate that genetic predisposition to AMD may not exert a major influence on the NRF2 signaling pathway
Gene editing treatment strategies for retinitis pigmentosa assessed in Xenopus laevis carrying a mutant Rhodopsin allele
No full textAim: To examine the utility of gene editing therapies for retinitis pigmentosa using Xenopus laevis carrying a mutation in Rhodopsin.Methods: Xenopus laevis were genetically modified using CRISPR-Cas9 based methods and characterized by Sanger sequencing, dot blot, electroretinography, and confocal microscopy.Results: We identified genetically modified Xenopus laevis carrying a net 12 base pair deletion in the Rho.L gene. These animals have a retinal degeneration that is apparent by 14 days, with abnormal or missing rod outer segments, and a reduced electroretinogram signal. We prevented the majority of this retinal degeneration via a treatment strategy using a single sgRNA to neutralize the mutant allele via non-homologous end joining, yielding long-term improvements in histology and the electroretinogram. A second strategy using two sgRNAs to generate large deletions in the mutant allele was also successful, but did not significantly improve outcomes relative to the single-guide strategy as it was less efficient. We found limited evidence of success with a third strategy dependent on homology-directed repair; this treatment was also too inefficient to generate an outcome superior to the single-guide strategy.Conclusion: Our results demonstrate the utility of this new Xenopus laevis model for rapidly assessing and comparing multiple gene-editing based treatment strategies. We conclude that it would be technically difficult to improve on the simple single-guide based strategy, as strategies requiring multiple successive events (such as cleavage followed by homology-directed repair) are likely to be less efficient
Selective expression of neurodegenerative diseases-related mutant p150Glued in midbrain dopaminergic neurons causes progressive degeneration of nigrostriatal pathway
No full textAim: Missense mutations of dynactin subunit p150Glued have been associated with multiple neurodegenerative diseases, including Perry syndrome, characterized by inherited parkinsonism, depression, weight loss, and hypoventilation. The current study investigated how the pathogenic mutant p150Glued affects the integrity and function of the nigrostriatal dopaminergic (DA) pathway in vivo.Methods: Using a tetracycline-controlled transcriptional regulation system, transgenic mouse models were generated with selective overexpression of wild-type, motor neuron disease-related G59S mutant, or Perry syndrome-related G71R mutant human p150Glued in midbrain DA neurons. A series of behavioral, neuropathological, neurochemical, electrochemical, and biochemical studies were performed on the mice to examine and compare the pathogenic impact of the two mutant p150Glued on the survival and function of midbrain DA neurons.Results: Compared with non-transgenic control mice, transgenic mice overexpressing wild-type human p150Glued showed neither motor phenotypes nor pathological, functional, or biochemical abnormalities of the nigrostriatal DA pathway. Transgenic mice overexpressing G59S mutant p150Glued displayed weight loss, motor deficits, early-onset defects in dopamine transmission, and early-onset loss of DA neurons and axons. Transgenic mice overexpressing G71R p150Glued mutant exhibited hyperactivities, impaired motor coordination, early-onset dysfunction of dopamine uptake, and late-onset loss of DA neurons and axons. In addition, overexpression of either G59S or G71R mutant p150Glued in midbrain DA neurons preferentially downregulated the expression of dopamine transporter at dopaminergic axon terminals. Furthermore, G59S mutant p150Glued rather than G71R mutant p150Glued formed aggregates in midbrain DA neurons in vivo, and the aggregates trapped dynein/dynactin, co-localized with lysosomes, and upregulated ubiquitination.Conclusion: These findings demonstrate that selective expression of either G59S or G71R mutant p150Glued in mouse midbrain DA neurons leads to progressive degeneration of the nigrostriatal DA pathway and indicate that G59S and G71R mutant p150Glued exhibit differential pathogenic impact on the survival and function of midbrain DA neurons in vivo
Insights on the disruption of glucose metabolism and hepatic insulin resistance induced by hepatitis C virus
No full textHepatitis C virus (HCV) is still considered as a major public health problem because in 2015 around 71 million people were chronically infected worldwide. It is important to note that chronic HCV infection is a systemic disease that is associated with diverse extrahepatic disorders including insulin resistance and type 2 diabetes mellitus. The discovery of new direct-acting antiviral agents (DAAs) has become a huge advance in the treatment of HCV infection. The complex interplay between HCV and glucose metabolic pathways remains to be fully elucidated, but it is becoming clearer that elimination of chronic HCV infection halts the progression of liver disease, but more evidence is still needed to better understand how successful antiviral treatment influences insulin resistance and other abnormalities of glucose metabolism linked to HCV infection. This review provides a comprehensive overview of the glucose metabolism disturbances related to chronic HCV infection, highlighting the new insights into the molecular basis of insulin resistance induced by HCV and the mechanisms underlying the reversion of this metabolic disorder by DAAs
How a cloud based platform can make ambulatory blood pressure monitoring more efficient, accessible, and evidence based
No full textAmbulatory blood pressure measurement (ABPM) is the gold-standard method for blood pressure assessment. However, it is markedly underutilized, in part because legacy software provided with ABPM devices is archaic and inefficient. Herein, we illustrate an example of a recently developed cloud-based ABPM platform. Such a platform offers several distinct advantages: (1) the ability to guide users through the testing process; (2) synchronizing inputs of the technician, patient, physician, and administrative assistant so that testing can be successful and efficient; (3) providing guideline-concordant study interpretations that can be e-signed, reducing physician interpretation times; (4) enabling central expert oversight and peripheral deployment of testing, thereby increasing accessibility of quality testing; and (5) facilitating integration into electronic medical records, improving dissemination of results. It is envisioned that increased use of cloud-based ABPM platforms will lead to the expansion of quality ABPM testing, thus improving the care of patients with known or suspected hypertension
Data sources:
Access Repository Dashboard
Do you manage OAE Publishing (via Crossref)? Access insider analytics, issue reports and manage access to outputs from your repository in the CORE Repository Dashboard!