Therapeutic targeting of cellular senescence in diabetic macular edema: preclinical and phase 1 trial results.

Compromised vascular endothelial barrier function is a salient feature of diabetic complications such as sight-threatening diabetic macular edema (DME). Current standards of care for DME manage aspects of the disease, but require frequent intravitreal administration and are poorly effective in large subsets of patients. Here we provide evidence that an elevated burden of senescent cells in the retina triggers cardinal features of DME pathology and conduct an initial test of senolytic therapy in patients with DME. In cell culture models, sustained hyperglycemia provoked cellular senescence in subsets of vascular endothelial cells displaying perturbed transendothelial junctions associated with poor barrier function and leading to micro-inflammation. Pharmacological elimination of senescent cells in a mouse model of DME reduces diabetes-induced retinal vascular leakage and preserves retinal function. We then conducted a phase 1 single ascending dose safety study of UBX1325 (foselutoclax), a senolytic small-molecule inhibitor of BCL-xL, in patients with advanced DME for whom anti-vascular endothelial growth factor therapy was no longer considered beneficial. The primary objective of assessment of safety and tolerability of UBX1325 was achieved. Collectively, our data suggest that therapeutic targeting of senescent cells in the diabetic retina with a BCL-xL inhibitor may provide a long-lasting, disease-modifying intervention for DME. This hypothesis will need to be verified in larger clinical trials. ClinicalTrials.gov identifier: NCT04537884 .

HIF1α-dependent hypoxia response in myeloid cells requires IRE1α.

Cellular adaptation to low oxygen tension triggers primitive pathways that ensure proper cell function. Conditions of hypoxia and low glucose are characteristic of injured tissues and hence successive waves of inflammatory cells must be suited to function under low oxygen tension and metabolic stress. While Hypoxia-Inducible Factor (HIF)-1α has been shown to be essential for the inflammatory response of myeloid cells by regulating the metabolic switch to glycolysis, less is known about how HIF1α is triggered in inflammation. Here, we demonstrate that cells of the innate immune system require activity of the inositol-requiring enzyme 1α (IRE1α/XBP1) axis in order to initiate HIF1α-dependent production of cytokines such as IL1ß, IL6 and VEGF-A. Knockout of either HIF1α or IRE1α in myeloid cells ameliorates vascular phenotypes in a model of retinal pathological angiogenesis driven by sterile inflammation. Thus, pathways associated with ER stress, in partnership with HIF1α, may co-regulate immune adaptation to low oxygen.

Early-life peripheral infections reprogram retinal microglia and aggravate neovascular age-related macular degeneration in later life.

Pathological neovascularization in age-related macular degeneration (nvAMD) drives the principal cause of blindness in the elderly. While there is a robust genetic association between genes of innate immunity and AMD, genome-to-phenome relationships are low, suggesting a critical contribution of environmental triggers of disease. Possible insight comes from the observation that a past history of infection with pathogens such as Chlamydia pneumoniae, or other systemic inflammation, can predispose to nvAMD in later life. Using a mouse model of nvAMD with prior C. pneumoniae infection, endotoxin exposure, and genetic ablation of distinct immune cell populations, we demonstrated that peripheral infections elicited epigenetic reprogramming that led to a persistent memory state in retinal CX3CR1+ mononuclear phagocytes (MNPs). The immune imprinting persisted long after the initial inflammation had subsided and ultimately exacerbated choroidal neovascularization in a model of nvAMD. Single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) identified activating transcription factor 3 (ATF3) as a central mediator of retina-resident MNP reprogramming following peripheral inflammation. ATF3 polarized MNPs toward a reparative phenotype biased toward production of proangiogenic factors in response to subsequent injury. Therefore, a past history of bacterial endotoxin-induced inflammation can lead to immunological reprograming within CNS-resident MNPs and aggravate pathological angiogenesis in the aging retina.

Past history of obesity triggers persistent epigenetic changes in innate immunity and exacerbates neuroinflammation.

Age-related macular degeneration is a prevalent neuroinflammatory condition and a major cause of blindness driven by genetic and environmental factors such as obesity. In diseases of aging, modifiable factors can be compounded over the life span. We report that diet-induced obesity earlier in life triggers persistent reprogramming of the innate immune system, lasting long after normalization of metabolic abnormalities. Stearic acid, acting through Toll-like receptor 4 (TLR4), is sufficient to remodel chromatin landscapes and selectively enhance accessibility at binding sites for activator protein-1 (AP-1). Myeloid cells show less oxidative phosphorylation and shift to glycolysis, ultimately leading to proinflammatory cytokine transcription, aggravation of pathological retinal angiogenesis, and neuronal degeneration associated with loss of visual function. Thus, a past history of obesity reprograms mononuclear phagocytes and predisposes to neuroinflammation.

Impact of tuberosity treatment in reverse shoulder arthroplasty after proximal humeral fractures: A multicentre study.

BACKGROUND: To assess how tuberosity treatment affects the short-term clinical outcome of patients with complex proximal humeral fractures (PHFs) treated with reverse shoulder arthroplasty (RSA). METHODS: This is a multicentre study on 90 patients affected by acute PHFs (Neer type-4/11C3.2 in 80% of patients, and a Neer type 3/11B3.2 in 20%) treated with RSA and followed at an average of 34 months. Patients were divided into two groups (reconstructed and non-reconstructed tuberosity) according to the surgical fixation of the tuberosities. Then, the "reconstructed tuberosity" was divided into "healed" and "non-healed" groups. All patients were clinically evaluated in terms of ROM and strength in elevation, as well as with 0-10 numerical rating scale (NRS), Constant and Murley Score (CMS), DASH Score, and EQ-VAS. X-rays in anteroposterior and Neer views were performed. RESULTS: Based on the status of the tuberosities, 18.9% were non-reconstructed (17 patients) and 81.1% were reconstructed (73 patients): out of these, 11 were correctly healed, 42 healed with malposition, and 20 were reabsorbed. Instability was found in 2/73 patients in the reconstructed group, and in 4/17 patients in the non-reconstructed group. NRS (1.4 vs 0.5), DASH (23.1 vs 13.9), and EQ-VAS (78.1 vs 83.7) scores had better final values in the non-reconstructed group (p < 0.05). However, the non-correctly healed tuberosity group (excision + resorption + malposition/migration) showed worse strength, as well as clinical scores when compared to the correctly healed tuberosity group. CONCLUSION: RSA ensures satisfactory functional results for PHFs. Patients with a successfully reconstructed tuberosity have an overall better outcome. However, in this series most of the reconstructed cases presented tuberosity reabsorption, malposition, or migration, which led to lower results. Thus, tuberosity reconstruction must be carefully considered and tuberosity reabsorption or migration factors should be investigated, to optimize tuberosity reconstruction and provide to a higher number of patients a better outcome of RSA for the treatment of PHFs.

Obesity triggers tumoral senescence and renders poorly immunogenic malignancies amenable to senolysis.

Obesity is a major risk factor for cancer. Conventional thought suggests that elevated adiposity predisposes to heightened inflammatory stress and potentiates tumor growth, yet underlying mechanisms remain ill-defined. Here, we show that tumors from patients with a body mass index >35 carry a high burden of senescent cells. In mouse syngeneic tumor models, we correlated a pronounced accretion of senescent cancer cells with poorly immunogenic tumors when mice were subjected to diet-induced obesity (DIO). Highly immunogenic tumors showed lesser senescence burden suggesting immune-mediated elimination of senescent cancer cells, likely targeted as a consequence of their senescence-associated secretory phenotype. Treatment with the senolytic BH3 mimetic small molecule inhibitor ABT-263 selectively stalled tumor growth in mice with DIO to rates comparable to regular diet-fed mice. Thus, consideration of body adiposity in the selection of cancer therapy may be a critical determinant for disease outcome in poorly immunogenic malignancies.

Myeloid-resident neuropilin-1 influences brown adipose tissue in obesity.

The beneficial effects of brown adipose tissue (BAT) on obesity and associated metabolic diseases are mediated through its capacity to dissipate energy as heat. While immune cells, such as tissue-resident macrophages, are known to influence adipose tissue homeostasis, relatively little is known about their contribution to BAT function. Here we report that neuropilin-1 (NRP1), a multiligand single-pass transmembrane receptor, is highly expressed in BAT-resident macrophages. During diet-induced obesity (DIO), myeloid-resident NRP1 influences interscapular BAT mass, and consequently vascular morphology, innervation density and ultimately core body temperature during cold exposure. Thus, NRP1-expressing myeloid cells contribute to the BAT homeostasis and potentially its thermogenic function in DIO.

Neutrophil extracellular traps target senescent vasculature for tissue remodeling in retinopathy.

In developed countries, the leading causes of blindness such as diabetic retinopathy are characterized by disorganized vasculature that can become fibrotic. Although many such pathological vessels often naturally regress and spare sight-threatening complications, the underlying mechanisms remain unknown. Here, we used orthogonal approaches in human patients with proliferative diabetic retinopathy and a mouse model of ischemic retinopathies to identify an unconventional role for neutrophils in vascular remodeling during late-stage sterile inflammation. Senescent vasculature released a secretome that attracted neutrophils and triggered the production of neutrophil extracellular traps (NETs). NETs ultimately cleared diseased endothelial cells and remodeled unhealthy vessels. Genetic or pharmacological inhibition of NETosis prevented the regression of senescent vessels and prolonged disease. Thus, clearance of senescent retinal blood vessels leads to reparative vascular remodeling.

Arthroscopically assisted and three-dimensionally modeled minimally invasive rim plate osteosynthesis via modified anterolateral approach for posterolateral tibial plateau fractures.

AIM: The aim of this study was to describe a new, closed, arthroscopically-assisted reduction of posterolateral tibial plateau fractures with minimally invasive plate osteosynthesis using a plate pre-contoured over a 3D-model based on a CT-scan of the injured tibial plateau and positioned by using a minimal anterolateral approach. METHODS: A five to six centimeter long curvilinear incision was made over the Gerdy's tubercle. After subcutaneous dissection, the fascia was incised, the ileo-tibial band was split, and the dissection was extended posteriorly. The knee was flexed to 90° and the space between the fibular collateral ligament and the posterolateral plateau rim (para-FCL space) was created. A variable-angle locking compression plate contoured on a 3D-model was inserted flush to the tibial plateau rim. Two cortical screws were placed to ensure support under the area of depression as far posteriorly as possible. Two additional screws were implanted, and a cortical screw was used for the most anterior screw hole. The custom pre-contoured plate based on a person-specific 3D-model, associated with arthroscopy reduction, provides a supporting and containing effect to the posterolateral periarticular fragments and allows a minimally invasive plate osteosynthesis fixation to be performed. This guarantees a proper reduction and fixation without the described limitations and risks associated with the classic approaches. CONCLUSIONS: This approach should be considered to treat fractures of the posterolateral plateau, isolated or associated with medial tibial plateau fractures, as it could improve the outcome in terms of lower associated risks, better reduction and fixation, and faster and improved patient recovery.

Orthopaedic nursing challenges in poly-traumatised patient management: A critical analysis of an Orthopaedic and Trauma Unit.

INTRODUCTION AND BACKGROUND: Trauma is the most frequent cause of death in people under 40 years old. It is an important problem not only because of the high mortality but also because of the consequential disability that can lead to serious economic consequences. STUDY AIMS: This descriptive, comparative study investigates the definitive management of poly-traumatised patients in an Italian Orthopaedic Ward in order to highlight its strengths and weaknesses in comparison with the most recent literature. This has led to the development of a pre-established algorithm for evaluation, preventive care and management of the poly-trauma patient and a flow-chart for improved patient care. RESEARCH METHODS: A five-step observational and exploratory approach was employed in this study which critically analysed the nursing management of 60 multiple trauma patients admitted to our Orthopaedic Unit from April 2013 to October 2014. RESULTS: The findings highlight the need for adherence to plans of care, which can be approached by a shared management of poly-trauma patients that involves the medical team, the patient and his family/caregiver. DISCUSSION: The protocols and guidelines in use in our Orthopaedic and Trauma Unit are in line with European standards, although there is still margin for improvement. The study has led to the development of an algorithm that allows health professionals to have reference values for the care of polytrauma patients. CONCLUSIONS AND RECOMMENDATIONS: This study demonstrates the use of theoretical and practical tools for the evaluation and management of poly-traumatised patients during their hospital stay. We recommend the use of both proposed tools: the general algorithm and the flow-chart for the management of the poly-trauma patient, as they allow identification of barriers and facilitators related to the implementation of international guidelines, currently well-defined for Emergency Departments but not yet for Orthopaedic Units.

Association between ambulatory physical activity and injuries during United States Army Basic Combat Training.

BACKGROUND: Associations between physical activity and injuries have been previously examined using self-reports. The present investigation examined this association using objective measures of activity and injury. METHODS: To quantify ambulatory activity, pedometers were worn daily by recruits in 10 Army Basic Combat Training companies during the 9-week training cycle. Injuries were obtained from a medical surveillance system, defined as traumatic or overuse events resulting in a medical care provider visit. A daily questionnaire documented whether or not recruits wore the pedometers and trained with their companies for the entire day. RESULTS: Training companies were categorized by activity level into 3 groups with higher activity (HA, 17,948±550 steps/day), 4 with moderate activity (MA, 16,346±768 steps/day) and 3 with lower activity (LA, 14,772±400 steps/day). Among men, the MA and HA groups were at 1.52 (95% confidence interval [95% CI]=1.15-2.01) and 1.94 (95% CI=1.46-2.61) times higher injury risk, respectively, compared with the LA group. Among women, the MA and HA groups were at 1.36 (95% CI=1.07-1.73) and 1.53 (95% CI=1.24-1.89) times higher injury risk, respectively, compared with low LA group. The relationships remained significant after considering physical characteristics and physical fitness. CONCLUSIONS: In consonance with previous self-report studies, higher physical activity was associated with higher injury risk.

Potentially deadly carcinogenic chromium redox cycle involving peroxochromium(IV) and glutathione.

Peroxochromium(IV) complexes are putative DNA-damaging and mutagenic agents in chromium(VI)-mediated carcinogenesis. The reaction between aquaethylenediaminebis(peroxo)chromium(IV) and glutathione at neutral pH exhibits a cyclic redox process displaying a persistent recycling of Cr(IV) and Cr(VI) with the intervention of chromium(V) intermediates. The coordination by a glutathione molecule triggers an autooxidation of the Cr(IV)-peroxo complex to Cr(VI) via an internal electron-transfer process followed by reduction to Cr(IV) via metastable chromium(V) intermediates. The cycle is repeated by the second peroxo species. The Cr(V) and -(IV) intermediates have been characterized as mono- and bisglutathionato complexes with or without a coordinated peroxo moiety. These intermediates are capable of damaging DNA, as evidenced by single strand breaks and DNA oxidation. The implication here is that the potential for a persistent, if not perpetual, deadly chromium carcinogenic cycle exists in the cellular milieu through the assistance of molecular oxygen and glutathione.

A systematic review of post-deployment injury-related mortality among military personnel deployed to conflict zones.

BACKGROUND: This paper reports on a systematic review of the literature on the post-conflict injury-related mortality of service members who deployed to conflict zones. METHODS: Literature databases, reference lists of articles, agencies, investigators, and other sources were examined to find studies comparing injury-related mortality of military veterans who had served in conflict zones with that of contemporary veterans who had not served in conflict zones. Injury-related mortality was defined as a cause of death indicated by International Classification of Diseases E-codes E800 to E999 (external causes) or subgroupings within this range of codes. RESULTS: Twenty studies met the review criteria; all involved veterans serving during either the Vietnam or Persian Gulf conflict. Meta-analysis indicated that, compared with non-conflict-zone veterans, injury-related mortality was elevated for veterans serving in Vietnam (summary mortality rate ratio (SMRR) = 1.26, 95% confidence interval (95%CI) = 1.08-1.46) during 9 to 18 years of follow-up. Similarly, injury-related mortality was elevated for veterans serving in the Persian Gulf War (SMRR = 1.26, 95%CI = 1.16-1.37) during 3 to 8 years of follow-up. Much of the excess mortality among conflict-zone veterans was associated with motor vehicle events. The excess mortality decreased over time. Hypotheses to account for the excess mortality in conflict-zone veterans included post-traumatic stress, coping behaviors such as substance abuse, ill-defined diseases and symptoms, lower survivability in injury events due to conflict-zone comorbidities, altered perceptions of risk, and/or selection processes leading to the deployment of individuals who were risk-takers. CONCLUSION: Further research on the etiology of the excess mortality in conflict-zone veterans is warranted to develop appropriate interventions.

Physical fitness and body composition after a 9-month deployment to Afghanistan.

PURPOSE: To examine change in physical fitness and body composition after a military deployment to Afghanistan. METHODS: One hundred and ten infantry soldiers were measured before and after a 9-month deployment to Afghanistan for Operation Enduring Freedom. Measurements included treadmill peak oxygen uptake (peak VO2), lifting strength, medicine ball put, vertical jump, and body composition estimated via dual-energy x-ray absorptiometry (percent body fat, absolute body fat, fat-free mass, bone mineral content, and bone mineral density). RESULTS: There were significant decreases (P < 0.01) in peak VO2 (-4.5%), medicine ball put (-4.9%), body mass (-1.9%), and fat-free mass (-3.5%), whereas percent body fat increased from 17.7% to 19.6%. Lifting strength and vertical jump performance did not change predeployment to postdeployment. CONCLUSIONS: Nine months deployment to Afghanistan negatively affected aerobic capacity, upper body power, and body composition. The predeployment to postdeployment changes were not large and unlikely to present a major health or fitness concern. If deployments continue to be extended and time between deployments decreased, the effects may be magnified and further study warranted.

Injuries and illnesses among armor brigade soldiers during operational training.

This study describes injury and illness rates and some risk factors among soldiers from an armor division during a rotation at the National Training Center (Fort Irwin, California). Soldiers from a brigade of the 1st Cavalry Division were involved in a 5-week training exercise at the National Training Center. Health care visits were systematically recorded by the unit medics. Of 4,101 men and 413 women who participated in the exercise, 504 soldiers (409 men and 95 women) sought medical care at the main support medical clinic or Weed Army Community Hospital. The rates of injury and illness visits were 1.2% and 0.6% per week for men and 2.3% and 2.2% per week for women, respectively. Women had twice the risk of an injury and 3.5 times the risk of an illness, compared with men. Compared with other branches, combat service support soldiers had higher rates of injuries and illnesses. Enlisted soldiers of lower rank (E1-E4) experienced higher injury and illness rates than did noncommissioned officers and commissioned officers. Musculoskeletal injuries, environmental conditions, and dermatological conditions accounted for most visits.

Increasing the physical fitness of low-fit recruits before basic combat training: an evaluation of fitness, injuries, and training outcomes.

Recruits arriving for basic combat training (BCT) between October 1999 and May 2004 were administered an entry-level physical fitness test at the reception station. If they failed the test, then they entered the Fitness Assessment Program (FAP), where they physically trained until they passed the test and subsequently entered BCT. The effectiveness of the FAP was evaluated by examining fitness, injury, and training outcomes. Recruits who failed the test, trained in the FAP, and entered BCT after passing the test were designated the preconditioning (PC) group (64 men and 94 women). Recruits who failed the test but were allowed to enter BCT without going into the FAP were called the no preconditioning (NPC) group (32 men and 73 women). Recruits who passed the test and directly entered BCT were designated the no need of preconditioning (NNPC) group (1,078 men and 731 women). Army Physical Fitness Test (APFT) scores and training outcomes were obtained from a company-level database, and injured recruits were identified from cases documented in medical records. The proportions of NPC, PC, and NNPC recruits who completed the 9-week BCT cycle were 59%, 83%, and 87% for men (p < 0.01) and 52%, 69%, and 78% for women (p < 0.01), respectively. Because of attrition, only 63% of the NPC group took the week 7 APFT, compared with 84% and 86% of the PC and NNPC groups, respectively. The proportions of NPC, PC, and NNPC recruits who passed the final APFT after all retakes were 88%, 92%, and 98% for men (p < 0.01) and 89%, 92%, and 97% for women (p < 0.01), respectively. Compared with NNPC men, injury risk was 1.5 (95% confidence interval, 1.0-2.2) and 1.7 (95% confidence interval, 1.0-3.1) times higher for PC and NPC men, respectively. Compared with NNPC women, injury risk was 1.2 (95% confidence interval, 0.9-1.6) and 1.5 (95% confidence interval, 1.1-2.1) times higher for PC and NPC women, respectively. This program evaluation showed that low-fit recruits who preconditioned before BCT had reduced attrition and tended to have lower injury risk, compared with recruits of similar low fitness who did not precondition.

Improvement of age-related endothelial dysfunction by simvastatin: effect on NO and COX pathways.

The effects of oral administration of the HMG-CoA reductase inhibitor, simvastatin (SV), on age-related endothelial dysfunction were investigated in the aorta of male Wistar rats. Adult (12-14 weeks) and old (60-80 weeks) rats were treated daily for 12 weeks with either vehicle or SV (1 mg kg(-1)). In old rats, SV treatment did not significantly affect systolic blood pressure and LDL-cholesterol, but it reduced plasma cholesterol, triglycerides and oxidised LDL though it did not affect total antioxidant status. SV improved endothelium-dependent relaxation to acetylcholine and A-23187 in vessels from aged, but not adult, rats. This effect was linked to a greater NO vasodilatation via an increased expression of endothelial NO-synthase. A mechanism sensitive to superoxide dismutase and catalase also accounts for enhanced endothelial vasodilatation. Finally, SV did not affect the release of prostacyclin, but it inhibited the generation of thromboxane (TX) A2 from COX-2 isoform. The effect of the latter was sensitive to the Tp receptor antagonist, ICI-192,605. The present study provides evidence that oral administration of SV improves endothelial dysfunction in the aorta from aged rats by mechanisms associated with enhanced NO vasodilatation, reduced release of TXA2 from cyclo-oxygenase, and increased antioxidant properties of the vessel wall. These data underscore a new therapeutic perspective for SV in age-related endothelial dysfunction.

Evaluation of a standardized physical training program for basic combat training.

A control group (CG, n = 1,138) that implemented a traditional Basic Combat Training (BCT) physical training (PT) program was compared to an evaluation group (EG, n = 829) that implemented a PT program newly designed for BCT. The Army Physical Fitness Test (APFT) was taken at various points in the PT program, and injuries were obtained from a medical surveillance system. After 9 weeks of training, the proportion failing the APFT was lower in the EG than in the CG (1.7 vs. 3.3%, p = 0.03). After adjustment for initial fitness levels, age, and body mass index, the relative risk of an injury in the CG was 1.6 (95% confidence interval [CI] =1.2-2.0) and 1.5 (95% CI = 1.2-1.8) times higher than in the EG for men and women, respectively. The newly designed PT program resulted in higher fitness test pass rates and lower injury rates compared to a traditional BCT physical training program.

Estudio comparativo de dos cepas avirulentas de toxoplasma gondii / Comparative study of 2 avirulent strains of toxoplasma gondii

Dos cepas avirulentas de T. gondii, la TCR-2 aislada de un buho (Glaucidium brasilianum) y la TCR-3 aislada de un ratón casero (Mus musculus), fueron estudiadas comparativamente en cuanto a su patogenicidad. Analizando la LD50 en ratones blancos (cepas NGP) y C3H se observó que ambas cepas de Toxoplasma son mucho menos virulentas que la cepa RH, siendo la TCR-3 la menos patógena, independientemente del tipo de ratón en el que se inocularan. En cuanto el número de quistes producidos en el cerebro, fue la cepa TCR-2 la que produjo mayor cantidad. También se analizaron las variaciones en virulencia de una cepa (TCR-2) mantenida en el laboratorio por 10 años. Fue evidente el aumento en patogenecidad después del período indicado tanto en cuanto a la LD50 como en el número de quistes formados en el cerebro de los animales. Se observó también que la virulencia fue mayor en términos generales en los ratones C3H. Se discute la importancia práctica de estos hallazgos desde el punto de vista clínico y la relevancia científica del análisis de cepas avirulentas de T. gondii

Cardiac transplantation in Puerto Rican patients at the Texas Heart Institute

Cardiac transplantation is the treatment of choice for patients suffering from end-stage cardiac disease unamenable to conventional medical or surgical treatment. More than 390 patients have undergone heart transplantation at the Texas Heart Institute in Houston, and nine were Puerto Rican. Overall survival of these patients is 88%. Our experience with patients from Puerto Rico is described