Repeated subrupture overload causes progression of nanoscaled discrete plasticity damage in tendon collagen fibrils

A critical feature of tendons and ligaments is their ability to resist rupture when overloaded, resulting in strains or sprains instead of ruptures. To treat these injuries more effectively, it is necessary to understand how overload affects the primary load‐bearing elements of these tissues: collagen fibrils. We have investigated how repeated subrupture overload alters the collagen of tendons at the nanoscale. Using scanning electron microscopy to examine fibril morphology and hydrothermal isometric tension testing to look at molecular stability, we demonstrated that tendon collagen undergoes a progressive cascade of discrete plasticity damage when repeatedly overloaded. With successive overload cycles, fibrils develop an increasing number of kinks along their length. These kinks—discrete zones of plastic deformation known to contain denatured collagen molecules—are accompanied by a progressive and eventual total loss of D‐banding along the surface of fibrils, indicating a loss of native molecular packing and further molecular denaturation. Thermal analysis of molecular stability showed that the destabilization of collagen molecules within fibrils is strongly related to the amount of strain energy dissipated by the tendon after yielding during tensile overload. These novel findings raise new questions about load transmission within tendons and their fibrils and about the interplay between crosslinking, strain‐energy dissipation ability, and molecular denaturation within these structures. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 731–737, 2013     

Effects of preexisting microdamage,collagen cross‐links,degree of mineralization,age, and architecture on compressive mechanical properties of elderly human vertebral trabecular bone

Previous studies have shown that the mechanical properties of trabecular bone are determined by bone volume fraction (BV/TV) and microarchitecture. The purpose of this study was to explore other possible determinants of the mechanical properties of vertebral trabecular bone, namely collagen cross‐link content, microdamage, and mineralization. Trabecular bone cores were collected from human L2 vertebrae (n = 49) from recently deceased donors 54–95 years of age (21 men and 27 women). Two trabecular cores were obtained from each vertebra, one for preexisting microdamage and mineralization measurements, and one for BV/TV and quasi‐static compression tests. Collagen cross‐link content (PYD, DPD, and PEN) was measured on surrounding trabecular bone. Advancing age was associated with impaired mechanical properties, and with increased microdamage, even after adjustment by BV/TV. BV/TV was the strongest determinant of elastic modulus and ultimate strength (r² = 0.44 and 0.55, respectively). Microdamage, mineralization parameters, and collagen cross‐link content were not associated with mechanical properties. These data indicate that the compressive strength of human vertebral trabecular bone is primarily determined by the amount of trabecular bone, and notably unaffected by normal variation in other factors, such as cross‐link profile, microdamage and mineralization. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29:481–488, 2011     

Mouse treadmill running enhances tendons by expanding the pool of tendon stem cells (TSCs) and TSC‐related cellular production of collagen

Exercise is known to enhance tendon size and strength, but the stem cell‐based mechanisms for such exercise‐induced effects are largely unknown. This study aims to explore these mechanisms by using a mouse treadmill running model to examine the effects of exercise on newly discovered tendon stem cells (TSCs). After treadmill running, patellar TSCs (PTSCs) and Achilles TSCs (ATSCs) were isolated from the mice, and their proliferation was measured in vitro. We found that treadmill running nearly doubled proliferation rates of both PTSCs and ATSCs compared to cage control mice. Moreover, using a mixed tendon cell culture consisting of TSCs and tenocytes, cellular production of collagen was found to increase by 70% and 200% in PTSCs and ATSCs, respectively, from the treadmill running group over cells from the cage control group. These findings suggest that exercise exerts its anabolic effects on tendons at least in part by increasing proliferation to expand the pool of TSCs and also by increasing TSC‐related cellular production of collagen, the predominant component of tendons. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:1178–1183, 2010     

Effects of platelet‐rich plasma on the quality of repair of mechanically induced core lesions in equine superficial digital flexor tendons: A placebo‐controlled experimental study

Tendon injuries are notorious for their slow and functionally inferior healing. Intratendinous application of platelet‐rich plasma (PRP) has been reported to stimulate the repair process of tendon injuries, but there is little conclusive evidence for its effectiveness. A placebo‐controlled experimental trial was performed to test the hypothesis that a single intratendinous PRP treatment enhances the quality of tendon repair, as evidenced by improved biochemical, biomechanical, and histological tissue properties. In six horses, tendon lesions were created surgically in the Superficial Digital Flexor Tendons (SDFT) of both front limbs, one of which was treated with PRP and the other with saline. After 24 weeks, the tendons were harvested for biochemical, biomechanical, and histological evaluations. Collagen, glycosaminoglycan, and DNA content (cellularity) was higher in PRP‐treated tendons (p = 0.039, 0.038, and 0.034, respectively). The repair tissue in the PRP group showed a higher strength at failure (p = 0.021) and Elastic Modulus (p = 0.019). Histologically, PRP‐treated tendons featured better organization of the collagen network (p = 0.031) and signs of increased metabolic activity (p = 0.031). It was concluded that PRP increases metabolic activity and seems to advance maturation of repair tissue over nontreated experimentally induced tendon lesions, which suggests that PRP might be beneficial in the treatment of clinical tendon injuries. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:211–217, 2010     

The native cell population does not contribute to central‐third graft healing at 6, 12, or 26 weeks in the rabbit patellar tendon

Investigators do not yet understand the role of intrinsic tendon cells in healing at the tendon‐to‐bone enthesis. Therefore, our first objective was to understand how the native cell population influences tendon autograft incorporation in the central‐third patellar tendon (PT) defect site. To do this, we contrasted the histochemical and biomechanical properties of de‐cellularized patellar tendon autograft (dcPTA) and patellar tendon autograft (PTA) repairs in the skeletally mature New Zealand white rabbit. Recognizing that soft tissues in many animal models require up to 26 weeks to incorporate into bone, our second objective was to investigate how recovery time affects enthesis formation and graft tissue biomechanical properties. Thus, we examined graft structure and mechanics at 6, 12, and 26 weeks post‐surgery. Our results showed that maintaining the native cell population produced no histochemical or biomechanical benefit at 6, 12, or 26 weeks. These findings suggest that PTA healing is mediated more by extrinsic rather than intrinsic cellular mechanisms. Moreover, while repair tissue biomechanical properties generally increased from 6 to 12 weeks after surgery, no further improvements were noted up to 26 weeks. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 638–644, 2013     

Cross‐cultural adaptation and psychometric validation of the Patient Scar Assessment Questionnaire to the Spanish language in head and neck surgery

External appearance is the main aesthetic outcome in patients who undergo surgical procedures. Scars located in exposed areas, such as the neck and face, are important for patients. There are at least eight instruments that are used to evaluate postoperative scars, but few fulfil standard methodological conditions. The Patient Scar Assessment Questionnaire (PSAQ) was designed and validated using psychometric methodology. However, this scale has not been translated or validated in the Spanish language. The aim of this study was to undergo a cross‐cultural adaptation and psychometric validation of the PSAQ scale to the Spanish language in patients who underwent head and neck surgery. We followed The Professional Society for Health Economics and Outcomes Research (ISPOR) guidelines for the translation and validation of health‐related scales. Forward and back translations were made by independent translators. We included adult patients who underwent thyroidectomy, parathyroidectomy, parotidectomy, and neck dissection. For the psychometric validation, we used a principal axis exploratory factor analysis with oblimin rotation. A reliability test involving Cronbachs alpha and the item‐total correlation was performed and for the convergent/concurrent validity, we selected the Spanish version of the Vancouver Scar Scale. A total of 180 patients were recruited. Factor analysis showed a five‐factor solution. Cronbachs alpha for the subscales was >0.7. The comparison between the PSAQ appearance subscale and the VSS demonstrated a high correlation (rho = − 0.89). In a sample of 62 patients, the test‐retest evaluation showed high correlation (0.74‐0.99). Our study supports the Spanish version of the PSAQ as a valid, reliable, and reproducible tool to assess the perception and impact of neck scars in Spanish‐speaking patients who undergo head and neck surgery.     

Relative contributions of mechanical degradation,enzymatic degradation,and repair of the extracellular matrix on the response of tendons when subjected to under‐ and over‐ mechanical stimulations in vitro

Tendon response to mechanical loading results in either homeostasis, improvement, or degeneration of tissue condition. In an effort to better understand the development of tendinopathies, this study investigated the mechanical and structural responses of tendons subjected to under‐ and over‐stimulations (1.2% and 1.8% strain respectively, 1 Hz). The objective was to examine three sub‐processes of tendon response: mechanical degradation, enzymatic degradation, and repair of the extracellular matrix. We subjected rat tail tendons to a 10‐day stimulation protocol with four periods of 6 h each day: 30 min of stimulation and 5 h 30 min of rest. To investigate the contribution of the three sub‐processes, we controlled the contribution of the cells through variations in the nutrient and protease inhibitor content in the in vitro solutions. Using nondestructive cyclic tests, we evaluated the daily changes in the peak stress. To assess structural changes, we carried out microscopic analyses at the end of the study period. We observed that the relative contributions of the sub‐processes differed according to the stimulation amplitude. With over‐stimulation of tendons immersed in DMEM, we succeeded in reducing enzymatic degradation and increasing peak stress. In under‐stimulation, the addition of protease inhibitors was required to obtain the same result. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:204–210, 2010     

Pre‐transplant dialysis modality does not influence short‐ or long‐term outcome in kidney transplant recipients: analysis of paired kidneys from the same deceased donor

Previous studies have reported contradictory results regarding the effect of pre‐transplant dialysis modality on the outcomes after kidney transplantation (KT). To minimize the confounding effect of donor‐related variables, we performed a donor‐matched retrospective comparison of 160 patients that received only one modality of pre‐transplant dialysis (peritoneal dialysis [PD] and hemodialysis [HD] in 80 patients each) and that subsequently underwent KT at our center between January 1990 and December 2007. Cox regression models were used to evaluate the association between pre‐transplant dialysis modality and primary study outcomes (death‐censored graft survival and patient survival). To control for imbalances in recipient‐related baseline characteristics, we performed additional adjustments for the propensity score (PS) for receiving pre‐transplant PD (versus HD). There were no significant differences according to pre‐transplant dialysis modality in death‐censored graft survival (PS‐adjusted hazard ratio [aHR]: 0.65; 95% confidence interval [95% CI]: 0.25–1.68) or patient survival (aHR: 0.58; 95% CI: 0.13–2.68). There were no differences in 10‐year graft function or in the incidence of post‐transplant complications either, except for a higher risk of lymphocele in patients undergoing PD (odds ratio: 4.31; 95% CI: 1.15–16.21). In conclusion, pre‐transplant dialysis modality in KT recipients does not impact short‐ or long‐term graft outcomes or patient survival.     

Meal conditions affect the absorption of supplemental vitamin D3 but not the plasma 25‐hydroxyvitamin D response to supplementation

It is sometimes assumed that dietary fat is required for vitamin D absorption, although the impact of different amounts of dietary fat on vitamin D absorption is not established. This study was conducted to determine whether the presence of a meal and the fat content of the meal influences vitamin D absorption or the 25‐hydroxyvitamin D [25(OH)D] response to supplemental vitamin D₃. Based on earlier studies in rats we postulated that absorption would be greatest in the low‐fat meal group. Sixty‐two healthy older men and women were randomly assigned to one of three meal groups: no meal, high‐fat meal, or low‐fat meal; each was given a monthly 50,000 IU vitamin D₃ supplement with the test breakfast meal (or after a fast for the no‐meal group) and followed for 90 days. Plasma vitamin D₃ was measured by liquid chromatography–mass spectroscopy (LC/MS) before and 12 hours after the first dose; plasma 25(OH)D was measured by radioimmunoassay at baseline and after 30 and 90 days. The mean 12‐hour increments in vitamin D₃, after adjusting for age and sex, were 200.9 nmol/L in the no‐meal group, 207.4 nmol/L in the high‐fat meal group, and 241.1 nmol/L in the low‐fat meal group (p = 0.038), with the increase in the low‐fat group being significantly greater than the increases in the other two groups. However, increments in 25(OH)D levels at 30 and 90 days did not differ significantly in the three groups. We conclude that absorption was increased when a 50,000 IU dose of vitamin D was taken with a low‐fat meal, compared with a high‐fat meal and no meal, but that the greater absorption did not result in higher plasma 25(OH)D levels in the low‐fat meal group.     

Filgrastim versus TBO‐filgrastim to reduce the duration of neutropenia after autologous hematopoietic stem cell transplantation: TBO,or not TBO,that is the question

After a hospital‐wide formulary change resulted in the replacement of filgrastim with TBO‐filgrastim for all on‐ and off‐label indications, we performed a retrospective comparison of patients with myeloma receiving 200 mg/m² melphalan with autologous hematopoietic stem cell transplantation to see whether the type of growth factor used post‐transplant made a difference. One hundred and eighty‐two consecutive patients with myeloma were studied, 91 receiving filgrastim immediately prior to the change and 91 receiving TBO‐filgrastim afterward. The CD34⁺ cell dose was comparable, as were other characteristics. Although the overall time to neutrophil recovery was similar for both groups, early engraftment (≤12 d) occurred more often (p = 0.05), and late engraftment (≥14 d) less often (p = 0.09) in filgrastim‐treated patients. The number of documented infections was significantly less in the TBO‐filgrastim group. Day 100 mortality and hospital stay were similar for the two groups. These data indicate that there is no material difference between filgrastim and TBO‐filgrastim in this clinical setting.     

Cost‐effectiveness of using Polyheal compared with surgery in the management of chronic wounds with exposed bones and/or tendons due to trauma in France,Germany and the UK

The objective of this study was to assess the cost‐effectiveness of Polyheal compared with surgery in treating chronic wounds with exposed bones and/or tendons (EB&T) due to trauma in France, Germany and the UK, from the perspective of the payers. Decision models were constructed depicting the management of chronic wounds with EB&T and spanned the period up to healing or up to 1 year. The models considered the decision by a plastic surgeon to treat these wounds with Polyheal or surgery and was used to estimate the relative cost‐effectiveness of Polyheal at 2010/2011 prices. Using Polyheal instead of surgery is expected to increase the probability of healing from 0·93 to 0·98 and lead to a total health‐care cost of €7984, €7517 and €8860 per patient in France, Germany and the UK, respectively. Management with surgery is expected to lead to a total health‐care cost of €12 300, €18 137 and €11 330 per patient in France, Germany and the UK, respectively. Hence, initial treatment with Polyheal instead of surgery is expected to lead to a 5% improvement in the probability of healing and a substantial decrease in health‐care costs of 35%, 59% and 22% in France, Germany and the UK, respectively. Within the models' limitations, Polyheal potentially affords the public health‐care system in France, Germany and the UK a cost‐effective treatment for chronic wounds with EB&T due to trauma, when compared with surgery. However, this will be dependent on Polyheal's healing rate in clinical practice when it becomes routinely available.     

Basal levels of salivary chromogranin A,but not α‐amylase,are related to plasma norepinephrine in the morning

To evaluate the activity of sympatho–adrenomedullary (SAM) system, testing for salivary chromogranin A (CgA) and α‐amylase (sAA) has been receiving attention. We investigated the correlation between levels of plasma norepinephrine (NE) and salivary CgA or sAA. From 21 healthy males, blood and saliva samples were collected at 8:00, 10:30, 12:30 and 17:30. Levels of plasma NE, salivary CgA and sAA were determined at each sampling point. To avoid the influence of the salivary flow, resultant levels of salivary CgA and sAA were adjusted according to salivary flow rates and salivary protein, respectively. A significant correlation between plasma NE levels and salivary CgA/protein was detected in samples taken at 8:00 (p < 0.01). In samples taken at 10:30, 12:30 and 17:30, however, there was no such correlation. Meanwhile, no significant correlation between plasma NE levels and sAA/min was detected during the sampling period. These findings suggest that morning results for CgA may be useful as a predictor for SAM system activity. Copyright © 2008 John Wiley & Sons, Ltd.     

Serial measurement of presepsin,procalcitonin, and C‐reactive protein in the early postoperative period and the response to antithymocyte globulin administration after heart transplantation

Differentiation between systemic inflammatory response syndrome and sepsis in surgical patients is of crucial significance. Procalcitonin (PCT) and C‐reactive protein (CRP) are widely used biomarkers, but PCT becomes compromised after antithymocyte globulin (ATG) administration, and CRP exhibits limited specificity. Presepsin has been suggested as an alternative biomarker of sepsis. This study aimed to demonstrate the role of presepsin in patients after heart transplantation (HTx). Plasma presepsin, PCT, and CRP were measured in 107 patients serially for up to 10 days following HTx. Time responses of biomarkers were evaluated for both noninfected (n=91) and infected (n=16) patients. Areas under the concentration curve differed in the two groups of patients for presepsin (P<.001), PCT (P<.005), and CRP (P<.001). The effect of time and infection was significant for all three biomarkers (P<.05 all). In contrast to PCT, presepsin was not influenced by ATG administration. More than 25% of noninfected patients had PCT above 42 μg/L on the first day, and the peak concentration of CRP in infected patients was reached on the third post‐transplant day (median 135 mg/L). Presepsin seems to be as valuable a biomarker as PCT or CRP in the evaluation of infectious complications in patients after HTx.