Proliferative human cell sources applied as biocomponent in bioartificial livers: a review

INTRODUCTION: Bioartificial livers (BALs) are urgently needed to bridge severe liver failure patients to liver transplantation or liver regeneration. When based on primary hepatocytes, their efficacy has been shown in animal experiments and their safety was confirmed in clinical trials. However, a proliferative human cell source with therapeutic functionality is needed to secure availability and move BAL application forward. AREAS COVERED: This review compares the performance of BALs based on proliferative human biocomponents and primary hepatocytes. This review evaluates relevant studies identified by searching the MEDLINE database until July 2011 and some of our own unpublished data. EXPERT OPINION: All the discussed hepatocyte-like biocomponents show deficiencies in their hepatic functionality compared with primary hepatocytes, particularly functions occurring late in liver development. Nonetheless, the HepaRG, HepG2-GS-CYP3A4, and mesenchymal stem cells show efficacy in a statistically well-powered animal model of acute liver failure, when applied in a BAL device. Various methods to gain higher functionality of BALs, including genetic modification, the usage of combinatory cell sources, and improvement of culture methods, have scarcely been applied, but may further pave the path for BAL application. Clinical implementation of a BAL based on a human proliferative biocomponent is still several years away.     

Bioartificial livers in vitro and in vivo: tailoring biocomponents to the expanding variety of applications

Introduction: Bioartificial livers (BALs) were originally developed to treat patients suffering from severe liver failure and relied on primary hepatocytes or on hepatoblastoma-derived cell lines. Currently, new in vitro BAL applications are emerging, including drug toxicity testing, disease modeling and basic clinical research, and in recent years, advances in the field of stem cell biology have resulted in potential alternative cell sources.

Areas covered: This review identifies the demands of clinical and in vitro BAL applications to their biocomponent and summarizes the functionality and developmental state of BAL technology and cell types currently available. Relevant studies identified by searching the MEDLINE database until April 2014 were reviewed, supplemented with some of our own unpublished data.

Expert opinion: BALs have the potential to meet demands currently left unmet in both clinical and in vitro applications. All the reviewed biocomponents show limitations towards one or more BAL applications. However, the generation of stem cell-derived hepatocyte-like cells is progressing rapidly, so the criteria for patient-specific drug toxicity screening and disease modeling are probably met in the near future. HepaRG cells are the most promising biocomponent for clinical BAL application, based on their proliferative and differentiation capacity.     

Emergency management of chlorine gas exposure – a systematic review

Introduction: Chlorine exposure can lead to pulmonary obstruction, reactive airway dysfunction syndrome, acute respiratory distress syndrome and, rarely, death.

Objective: We performed a systematic review of published animal and human data regarding the management of chlorine exposure.

Methods: Three databases were searched from 2007 to 2017 using the following keywords “(“chlorine gas” OR “chlorine-induced” OR” chlorine-exposed”) AND (“therapy” OR “treatment” OR “post-exposure”)”. Forty-five relevant papers were found: 22 animal studies, 6 reviews, 19 case reports and 1 human randomized controlled study.

General management: Once the casualty has been removed from the source of exposure and adequately decontaminated, chlorine-exposed patients should receive supportive care.

Humidified oxygen: If dyspnea and hypoxemia are present, humidified oxygen should be administered.

Inhaled bronchodilators: The use of nebulized or inhaled bronchodilators to counteract bronchoconstriction is standard therapy, and the combination of ipratropium bromide with beta₂-agonists effectively reversed bronchoconstriction, airway irritation and increased airway resistance in experimental studies.

Inhaled sodium bicarbonate: In a randomized controlled trial, humidified oxygen, intravenous prednisolone and inhaled salbutamol were compared with nebulized sodium bicarbonate. The only additional benefit of sodium bicarbonate was to increase the forced expiratory volume in one second, 2 and 4?h after administration.

Corticosteroids: Dexamethasone 100?mg/kg intraperitoneally (IP) reduced lung edema when given within 1?h of chlorine inhalation and when administered within 6?h significantly decreased (p?Antioxidants: An ascorbic acid/deferoxamine combination (equivalent to 100?mg/kg and 15?mg/kg, respectively) was administered intramuscularly 1?h after chlorine exposure, then every 12?h up to 60?h, then as an aerosol, and produced a significant reduction (p?p?Sodium nitrite: Sodium nitrite 10?mg/kg intramuscularly (IM), 30?min post-chlorine exposure in mice and rabbits significantly reduced (p?Dimethylthiourea: Dimethylthiourea 100?mg/kg IP significantly decreased (p?AEOL 10150: Administration of AEOL10150 5?mg/kg IP at 1?h and 9?h post-chlorine exposure reduced significantly the neutrophil (p?p?Transient receptor potential vanilloid 4 (TRPV4): IM or IP TRPV4 reduced significantly (p?Reparixin and triptolide: In experimental studies, triptolide 100–1000 µg/kg IP 1?h post-exposure caused a significant decrease (p?Rolipram: Nanoemulsion formulated rolipram administered intramuscularly returned airway resistance to baseline. Rolipram (40%)/poly(lactic-co-glycolic acid) (60%) 0.36?mg/mouse given intramuscularly 1?h post-exposure significantly reduced (p?t?+?6?h.

Prophylactic antibiotics: Studies in patients have failed to demonstrate benefit.

Sevoflurane: Sevoflurane has been used in one intubated patient in addition to beta₂-agonists. Although the peak inspiratory pressure was decreased after 60?min, the role of sevofluorine is not known.

Conclusions: Various therapies seem promising based on animal studies or case reports. However, these recommendations are based on low-level quality data. A systematic list of outcomes to monitor and improve may help to design optimal therapeutic protocols to manage chlorine-exposed patients.     

Multicenter evaluation of a lateral-flow device test for diagnosing invasive pulmonary aspergillosis in ICU patients

IntroductionThe incidence of invasive pulmonary aspergillosis (IPA) in intensive care unit (ICU) patients is increasing, and early diagnosis of the disease and treatment with antifungal drugs is critical for patient survival. Serum biomarker tests for IPA typically give false-negative results in non-neutropenic patients, and galactomannan (GM) detection, the preferred diagnostic test for IPA using bronchoalveolar lavage (BAL), is often not readily available. Novel approaches to IPA detection in ICU patients are needed. In this multicenter study, we evaluated the performance of an Aspergillus lateral-flow device (LFD) test for BAL IPA detection in critically ill patients.MethodsA total of 149 BAL samples from 133 ICU patients were included in this semiprospective study. Participating centers were the medical university hospitals of Graz, Vienna and Innsbruck in Austria and the University Hospital of Mannheim, Germany. Fungal infections were classified according to modified European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria.ResultsTwo patients (four BALs) had proven IPA, fourteen patients (sixteen BALs) had probable IPA, twenty patients (twenty-one BALs) had possible IPA and ninety-seven patients (one hundred eight BALs) did not fulfill IPA criteria. Sensitivity, specificity, negative predictive value, positive predictive value and diagnostic odds ratios for diagnosing proven and probable IPA using LFD tests of BAL were 80%, 81%, 96%, 44% and 17.6, respectively. Fungal BAL culture exhibited a sensitivity of 50% and a specificity of 85%.ConclusionLFD tests of BAL showed promising results for IPA diagnosis in ICU patients. Furthermore, the LFD test can be performed easily and provides rapid results. Therefore, it may be a reliable alternative for IPA diagnosis in ICU patients if GM results are not rapidly available.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02058316","term_id":"NCT02058316"}}NCT02058316. Registered 20 January 2014.     

Recombinant AAV-directed gene therapy for type I glycogen storage diseases

Introduction: Glycogen storage disease (GSD) type Ia and Ib are disorders of impaired glucose homeostasis affecting the liver and kidney. GSD-Ib also affects neutrophils. Current dietary therapies cannot prevent long-term complications. In animal studies, recombinant adeno-associated virus (rAAV) vector-mediated gene therapy can correct or minimize multiple aspects of the disorders, offering hope for human gene therapy.

Areas covered: A summary of recent progress in rAAV-mediated gene therapy for GSD-I; strategies to improve rAAV-mediated gene delivery, transduction efficiency and immune avoidance; and vector refinements that improve expression.

Expert opinion: rAAV-mediated gene delivery to the liver can restore glucose homeostasis in preclinical models of GSD-I, but some long-term complications of the liver and kidney remain. Gene therapy for GSD-Ib is less advanced than for GSD-Ia and only transient correction of myeloid dysfunction has been achieved. A question remains as to whether a single rAAV vector can meet the expression efficiency and tropism required to treat all aspects of GSD-I, or if a multi-pronged approach is needed. An understanding of the strengths and weaknesses of rAAV vectors in the context of strategies to achieve efficient transduction of the liver, kidney and hematopoietic stem cells is required for treating GSD-I.     

Rituximab for chronic lymphocytic leukemia

Introduction: Significant advances have been made to understand the mechanisms involved in cardiac cell-based therapies. The early translational application of basic science knowledge has led to several animal and human clinical trials. The initial promising beneficial effect of stem cells on cardiac function restoration has been eclipsed by the inability of animal studies to translate into sustained clinical improvements in human clinical trials.

Areas covered: In this review, the authors cover an updated overview of various stem cell populations used in chronic heart failure. A critical review of clinical trials conducted in advanced heart failure patients is proposed, and finally promising avenues for developments in the field of cardiac cell-based therapies are presented.

Expert opinion: Several questions remain unanswered, and this limits our ability to understand basic mechanisms involved in stem cell therapeutics. Human studies have revealed critical unresolved issues. Further elucidation of the proper timing, mode delivery and prosurvival factors is imperative, if the field is to advance. The limited benefits seen to date are simply not enough if the potential for substantial recovery of nonfunctioning myocardium is to be realized.     

Therapeutic evaluation of a microbioartificial liver with recombinant HepG2 cells for rats with hepatic failure

Background: HepG2/(ArgI+OTC)4 (previously constructed) is a recombinant human liver cell line with a strong ability to reduce ammonia in vitro. However, its application value ex vivo has not been investigated.

Objectives: To examine the efficacy of HepG2/(ArgI+OTC)4 cells in a micro-bioartificial liver (micro-BAL) device for application ex vivo.

Methods: A simple micro-BAL device containing a microbioreactor and a small-type peristaltic pump was installed. The rats with hepatic failure were randomly divided into three groups (n = 10) and were treated with different micro-BAL loaded HepG2/(ArgI+OTC)4 cells, HepG2 cells and control (without cells), respectively. Changes in the liver and kidney function of the rats were determined before and after the treatment. The lifespan of the rats were observed and recorded.

Results: Despite the difference in survival time between experimental groups of rat model was not statistically significant, the capacity of HepG2/(ArgI+OTC)4 cells treatment group for tolerance and detoxifying ammonia was increased much more than that of HepG2 cells (p < 0.05), and other biochemical indicators of HepG2/(ArgI+OTC)4 cells treatment group were also better than that of HepG2 cells treatment group (p < 0.05).

Conclusions: HepG2/(ArgI+OTC)4 cells can provide a better biological support for rats with hepatic failure in a short period of time, and they may be used as a convenient and useful choice for further cell material research of BAL.     

Adipose stem cell-based soft tissue regeneration

Introduction: Since their isolation and characterization nearly a decade ago, adipose-derived stem cells (ASCs) have become one of the most popular adult stem cell populations for research in soft tissue engineering and regenerative medicine applications. Compared with other stem cell sources, ASCs offer several advantages including an abundant autologous source, minor invasive harvesting (liposuction), significant proliferative capacity in culture and multi-lineage potential. Numerous preclinical studies have been pursued, with early clinical data appearing in the literature.

Areas covered: Autologous fat grafting has gained tremendous momentum in clinical practice over the past several years due to its potential applications in trauma and reconstructive surgery. This review focuses on the published clinical and pre-clinical (i.e., animal) data to date using ASCs for soft tissue reconstruction, with particular attention to experimental models and methodologies. Future directions for rendering soft tissue reconstructive therapies more effective are discussed.

Expert opinion: Although standardization of ASC harvesting and processing techniques, as well as long-term results of existing clinical studies, remains to be addressed, the known biological properties of ASCs suggest a potential role in enhancing fat graft retention and facilitating minimally invasive reconstructive treatments. While clinical applications are being reported, well controlled clinical studies are needed to demonstrate safety and efficacy.     

Navigated laparoscopy – liver shift and deformation due to pneumoperitoneum in an animal model

Abstract

Background: Precise laparoscopic liver resection requires accurate planning and visualization of important anatomy such as vessels and tumors. Combining laparoscopic ultrasound with navigation technology could provide this. Preoperative images are valuable for planning and overview of the procedure, while intraoperative images provide an updated view of the surgical field. Purpose: To validate the accuracy of navigation technology based on preoperative images, we need to understand how much the liver shifts and deforms due to heartbeat, breathing, surgical manipulation and pneumoperitoneum. In this study, we evaluated liver tumor shift and deformation due to pneumoperitoneum in an animal model. Methods: Tumor models were injected into the liver of the animal, and 3D CT images were acquired before and after insufflation. Tumor shifts and deformation were determined. Results: The results showed significant tumor position shift due to pneumoperitoneum, with a maximum of 28 mm in cranio-caudal direction. No significant tumor deformation was detected. Small standard deviations suggest rigid body transformation of the liver as a whole, but this needs further investigation. Conclusion: The findings indicate a need for anatomic shift correction of preoperative images before they are used in combination with LUS guidance during a laparoscopic liver resection procedure.     

Blood coagulation in anhepatic pigs: effects of treatment with the AMC-bioartificial liver

Summary. The function of a newly devised bioartificial liver (AMC‐BAL) based on viable, freshly isolated porcine hepatocytes has been evaluated in anhepatic pigs. The aim of this study was to assess the contribution of BAL treatment on blood coagulation parameters. Pigs were anesthetized and a total hepatectomy was performed (n = 15). The infrahepatic caval vein and the portal vein were connected to the subdiaphragmatic caval vein using a three‐way prosthesis. Animals received standard intensive care (control, n= 5), treatment with an empty BAL (device control, n= 5) or with a cell‐loaded BAL (BAL‐treatment, n= 5) for a period of 24 h starting 24 h after hepatectomy. Coagulation parameters studied concerned prothrombin time (PT), platelet count, the procoagulant system (factors (F)II, FV, FVII, FVIII and fibrinogen), anticoagulant system (AT III), fibrinolytic system (t‐PA, PAI‐1) as well as markers of coagulation factor activation (TAT complexes, prothrombin fragment F1 + 2). FII, FV, FVII, AT III and fibrinogen rapidly decreased after total hepatectomy in pigs in accordance with the anhepatic state of the animals. FVIII levels were not influenced by the hepatectomy. A mild drop in platelet count was seen in all groups. Treatment of anhepatic pigs with the cell‐loaded BAL did not restore PT or clotting factor levels. TAT and F1 + 2 complexes, however, were significantly increased in this group. Levels of t‐PA and PAI‐1 were not influenced by cell‐loaded BAL treatment. Treatment of anhepatic pigs with the AMC‐BAL based on freshly isolated porcine hepatocytes does not result in an improved coagulation state due to extensive consumption of clotting factors. However, increased levels of TAT complexes and prothrombin fragments F1 + 2 during treatment of anhepatic pigs indicate synthesis and direct activation of coagulation factors, leading to thrombin generation. This demonstrates that this bioartificial liver is capable of synthesizing coagulation factors.     

Candida sp. isolated from bronchoalveolar lavage: clinical significance in critically ill trauma patients

Objective Based on limited data, Candida sp. isolates from bronchoalveolar lavage (BAL) cultures in immunocompetent patients are thought to be contaminants rather than pathogens. The objective of this study was to determine the clinical significance of Candida sp. isolated from BAL cultures in critically ill trauma patients. Design and setting Retrospective study in a level 1 trauma intensive care unit. Patients and participants All patients with Candida sp. isolated from BAL cultures over a 3-year period; 85 Candida positive BAL cultures from 62 patients were studied. Measurements and results The primary outcomes were the incidence of Candida sp. in BAL, antifungal use, course of the possible infection, and mortality. Of 1077 BAL cultures 85 (8%) grew Candida sp., representing 64 episodes of possible Candida sp. ventilator-associated pneumonia. No colony counts exceeded the diagnostic threshold for bacterial VAP (≥ 10⁵ cfu/ml). Only 2 of 64 episodes (3%) were treated with systemic antifungals. Three other episodes (5%) were treated because of concomitant therapy for Candida sp. at other sites. The majority of episodes were not treated with antifungals and were considered contaminants (59/64, 92%). No patients developed subsequent candidemia, and most follow-up BALs (74%) were negative for Candida sp. Overall mortality (17%) was similar to previous patients with similar severity of injury at the study center (18%). Conclusions The results of this study suggest that isolation of Candida sp. from BAL in quantities below the diagnostic threshold for VAP in this population does not require antifungal therapy.     

Acoustic characterization of Thiel liver for magnetic resonance-guided focused ultrasound treatment

Background: The purpose of this work was to measure the essential acoustic parameters, i.e., acoustic impedance, reflection coefficient, attenuation coefficient, of Thiel embalmed human and animal liver. The Thiel embalmed tissue can be a promising, pre-clinical model to study liver treatment with Magnetic Resonance-guided Focused Ultrasound (MRgFUS).

Material and methods: Using a single-element transducer and the contact pulse-echo method, the acoustic parameters, i.e., acoustic impedance, reflection coefficient and attenuation coefficient of Thiel embalmed human and animal liver were measured.

Results: The Thiel embalmed livers had higher impedance, similar reflection and lower attenuation compared to the fresh tissue.

Conclusions: Embalming liver with Thiel fluid affects its acoustic properties. During MRgFUS sonication of a Thiel organ, more focused ultrasound (FUS) will be backscattered by the organ, and higher acoustic powers are required to reach coagulation levels (temperatures >56?°C).     

Gene therapy for pulmonary hypertension: prospects and challenges

Introduction: Recent evidence shows that pulmonary arterial hypertension (PAH) remains a fatal disease despite the introduction of new pharmacological treatments. New options are therefore needed and gene therapy approaches are a rational consideration based on emerging understanding of the genetic basis of PAH.

Areas covered: This review briefly discusses the recent developments in clinical management of PAH and the investigation of gene delivery techniques for pulmonary vascular disease from 1997 to 2010, relating this to improved understanding of disease pathogenesis during this period. There is a focus on bone morphogenetic protein receptor type 2, as mutations in this gene are clearly linked to disease pathogenesis and outcomes. The reader will gain insight into the gene vector strategies being used, the target cells and the specific genes being delivered as candidate therapeutic approaches for PAH.

Expert opinion: Various genes and strategies for delivery have achieved improvements in PAH in animal models, which is encouraging for the development of this technology for human application. The main limiting factor for clinical progress relates to gene delivery vector technology.     

Effectiveness of an Occupational Therapy Program on Cancer Patients with Dyspnea: Randomized Trial

Abstract

Background: Dyspnea is one of the leading causes of loss of autonomy among patients with advanced cancer. The management of these symptoms relies exclusively on pharmacological measures.

Aims: To assess the effectiveness of a “occupational therapy program” to improve both personal functionality and respiratory function in patients with dyspnea.

Methods: Experimental, prospective, longitudinal, and randomized study. A total of 102 individuals from the inpatient oncology unit of the University Salamanca Hospital Complex were participated in this study. In addition to pharmacological treatment, the intervention group participated in the occupational therapy program.

Results: The study yielded statistically significant differences between the members of the experimental group and those of the control group in functionality levels, as well as statistically significant differences in the BODE global respiratory index scores (p?<?0.001), and in the dyspnea level scores (p?<?0.001) between both groups.

Conclusions: Comprehensive respiratory rehabilitation program from an occupational therapy perspective improve functionality and overall respiratory function levels in cancer patients suffering from dyspnea.     

Visceral leishmaniasis elimination targets in India,strategies for preventing resurgence

ABSTRACT

Introduction: Visceral leishmaniasis (VL) is a fatal parasitic disease caused by a parasite belonging to the Leishmania donovani complex and transmitted by infected female Phlebotomous argentipes sand flies. The VL elimination strategy in the Indian subcontinent (ISC), which has a current goal of reducing the incidence of VL to below 1/10,000 of population by the year 2020, consists of rapid detection and treatment of VL to reduce the number of human reservoirs as well as vector control using indoor residual spraying (IRS). However, as the incidence of VL declines toward the elimination goal, greater targeting of control methods will be required to ensure appropriate early action to prevent the resurgence of VL.

Area covered: We discuss the current progress and challenges in the VL elimination program and strategies to be employed to ensure sustained elimination of VL.

Expert commentary: The VL elimination initiative has saved many human lives; however, for VL elimination to become a reality in a sustained way, an intense effort is needed, as substantial numbers of endemic subdistricts (primary health centers (PHCs) blocks level) are yet to reach the elimination target. In addition to effective epidemiological surveillance, appropriate diagnostic and treatment services for VL at PHCs will be needed to ensure long-term sustainability and prevent reemergence of VL.     

Does providing routine liver volume assessment add value when performing CT surveillance in cirrhotic patients?

Background

The measurement of liver volume (LV) is considered to be an effective prognosticator for postoperative liver failure in patients undergoing hepatectomy. It is unclear whether LV can be used to predict mortality in cirrhotic patients.

Methods

We enrolled 584 consecutive cirrhotic patients who underwent computerized topography (CT) of the abdomen for hepatocellular carcinoma surveillance and 50 age, gender, race, and BMI-matched controls without liver disease. Total LV (TLV), functional LV (FLV), and segmental liver volume (in cm³) were measured from CT imaging. Cirrhotic subjects were followed until death, liver transplantation, or study closure date of July 31, 2016. The survival data were assessed with log-rank statistics and independent predictors of survival were performed using Cox hazards model.

Results

Cirrhotic subjects had significantly lower TLV, FLV, and segmental (all except for segments 1, 6, 7) volume when compared to controls. Subjects presenting with hepatic encephalopathy had significantly lower TLV and FLV than those without HE (p = 0.002). During the median follow-up of 1145 days, 112 (19%) subjects were transplanted and 131 (23%) died. TLV and FLV for those who survived were significantly higher than those who were transplanted or dead (TLV:1740 vs. 1529 vs. 1486, FLV 1691 vs. 1487 vs. 1444, p < 0.0001). In the Cox regression model, age, MELD score, TLV, or FLV were independent predictors of mortality.

Conclusion

Baseline liver volume is an independent predictor of mortality in subjects with cirrhosis. Therefore, it may be useful to provide these data while performing routine surveillance CT scan as an important added value. Further studies are needed to validate these findings and to better understand their clinical utility.

     

The therapeutic potential of phiC31 integrase as a gene therapy system

Introduction: The φC31 integrase system is a phage-derived system that offers the ability to integrate plasmid DNA into the chromosomes at a subset of endogenous preferred locations associated with robust gene expression. Recent progress highlights the unique advantages of this system for in vivo gene therapy and for use in stem cells.

Areas covered: The φC31 integrase system has been under development for ten years and has been demonstrated to be effective for integration of plasmids in a variety of tissues and organs for gene therapy in animal systems, as well as in isolated human cells. We focus on work with the φC31 integrase system during the past 12 – 18 months. This work has centered on a series of papers involving in vivo delivery of the integrase system to the liver and a variety of studies demonstrating the utility of the integrase system in stem cells.

Expert opinion: We conclude that the φC31 integrase system has significant potential for liver gene therapy, if effective DNA delivery methods for large mammals become available. The φC31 integrase system displays an outstanding fit for use in pluripotent stem cells, and this area is expected to be the subject of intense development.     

Caspase-Based PET for Evaluating Pro-Apoptotic Treatments in a Tuberculosis Mouse Model

Purpose

Despite recent advances in antimicrobial treatments, tuberculosis (TB) remains a major global health threat. Mycobacterium tuberculosis proliferates in macrophages, preventing apoptosis by inducing anti-apoptotic proteins leading to necrosis of the infected cells. Necrosis then leads to increased tissue destruction, reducing the penetration of antimicrobials and immune cells to the areas where they are needed most. Pro-apoptotic drugs could be used as host-directed therapies in TB to improve antimicrobial treatments and patient outcomes.

Procedure

We evaluated [¹⁸F]-ICMT-11, a caspase-3/7-specific positron emission tomography (PET) radiotracer, in macrophage cell cultures and in an animal model of pulmonary TB that closely resembles human disease.

Results

Cells infected with M. tuberculosis and treated with cisplatin accumulated [¹⁸F]-ICMT-11 at significantly higher levels compared with that of controls, which correlated with levels of caspase-3/7 activity. Infected mice treated with cisplatin with increased caspase-3/7 activity also had a higher [¹⁸F]-ICMT-11 PET signal compared with that of untreated infected animals.

Conclusions

[¹⁸F]-ICMT-11 PET could be used as a noninvasive approach to measure intralesional pro-apoptotic responses in situ in pulmonary TB models and support the development of pro-apoptotic host-directed therapies for TB.

     

Animal models of tendinopathy

Purpose. The term tendinopathy describes non-ruptured tendon injuries. While several important studies have evaluated the aetiology, pathogenesis, and treatment of this common condition, further study is needed. Several animal models, which allow for full tissue evaluation on different organizational levels and stages of disease, have been used to investigate tendinopathy.

Method. A literature review was conducted to identify and evaluate animal models that have been developed and used to study the aetiology and pathology of tendinopathy.

Results. Animal models of tendinopathy fit into two general categories based on the mode of injury application: (i) models that induce tendinopathy through a change in the mechanical environment, and (ii) models that induce tendinopathy through a chemical agent. The cost, difficulty, invasiveness, reproducibility and time required to induce injury in these models varies. Mechanically-induced models are beneficial since they induce injury through repetitive mechanical loading, similar to how tendinopathy is believed to develop in the human condition. Chemically-induced models are beneficial by allowing for the study of the interplay among inflammatory cells, mechanical loading and tissue healing.

Conclusion. Further work is needed to fully characterize and understand tendinopathy. Appropriate animal models provide a greater understanding of human tendinopathy, leading to better prevention and treatment.