Search

We previously demonstrated that a two-cell syncytium, composed of a ventricular myocyte and an mHCN2 expressing cell, recapitulated most properties of in vivo biological pacing induced by mHCN2-transfected hMSCs in the canine ventricle. Here, we use the two-cell syncytium, employing dynamic clamp, to study the roles of gf (pacemaker conductance), gK1 (background K+ conductance), and gj (intercellular coupling conductance) in biological pacing. We studied gf and gK1 in single HEK293 cells expressing cardiac sodium current channel Nav1.5 (SCN5A). At fixed gf, increasing gK1 hyperpolarized the cell and initiated pacing. As gK1 increased, rate increased, then decreased, finally ceasing at membrane potentials near EK. At fixed gK1, increasing gf depolarized the cell and initiated pacing. With increasing gf, rate increased reaching a plateau, then decreased, ceasing at a depolarized membrane potential. We studied gj via virtual coupling with two non-adjacent cells, a driver (HEK293 cell) in which gK1 and gf were injected without SCN5A and a follower (HEK293 cell), expressing SCN5A. At the chosen values of gK1 and gf oscillations initiated in the driver, when gj was increased synchronized pacing began, which then decreased by about 35% as gj approached 20 nS. Virtual uncoupling yielded similar insights into gj. We also studied subthreshold oscillations in physically and virtually coupled cells. When coupling was insufficient to induce pacing, passive spread of the oscillations occurred in the follower. These results show a non-monotonic relationship between gK1, gf, gj, and pacing. Further, oscillations can be generated by gK1 and gf in the absence of SCN5A.

Around 10 % of long bone fractures show inadequate bone healing resulting in non-union development. A deregulated arginine-citrulline-nitric oxide metabolism caused by a poor nutritional status of the patients is a risk factor for non-unions. Additionally, previous research in mice with a disrupted arginine to citrulline conversion showed delayed healing. The study hypothesis was that stimulating said metabolism could positively influence the healing process through promotion of collagen synthesis and angiogenesis.Adult wild-type mice underwent a femur osteotomy and plate-screw osteosynthesis. Mice were randomly divided into three groups and received daily oral supplementation of arginine, citrulline or 0.9 % saline (control). Body weight and food intake were measured daily. After 14 d, the mice were euthanised and femora collected. Callus formation was assessed by micro-computed tomography and concentrations of amino acids and enzymes in the femora were measured.Only citrulline-treated mice showed significantly increased bridging of the fracture gap when compared to control mice. Femur citrulline and ornithine concentrations were increased in citrulline-treated animals. qPCR showed significantly decreased expression of inflammatory markers, whereas increased expression of angiogenic and collagen-producing factors was observed in citrulline-treated mice. Although food intake did not show any difference between the three groups, animals treated with citrulline showed a weight gain of 0.3 g, compared with a 0.1 g decline in the control group.Daily oral citrulline supplementation stimulated callus formation and improved the inflammatory response, positively contributing to the enhanced healing response. Finally, the increased weight gain pointed toward a better post-operative recovery.

Objective: To assess the availability of explicitly reported protocols describing post-surgery rehabilitation of (peri-) articular fractures of the proximal humerus, acetabulum and/or tibial plateau, and to critically review any scientific evidence on the effectiveness of these protocols. Data sources: MEDLINE (PubMed), Cochrane databases, CINAHL, PEDro and Embase (Ovid) were searched to November 2018. Furthermore, stakeholder internet sites, clinical guidelines and standard textbooks were searched. Study selection: Screening was performed independently by 2 researchers based on a priori defined eligibility criteria. Data synthesis: Five papers addressed post-surgical rehabilitation of proximal humerus fractures, one paper addressed acetabulum fractures. No eligible information was found on stakeholder sites or in standard textbooks. Overall, the main focus of the protocols identified was on the International Classification of Functioning, Disability and Health (ICF) "Body Functions and Structures" level. In general, little information about therapy dosage was reported. None of the protocols provided scientific evidence on which the content of described rehabilitation programmes was based. Conclusion: This review reveals a paucity of explicitly formulated protocols focussing on post-surgical rehabilitation of common (peri-) articular fractures targeting patient-centred care at all ICF levels. There is a need for more scientific evidence on which to base protocols regarding common (peri-) articular fracture rehabilitation.

Several guidelines recommend a bone and fall-related osteoporosis risk assessment in all patients with fracture and age 50 years. In practice, however, there is no consensus whether screening 85 years is useful.To evaluate the subsequent fracture risk in all patient 85 years, comparing the two populations of Fracture Liaison Service (FLS) attenders and non-attenders.All patients 85 years that presented at the FLS with a non-vertebral fracture were included in the study during a 5-year period (September 2004 and December 2009). Excluded were pathologic fractures, death 30 days, or patients on osteoporosis treatment. in patients that attended the FLS, assessment of bone mineral density and fall-risk factors were screened. In both the attenders and non-attenders groups, mortality and subsequent fracture rates were scored during a follow-up of 2 years.282 patients fulfilled inclusion criteria for screening, of which 160 (57%) patients did not attend the FLS. 122 patients were screened for osteoporosis and fall-related risk of whom 72 were diagnosed with osteoporosis. Subsequent fracture risk in both groups was 19%. Medical treatment was started in 51 patients, of which 15 patients developed a subsequent fracture. Cox-regression analysis indicated a significantly lower mortality rate, but not a diminished subsequent fracture rate in the FLS screened population compared to the non-attenders.The advantage of a FLS in reducing subsequent fracture risk in patients 85 years seems to be limited. In practice a large proportion of these patients are not screened.

Symptoms related to stroke diverge and may mimic many other conditions.To evaluate clinical findings among patients with a clinical suspicion of stroke in a prehospital setting and find independent predictors of a final diagnosis of stroke or transient ischemic attack (TIA).An observational multicenter study includes nine emergency hospitals in western Sweden. All patients transported to hospital by ambulance and in whom a suspicion of stroke was raised by the emergency medical service clinician before hospital admission during a four-month period were included.Of 1081 patients, a diagnosis of stroke was confirmed at hospital in 680 patients (63%), while 69 (6%) were diagnosed as TIA and 332 patients (31%) received other final diagnoses. In a multiple logistic regression analysis, factors independently associated with a final diagnosis of stroke or TIA were increasing age, odds ratio (OR) per year: 1.02, P = 0.007, a history of myocardial infarction (OR: 1.77, P = 0.01), facial droop (OR: 2.81, P 0.0001), arm weakness (OR: 2.61, P 0.0001), speech disturbance (OR: 1.92, P 0.0001), and high systolic blood pressure (OR: 1.50, P = 0.02), while low oxygen saturation was significantly associated with other diagnoses (OR: 0.41, P = 0.007). More than half of all patients among patients with both stroke/TIA and other final diagnoses died during the five-year follow-up.Seven factors including the three symptoms included in the Face Arm Speech Test were significantly associated with a final diagnosis of stroke or TIA in a prehospital assessment of patients with a suspected stroke.

Introduction A Dutch survey among orthopedic surgeons and trauma surgeons showed that almost 90% of the surgeons do not follow protocols regarding the weight bearing aftercare for tibial plateau fractures. Clinical studies comparing permissive weight bearing (PWB) versus restricted weight bearing (RWB) after surgically treated tibial plateau fractures are not available. The aim of this study was to inventory potential differences in quality of life and pain, and number of complications in patients with surgically treated tibial plateau fractures who followed a PWB regime, relative to those that followed a RWB regime. Materials and methods This retrospective cohort study included surgically treated trauma patients with tibial plateau fractures, who underwent rehabilitation according to PWB or RWB between 2005 and 2015. Data such as demographics, patient-reported quality of life and pain, and patient outcome were collected. Results This cohort study included 91 patients with a tibial plateau fracture (31 and 60 patients in the PWB and RWB groups respectively). No significant between-group differences in either age or gender were found. However, a significant difference in fracture type was found between groups, (p = 0.04). No significant differences were found in either patient-reported SF-12 or VAS scores between the PWB group and RWB group. Time to full weight bearing was significantly shorter in the PWB than in the RWB group, i.e., 14.7 versus 20.7 weeks, (p = 0.02). No significant differences were found regarding postoperative complications between the PWB and the RWB groups, i.e., 6.5% versus 10.0%, respectively. Conclusion PWB after surgically treated tibial plateau fractures is safe and is related to a significantly reduced time to full weight bearing with no significant differences in patient-reported quality of life and pain or complication rates.

Objective: To optimize rapid clinical recovery and restoration of function and functionality, permissive weight-bearing has been designed as a new aftercare mobilization regimen, within the upper boundary of the therapeutic bandwidth, yet safe enough to avoid overloading. The aim of the present paper is to describe a comprehensive protocol for permissive weight-bearing during allied health therapy and to report on the time to full weight-bearing, as well as the number of complications, in patients with surgically treated fractures of the pelvis and lower extremities undergoing permissive weight-bearing.Patients and methods: This study included surgically treated trauma patients with (pert)- or intra-articular fractures of the pelvis and lower extremities. A standardized permissive weight-bearing protocol was used for all patients. Time to full weight-bearing and number of complications were recorded.Results: This study included 150 patients, 69% male, with a median age of 48 years (interquartiie range (IQR) 33.0, 57.0). The median time to full weight bearing was 12.0 weeks (IQR 6.8, 19.2). The complication rate during rehabilitation was 10%.Conclusion: The permissive weight-bearing protocol, as described, might be beneficial and has potential to be implemented in trauma patients with surgically treated (peri)- or intra-articular fractures of the pelvis and lower extremities.

One promising approach to cancer therapeutics is to induce changes in gene expression that either reduce cancer cell proliferation or induce cancer cell death. Therefore, delivering oligonucleotides (siRNA/miRNA) that target specific genes or gene programs might have a potential therapeutic benefit. The aim of this study was to examine the potential of cell-based delivery of oligonucleotides to cancer cells via two naturally occurring intercellular pathways: gap junctions and vesicular/exosomal traffic. We utilized human mesenchymal stem cells (hMSCs) as delivery cells and chose to deliver in vitro two synthetic oligonucleotides, AllStars HS Cell Death siRNA and miR-16 mimic, as toxic (therapeutic) oligonucleotides targeting three cancer cell lines: prostate (PC3), pancreatic (PANC1) and cervical (HeLa). Both oligonucleotides dramatically reduced cell proliferation and/or induced cell death when transfected directly into target cells and delivery hMSCs. The delivery and target cells we chose express gap junction connexin 43 (Cx43) endogenously (PC3, PANC1, hMSC) or via stable transfection (HeLaCx43). Co-culture of hMSCs (transfected with either toxic oligonucleotide) with any of Cx43 expressing cancer cells induced target cell death (~20% surviving) or senescence (~85% proliferation reduction) over 96 hours. We eliminated gap junction-mediated delivery by using connexin deficient HeLaWT cells or knocking out endogenous Cx43 in PANC1 and PC3 cells via CRISPR/Cas9. Subsequently, all Cx43 deficient target cells co-cultured with the same toxic oligonucleotide loaded hMSCs proliferated, albeit at significantly slower rates, with cell number increasing on average ~2.2-fold (30% of control cells) over 96 hours. Our results show that both gap junction and vesicular/exosomal intercellular delivery pathways from hMSCs to target cancer cells deliver oligonucleotides and function to either induce cell death or significantly reduce their proliferation. Thus, hMSC-based cellular delivery is an effective method of delivering synthetic oligonucleotides that can significantly reduce tumor cell growth and should be further investigated as a possible approach to cancer therapy.

Cell-to-cell communication between bone, cartilage and the synovial membrane is not fully understood and it is only attributed to the diffusion of substances through the extracellular space or synovial fluid. In this study, we found for the first time that primary bone cells (BCs) including osteocytes, synovial cells (SCs) and chondrocytes (CHs) are able to establish cellular contacts and to couple through gap junction (GJ) channels with connexin43 (Cx43) being dominant. Transwell co-culture and identification by mass spectrometry revealed the exchange of essential amino acids, peptides and proteins including calnexin, calreticulin or CD44 antigen between contacting SCs, BCs and CHs. These results reveal that CHs, SCs and BCs are able to establish intercellular connections and to communicate through GJ channels, which provide a selective signalling route by the direct exchange of potent signalling molecules and metabolites.

Gap junction channels mediate the direct intercellular passage of small ions as well as larger solutes such as second messengers. A family of proteins called connexins make up the subunits of gap junction channels in chordate animals. Each individual connexin forms channels that exhibit distinct permeability to molecules that influence cellular signaling, such as calcium ions, cyclic nucleotides, or inositol phosphates. In this review, we examine the permeability of connexin channels containing Cx43, Cx46, and Cx50 to signaling molecules and attempt to relate the observed differences in permeability to possible in vivo consequences that were revealed by studies of transgenic animals where these connexin genes have been manipulated. Taken together, these data suggest that differences in the permeability of individual connexin channels to larger solutes like 3′,5′-cyclic adenosine monophosphate (cAMP) and inositol 1,4,5-trisphosphate (IP3) could play a role in regulating epithelial cell division, differentiation, and homeostasis in organs like the ocular lens.

We previously demonstrated that a two-cell syncytium, composed of a ventricular myocyte and an mHCN2 expressing cell, recapitulated most properties of in vivo biological pacing induced by mHCN2-transfected hMSCs in the canine ventricle. Here, we use the two-cell syncytium, employing dynamic clamp, to study the roles of g

This review focuses on the biophysical properties and structure of the pore and vestibule of homotypic gap junction channels as they relate to channel permeability and selectivity. Gap junction channels are unique in their sole role to connect the cytoplasm of two adjacent cells. In general, these channels are considered to be poorly selective, possess open probabilities approximating unity, and exhibit mean open times ranging from milliseconds to seconds. These properties suggest that such channels can function as delivery pathways from cell to cell for solutes that are significantly larger than monovalent ions. We have taken quantitative data from published works concerning unitary conductance, ion flux, and permeability for homotypic connexin 43 (Cx43), Cx40, Cx26, Cx50, and Cx37, and performed a comparative analysis of conductance and/or ion/solute flux versus diffusion coefficient. The analysis of monovalent cation flux portrays the pore as equivalent to an aqueous space where hydrogen bonding and weak interactions with binding sites dominate. For larger solutes, size, shape and charge are also significant components in determining the permeation rate. This article is part of a Special Issue entitled: Gap Junction Proteins edited by Jean Claude Herve.

BackgroundSpinal immobilisation using a rigid long spineboard is a well-established procedure in trauma care. During immobilisation, the body is exposed to high tissue-interface pressures. This may lead to a localised inflammatory response of the skin, which may be used to monitor the body's response to different types of immobilisation device.AimIn this study we compared the standard rigid spineboard with a new soft-layered spineboard regarding tissue-interface pressures, skin redness as an indicator of reactive hyperaemia and cutaneous IL1α and lactate release.MethodsTwelve healthy male participants were asked to lie supine on both a rigid and a soft-layered spineboard, loading the sacrum for one hour, followed by one hour in unloaded position. Tissue-interface pressures on the buttocks during loading were measured continuously using a pressure mapping mat. Cutaneous IL1α and lactate concentrations were assessed using Sebutapes, during 20-minute periods. After each 20-minute period, a photo of the buttocks was taken, which was later assessed for redness by two observers.ResultsSignificant differences in tissue-interface pressure and reactive hyperaemia were found between the two types of spineboard. Release of IL1α and lactate were found to increase with prolonged exposure to pressure, and to decrease in the unloaded prone position. A significant relationship was found between tissue-interface pressure and reactive hyperaemia, but not with IL1α nor lactate release. Time course of IL1α and lactate release was similar for both types of spineboard.ConclusionsIL1α and lactate both have a strong relationship with pressure exposure time, but not with pressure magnitude. Furthermore, IL1α was measured even in the absence of visible redness of the skin. The study offers the potention of biomarkers, reflecting inflammation and/or tissue metabolism, for use in assessing the effects of prolonged spineboard support.

Introduction The standard aftercare treatment (according to the AO guideline) for surgically treated trauma patients with fractures of the tibial plateau is non-weight bearing or partial weight bearing for 10-12 weeks. The purpose of this study was to investigate the current state of practice among orthopaedic surgeons and trauma surgeons in choosing the criteria and the time period of restricted weight bearing after surgically treated tibial plateau fractures.Materials and methods A web-based survey was distributed among members of the Dutch Trauma Society and Dutch Orthopaedic Society to identify the most commonly applied protocols in terms of the post-operative initiation and level of weight bearing in patients with tibial plateau fractures.Results One hundred and eleven surgeons responded to the survey. 72.1% of the respondents recommended starting weight bearing earlier than the 12 weeks recommended by the AO guideline; 11.7% recommended starting weight bearing immediately, 4.5% after 2 weeks and 55.9% after 6 weeks. Moreover, 88.7% of the respondents reported deviating from their own local protocol. There is little consensus about the definition of 100% weight bearing and how to build up weight bearing over time.Conclusion This study demonstrates that consensus about the weight bearing aftercare for tibial plateau fractures are limited. A large majority of surgeons do not follow the AO guideline or their own local protocol. More transparent criteria and predictors are needed to design optimal weight-bearing regimes for the aftercare of tibial plateau fractures.

Purpose Gap junction channels exhibit connexin specific biophysical properties, including the selective intercellular passage of larger solutes, such as second messengers. Here, we have examined the cyclic nucleotide permeability of the lens connexins, which could influence events like epithelial cell division and differentiation. Methods We compared the cAMP permeability through channels composed of Cx43, Cx46, or Cx50 using simultaneous measurements of junctional conductance and intercellular transfer. For cAMP detection, the recipient cells were transfected with a cAMP sensor gene, the cyclic nucleotide-modulated channel from sea urchin sperm (SpIH). cAMP was introduced via patch pipette into the cell of the pair that did not express SpIH. SpIH-derived currents were recorded from the other cell of a pair that expressed SpIH. cAMP permeability was also directly visualized in transfected cells using a chemically modified fluorescent form of the molecule. Results cAMP transfer was observed for homotypic Cx43 channels over a wide range of junctional conductance. Homotypic Cx46 channels also transferred cAMP, but permeability was reduced compared with Cx43. In contrast, homotypic Cx50 channels exhibited extremely low permeability to cAMP, when compared with either Cx43, or Cx46. Conclusions These data show that channels made from Cx43 and Cx46 result in the intercellular delivery of cAMP in sufficient quantity to activate cyclic nucleotide-modulated channels. The data also suggest that the greatly reduced cAMP permeability of Cx50 channels could play a role in the regulation of cell division in the lens.

Contains fulltext : 203315.pdf (Publisher’s version ) (Open Access) BACKGROUND: Multidisciplinary rehabilitation has been recommended for multi-trauma patients, but there is only low-quality evidence to support its use with these patients. This study examined whether a Supported Fast track multi-Trauma Rehabilitation Service (Fast Track) was cost-effective compared to conventional trauma rehabilitation service (Care As Usual) in patients with multi-trauma from a societal perspective with a one-year follow-up. METHODS: An economic evaluation alongside a prospective, multi-center, non-randomized, controlled clinical study, was conducted in the Netherlands. The primary outcome measure was the Functional Independence Measure (FIM). Generic Quality of Life and Quality Adjusted Life Years (QALYs) of the patients were derived using the Short-form 36 Health Status Questionnaire. Incremental Cost-Effectiveness Ratios (ICERs) were stated in terms of costs per unit of FIM improvement and costs per QALY. To investigate the uncertainty around the ICERs, non-parametric bootstrapping was used. RESULTS: In total, 132 patients participated, 65 Fast Track patients and 67 Care As Usual patients. Mean total costs per person were euro18,918 higher in the Fast Track group than in the Care As Usual group. Average incremental effects on the FIM were 3.7 points (in favor of the Fast Track group) and the incremental (extra) bootstrapped costs were euro19,033, resulting in an ICER for cost per FIM improvement of euro5,177. Care As Usual dominated Fast Track in cost per QALY as it gave both higher QALYs and lower costs. All sensitivity analyses attested to the robustness of our results. CONCLUSIONS: This study demonstrated that a multidisciplinary rehabilitation program for multi-trauma patients according to the supported fast track principle is promising but cost-effectiveness evidence remains inconclusive. In terms of functional outcome, Fast Track was more expensive but yielded also more effects compared to the Care As Usual group. Looking at the costs per QALYs, unfavorable ICERs were found. Given the lack of a willingness-to-pay threshold for functional recovery and the relatively short time horizon, it is not possible to draw firm conclusions about the first. TRIAL REGISTRATION: (Current Controlled Trials register: ISRCTN68246661).

Introduction: The use of a multidisciplinary clinical pathway (MCP) for patients with hip fracture tends to be more effective than usual care (UC). The aim of this study was to evaluate the effects of an MCP approach on time to surgery, length of stay, postoperative complications, and 30-day mortality, compared to UC. Materials and Methods: This multicenter retrospective cohort study included patients aged 50 years or older with a proximal hip fracture who underwent surgery in one of the 6 hospitals in the Limburg trauma region of the Netherlands in 2012. Data such as demographics, process outcome measures, and clinical outcome were collected. Results: This study included a total of 1193 patients (665 and 528 patients in the MCP and UC groups, respectively). There were no differences in patient demographics present. Time to surgery was significantly shorter in the MCP compared to the UC group (19.2 vs 24.4 hours, P < .01). The mean length of stay was 10 versus 12 days ( P < .01). In the MCP group, significantly lower rates of postoperative complications were observed and significantly more patients were institutionalized than in the UC group. Mortality within 30 days after admission was comparable between the groups (overall mortality 6%). Conclusion: An MCP approach is associated with reduced time to surgery, postoperative complications, and length of stay, without a significant difference in 30-day mortality. The institutionalization rate was significantly higher in the MCP group.

Trauma patients at risk for, or suspected of, spinal injury are frequently transported to hospital using full spinal immobilisation. At the emergency department, immobilisation is often maintained until radiological work-up is completed. In this study, we examined how these devices for spinal stabilization influence visual image quality. Image quality was judged for both patient CT scans and phantom CT scans. CT scans of 217 patients were assessed retrospectively by two radiologists for visual scoring of image quality, scoring both quantity and impact of artifacts caused by the immobilization devices. For the phantom CT scans, eight set-ups were made, using a vacuum mattress without headblocks and a rigid and a soft-layered spineboard without headblocks, with standard soft-foam headblocks, or with new design headblocks. Overall, artifacts were found in 67 % of CT scans of patients on immobilization devices, which hampered diagnosis in 10 % of the cases. In the phantom CT scans, artifacts were present in all set-ups with one or more devices present and were seen in 20 % of all scan slices. The presence of headblocks resulted in more artifacts in both the patient CT scans and the phantom CT scans. Considerable effort should therefore be made to adjust the design of the immobilization devices and to remove the headblocks before CT scans are made.

Operative treatment using plate fixation is an important adjunct in the treatment of distal radius fractures, although the evidence for its superiority over other modalities remains limited. We propose a new concept for fractures of the distal radius, based on the three-column model of the distal radius, and on the expanding knowledge about the different fracture patterns obtained by evaluation of the distal radius by computed tomographic (CT) scan. All fracture types can be characterized by subdividing the wrist joint into four corners, each with its own characteristics in terms of mobility, stability, and transfer of forces in the intact distal radius. Recognition of the specific fracture types based on this four-corner concept enables a tailored approach to treatment.

With the increasing incidence of fractures now, and in the future, the absolute number of bone-healing complications such as nonunion development will also increase. Next to fracture-dependent factors such as large bone loss volumes and inadequate stabilization, the nutritional state of these patients is a major influential factor for the fracture repair process. In this review, we will focus on the influence of protein/amino acid malnutrition and its influence on fracture healing. Mainly, the arginine-citrulline-nitric oxide metabolism is of importance since it can affect fracture healing via several precursors of collagen formation, and through nitric oxide synthases it has influences on the bio-molecular inflammatory responses and the local capillary growth and circulation.

Background The standard aftercare treatment in surgically treated trauma patients with fractures around or in a joint, known as (peri)- or intra-articular fractures of the lower extremities, is either non-weight bearing or partial weight bearing. We have developed an early permissive weight bearing post-surgery rehabilitation protocol in surgically treated patients with fractures of the lower extremities. In this proposal we want to compare our early permissive weight bearing protocol to the existing current non-weight bearing guidelines in a prospective comparative cohort study. Methods/design The study is a prospective multicenter comparative cohort study in which two rehabilitation aftercare treatments will be contrasted, i.e. permissive weight bearing and non-weight bearing according to the AO-guideline. The study population consists of patients with a surgically treated fracture of the pelvis/acetabulum or a surgically treated (peri)- or intra-articular fracture of the lower extremities. The inclusion period is 12 months. The duration of follow up is 6 months, with measurements taken at baseline, 2,6,12 and 26 weeks post-surgery. Primary outcome measure: ADL with Lower Extremity Functional Scale. Outcome variables for compliance, as measured with an insole pressure measurement system, encompass peak load and step duration. Discussion This study will investigate the (cost-) effectiveness of a permissive weight bearing aftercare protocol. The results will provide evidence whether a permissive weight bearing protocol is more effective than the current non-weight bearing protocol. Trial registration The study is registered in the Dutch Trial Register (NTR6077). Date of registration: 01–09-2016.

Prolonged and high pressure diving may lead to various physiological changes including significant alterations of autonomic nervous system (ANS) activity that may be associated with altered physical performance, decompression sickness, or central nervous system oxygen toxicity. Ideally, researchers could elucidate ANS function before, during, and after dives that are most associated with altered function and adverse outcomes. However, we have a limited understanding of the activities of the ANS especially during deeper prolonged SCUBA diving because there has never been a convenient way to collect physiological data during deep dives. This work is one of the first studies which was able to collect electrocardiogram (ECG) data from SCUBA divers at various depths (33, 66, 99, 150, and 200 ftsw; equivalent to 10.05, 20.10, 30.17, 45.72, and 60.96 m of salt water, respectively) breathing different gas mixtures (air, nitrox and trimix). The aim of this study was to shed light on cardiac ANS behavior during dives, including deep dives. With the aid of dry suits, a Holter monitor that could handle the pressure of a 200 ft. dive, and a novel algorithm that can provide a useful assessment of the ANS from the ECG signal, we investigated the effects of SCUBA dives with different time durations, depths and gas mixtures on the ANS. Principal dynamic mode (PDM) analysis of the ECG, which has been shown to provide accurate separation of the sympathetic and parasympathetic dynamics, was employed to assess the difference of ANS behavior between baseline and diving conditions of varying depths and gas mixtures consisting of air, nitrox and trimix. For all depths and gas mixtures, we found consistent dominance in the parasympathetic activity and a concomitant increase of the parasympathetic dynamics with increasing diving duration and depth. For 33 and 66 ft. dives, we consistently found significant decreases in heart rates (HR) and concomitant increases in parasympathetic activities as estimated via the PDM and root mean square of successive differences (RMSSD) for all time intervals (from the first 5 min to the last 30 min) at the bottom depth when compared to the baseline depth at sea level. The sympathetic dynamics did not change with dive duration or gas mixtures, but at the 150 and 200 ft. dives, we found a significant increase in the sympathetic dynamics in addition to the elevated parasympathetic dynamics when compared to baseline The power spectral density (PSD) measures such as the low frequency (LF), high frequency (HF) and its ratio, and approximate entropy (ApEn) indices were not as consistent when compared to PDM-derived parasympathetic dynamics and RMSSD index.

BackgroundEquestrian-related injuries (ERIs) are relatively severe compared with injuries in other popular sports. Previous studies on epidemiology of ERIs vary widely and mainly focus on incidence instead of severity of the injury.PurposeThe aim of this study was to determine incidence, mechanisms and severity of ERIs in two Dutch hospitals (level 1 and level 2 trauma centers) over a 5-year period.Patients and methodsAll patients with ERIs who visited the emergency departments of VieCuri Medical Centre in Venlo and Maastricht University Medical Centre+ in Maastricht, The Netherlands, between July 2010 and June 2015 were retrospectively included. Clinical data were extracted from medical records.ResultsMost ERIs occurred in mounted riders (646 events; 68%); 94.9% of which involved a fall. Being kicked (42.5%) or trapped (30.1%) was the most common cause of injury in unmounted riders. Most frequently injured body parts were the upper extremities (43.8%) in mounted riders and lower extremities (40.5%) in the unmounted group. A relatively high percentage of facial injuries (9.7%) were found in the unmounted group. Seventeen per cent of all ERIs required admission. The median Injury Severity Score was 5 in the admitted population and 1 in the total population.ConclusionHorseback riding is a risky activity. Prior studies particularly studied admitted patients in level 1 trauma centers outside of Europe and demonstrated a high risk of significant injury. However, our study demonstrates that these studies in selected groups might have overestimated the severity of ERIs in the general population.

Background Chronic, dynamic bidirectional instability in the distal radioulnar joint (DRUJ) is diagnosed clinically, based on the patient's complaints and the finding of abnormal laxity in the vicinity of the distal ulna. In cases where malunion is ruled out or treated and there are no signs of osteoarthritis, stabilization of the DRUJ may offer relief. To this end, several different techniques have been investigated over the past 90 years. Materials and Methods In this article we outline the procedure for a new technique using a tendon graft to reinforce the distal edge of the interosseous membrane. Description of Technique A percutaneous technique is used to harvest the palmaris longus tendon and to create a tunnel, just proximal to the sigmoid notch, through the ulna and radius in an oblique direction. By overdrilling the radial cortex, the knotted tendon can be pulled through the radius and ulna and the knot blocked at the second radial cortex, creating a strong connection between the radius and ulna at the site of the distal oblique bundle (DOB). The tendon is fixed in the ulna with a small interference screw in full supination, preventing subluxation of the ulna out of the sigmoid notch during rotation. Results Fourteen patients were treated with this novel technique between 2011 and October 2013. The QuickDASH score at 25 months postoperatively (range 16-38 months) showed an improvement of 32 points. Similarly, an improvement of 33 points (67-34 months) was found on the PRWHE. Only one recurrence of chronic, dynamic bidirectional instability in the DRUJ was observed. Conclusion This simple percutaneous tenodesis technique between radius and ulna at the position of the distal edge of the interosseous membrane shows promise in terms of both restoring stability and relieving complaints related to chronic subluxation in the DRUJ.

Human bone marrow stromal cells (hBMSCs, also known as bone marrow-derived mesenchymal stem cells) are a population of progenitor cells that contain a subset of skeletal stem cells (hSSCs), able to recreate cartilage, bone, stroma that supports hematopoiesis and marrow adipocytes. As such, they have become an important resource in developing strategies for regenerative medicine and tissue engineering due to their self-renewal and differentiation capabilities. The differentiation of SSCs/BMSCs is dependent on exposure to biophysical and biochemical stimuli that favor early and rapid activation of the in vivo tissue repair process. Exposure to exogenous stimuli such as an electromagnetic field (EMF) can promote differentiation of SSCs/BMSCs via ion dynamics and small signaling molecules. The plasma membrane is often considered to be the main target for EMF signals and most results point to an effect on the rate of ion or ligand binding due to a receptor site acting as a modulator of signaling cascades. Ion fluxes are closely involved in differentiation control as stem cells move and grow in specific directions to form tissues and organs. EMF affects numerous biological functions such as gene expression, cell fate, and cell differentiation, but will only induce these effects within a certain range of low frequencies as well as low amplitudes. EMF has been reported to be effective in the enhancement of osteogenesis and chondrogenesis of hSSCs/BMSCs with no documented negative effects. Studies show specific EMF frequencies enhance hSSC/BMSC adherence, proliferation, differentiation, and viability, all of which play a key role in the use of hSSCs/BMSCs for tissue engineering. While many EMF studies report significant enhancement of the differentiation process, results differ depending on the experimental and environmental conditions. Here we review how specific EMF parameters (frequency, intensity, and time of exposure) significantly regulate hSSC/BMSC differentiation in vitro. We discuss optimal conditions and parameters for effective hSSC/BMSC differentiation using EMF treatment in an in vivo setting, and how these can be translated to clinical trials.

Background Flexor carpi radialis (FCR) tendinopathy is an entity with a chronic form (repetitiveness of work) and an acute form (acute overstretching of the wrist). Confirmation of this syndrome can be established by injection of a small amount of a local anesthetic in the sheet of the FCR at this tender point. Complete relieve of the symptoms after injection confirms the existence of a tendinopathy of the FCR. Whereas rest and/or local application of steroids do not have a persistent effect on the short term outcome, a tenolysis could be performed. Before performing a tenolysis underlying causes should be excluded or treated. Methods In this article a simple and save technique is described, using a small Beaver knife to open the osteofibrous tunnel of the flexor carpi radialis tendon, without opening the carpal tunnel. Results Relieve of complaints could be reached up to almost two third of all cases. Conclusion In cases in which non-operative treatment is not effective regarding FCR tendinopathy, a simple blind technique by opening the osteofibrous tunnel could be successful.

INTRODUCTION: Conventional radiographic imaging is the first imaging tool of choice in scaphoid fractures. The majority of undisplaced scaphoid waist fractures unite after 6 weeks of cast immobilization. We hypothesized that conventional radiographic imaging at 6 weeks after injury can both accurately and reliably predict union in undisplaced scaphoid waist fractures. MATERIALS AND METHODS: Fleiss' kappa statistics were used concerning the opinions of four observers reviewing 47 sets of good-quality scaphoid radiographs of undisplaced scaphoid waist fractures. As reference standard for union, radiographs were taken at a minimum of 6 months after injury to determine validity. RESULTS: Overall agreement was defined as moderate. (kappa = 0.583) "No consolidation" (kappa = 0.816), "full consolidation" (kappa = 0.517) and "partial consolidation" (kappa = 0.390) were defined as good, moderate and fair agreement, respectively. The average sensitivity and specificity of diagnosing scaphoid waist fracture union on standard scaphoid radiographs were 0.65 and 0.67, respectively. The positive predictive value for diagnosing union was 0.93 and the negative predictive value was 0.22. CONCLUSIONS: Conventional radiographic imaging is accurate and moderately reliable in diagnosing union, and reliable but inaccurate in diagnosing nonunion of scaphoid waist fractures at 6 weeks follow-up.

Alterations in the permeability and conductance of mutant atrial connexins may contribute to reentry arrhythmias., Gap junctions ensure the rapid propagation of the action potential throughout the myocardium. Three mutant forms of connexin40 (Cx40; A96S, M163V, and G38D), the primary component of the atrial gap junction channel, are associated with atrial fibrillation and retain the ability to form functional channels. We determined the biophysical properties of these mutant gap junctions in transiently transfected HeLa and N2A cells. All three mutants showed macroscopic junctional conductances over the range of 0.5 to 40 nS, and voltage dependences comparable to those of wild-type (WT) Cx40. However, the unitary conductance of G38D channels was ∼1.6-fold higher than that of WT Cx40 channels (∼220 vs. ∼135 pS), whereas the unitary conductances of the A96S and M163V mutants were similar to that of WT Cx40. Furthermore, the M163V and G38D channels exhibited approximately two- and approximately fivefold higher permeability to the anionic dye Lucifer yellow (LY) relative to K+ (LY/K+) compared with that of WT Cx40, whereas A96S LY transfer was similar to that of WT (G38D > M163V > A96S ≈ Cx40WT). In contrast, G38D channels were almost impermeable to cationic ethidium bromide (EtBr), suggesting that G38D alters channel selectivity. Conversely, A96S and M163V channels showed enhanced EtBr permeability relative to WT Cx40, with the following permeability order: M163V > A96S > Cx40WT > G38D. Altered conductive and permeability properties of mutant channels suggest an essential role for Cx40-mediated biochemical and electrical coupling in cardiac tissues. The altered properties of the three single-base substitution mutants may play a role in mechanisms of reentry arrhythmias.

Although communication failures between professionals in acute care delivery occur, explanations for these failures remain unclear. We aim to gain a deeper understanding of interprofessional communication failures by assessing two different explanations for them. A multiple case study containing six cases (i.e. acute care chains) was carried out in which semi-structured interviews, physical artifacts and archival records were used for data collection. Data were entered into matrices and the pattern-matching technique was used to examine the two complementary propositions. Based on the level of standardization and integration present in the acute care chains, the six acute care chains could be divided into two categories of care processes, with the care chains equally distributed among the categories. Failures in communication occurred in both groups. Communication routines were embedded within organizations and descriptions of communication routines in the entire acute care chain could not be found. Based on the results, failures in communication could not exclusively be explained by literature on process typology. Literature on organizational routines was useful to explain the occurrence of communication failures in the acute care chains. Organizational routines can be seen as repetitive action patterns and play an important role in organizations, as most processes are carried out by means of routines. The results of this study imply that it is useful to further explore the role of organizational routines on interprofessional communication in acute care chains to develop a solution for failures in handover practices.

Abstract An isolated fracture of the pisiform bone is a rare condition, especially in children. The fracture may be missed in the emergency department because of the complex anatomy of the carpal region. Early diagnosis and treatment are, however, important for the functional outcome of the patient, since untreated dislocated carpal fractures may result in nonunion. We report one case of a 9-year-old boy with an unrecognized fracture of the pisiform bone who underwent a pisiformectomy 10 months after injury due to a nonunion of the pisiform bone. Good results were obtained and the wrist did not show any functional impairment.

The early chain of care is critical for stroke patients. The most important part is the so-called 'system delay' i.e. the delay time from call to the emergency medical services until a diagnosis is established (computer tomography).The purpose of this study was to relate the initial priority level given by the dispatch centre to the early chain of care in acute stroke and to short-term and long-term mortality.All patients hospitalised with the first and the final diagnosis of acute stroke, 15 December 2010-15 April 2011, were recruited across nine hospitals, each hospital with a stroke care unit.In all, 897 stroke patients were included. Priority at the dispatch centre: 54% received highest priority 1, 41% priority 2 and 5% priority 3. Median system delay from call to emergency medical services until diagnosis by computer tomography was 2 h and 52 min, 4 h and 49 min and 6 h and 33 min respectively in the three priority groups ( p0.0001). There was a similarly strong association between priority level at the dispatch centre and system delay to arrival in a hospital ward, suspicion of stroke by the emergency medical services nurse as well as the physician on hospital admission and the proportion of patients given thrombolysis. Mortality during the subsequent 30 days was 22% among patients with priority 1 and 14% among patients with priority 2.Patients given a lower priority level at the dispatch centre had the longest system delay. Although many of these patients died, the risk of death was highest among those given the highest priority.

Background: In this work, we used a sensitive and noninvasive computational method to assess diabetic cardiovascular autonomic neuropathy (DCAN) from pulse oximeter (photoplethysmographic; PPG) recordings from mice. The method, which could be easily applied to humans, is based on principal dynamic mode (PDM) analysis of heart rate variability (HRV). Unlike the power spectral density, PDM has been shown to be able to separately identify the activities of the parasympathetic and sympathetic nervous systems without pharmacological intervention. Method: HRV parameters were measured by processing PPG signals from conscious 1.5- to 5-month-old C57/BL6 control mice and in Akita mice, a model of insulin-dependent type 1 diabetes, and compared with the gold-standard Western blot and immunohistochemical analyses. Results: The PDM results indicate significant cardiac autonomic impairment in the diabetic mice in comparison to the controls. When tail-cuff PPG recordings were collected and analyzed starting from 1.5 months of age in both C57/Bl6 controls and Akita mice, onset of DCAN was seen at 3 months in the Akita mice, which persisted up to the termination of the recording at 5 months. Conclusions: Western blot and immunohistochemical analyses also showed a reduction in nerve density in Akita mice at 3 and 4 months as compared to the control mice, thus, corroborating our PDM data analysis of HRV records. Western blot analysis of autonomic nerve proteins corroborated the PPG-based HRV analysis via the PDM approach. In contrast, traditional HRV analysis (based on either the power spectral density or time-domain measures) failed to detect the nerve rarefaction.

We hypothesised that the use of pulsed electromagnetic field (PEMF) bone growth stimulation in acute scaphoid fractures would significantly shorten the time to union and reduce the number of nonunions in a randomised, double-blind, placebo-controlled multicentre trial. A total of 102 patients (78 male, 24 female; mean age 35 years (18 to 77)) from five different medical centres with a unilateral undisplaced acute scaphoid fracture were randomly allocated to PEMF (n = 51) or placebo (n = 51) and assessed with regard to functional and radiological outcomes (multiplanar reconstructed CT scans) at 6, 9, 12, 24 and 52 weeks. The overall time to clinical and radiological healing did not differ significantly between the active PEMF group and the placebo group. We concluded that the addition of PEMF bone growth stimulation to the conservative treatment of acute scaphoid fractures does not accelerate bone healing. Cite this article: Bone Joint J 2014; 96-B:1070–6.

Electronic pacemakers are the standard therapy for bradycardia-related symptoms but have shortcomings. Over the past 15 years, experimental evidence has demonstrated that gene and cell-based therapies can create a biological pacemaker. Recently, physiologically acceptable rates have been reported with an adenovirus-based approach. However, adenovirus-based protein expression does not last more than 4 weeks, which limits its clinical applicability. Cell-based platforms are potential candidates for longer expression. Currently there are two cell-based approaches being tested: (i) mesenchymal stem cells used as a suitcase for delivering pacemaker genes and (ii) pluripotent stem cells differentiated down a cardiac lineage with endogenous pacemaker activity. This review examines the current achievements in engineering a biological pacemaker, defines the patient population for whom this device would be useful and identifies the challenges still ahead before cell therapy can replace current electronic devices.

Loss of contact between radial head fracture fragments is strongly associated with other elbow or forearm injuries. If this finding has adequate interobserver reliability, it could help examiners identify and treat associated ligament injuries and fractures (eg, forearm interosseous ligament injury or elbow dislocation). (1) What is the interobserver agreement on radiographic loss of contact between radial head fracture fragments? (2) Are there factors associated with the observer such as location of practice or subspecialization that increase interobserver reliability? Fully trained practicing orthopaedic and trauma surgeons from around the world evaluated 27 anteroposterior and lateral radiographs of radial head fractures on a web-based platform for the following characteristics: (1) loss of contact between at least one radial head fracture fragment and the remaining radial head and neck; (2) a gap between fragments of 2 mm or greater; (3) anticipated fracture instability (mobility) on operative exposure; (4) anticipated associated ligament injuries; and (5) recommendation for treatment. Agreement among observers was measured using the multirater kappa measure. Kappas for various observer characteristics were compared using 95% confidence intervals. The overall interobserver agreement was moderate (range, 0.49-0.55) for each question except associated ligament injury, which was fair (0.33). Shoulder and elbow surgeons had substantial agreement (range, 0.51-0.61) in many areas, but kappas were generally in the moderate range (0.41-0.59) based on number of years in practice, radial head fractures treated per year, and trainee supervision. Radiographic signs of radial head fracture instability such as loss of contact have moderate reliability. This characteristic seems clinically useful, because loss of contact between at least one radial head fracture fragment and the remaining radial head and neck is strongly associated with associated ligament injury or other fractures. Level III, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence

Summary Objective The development of chondrocytic cell lines has enabled the investigation of the role of cellular phenotype and mechanisms in articular cartilage biology and physiopathology of several rheumatic diseases. Among them, the T/C-28a2 cell line has become a common tool in cartilage research. Recent results from our group have revealed that primary human chondrocytes in tissue and in monolayer culture contain high levels of connexin 43 (Cx43) and are able to directly communicate through gap junction (GJ) channels. These results challenge the existing thesis of cartilage physiology, that chondrocytes do not have the capacity to physically communicate with each other. Established cell lines offer the advantage of convenience and uniformity; however, the establishment process may cause a disruption of GJ. This study was performed to investigate if T/C-28a2 cells contain Cx43 protein and form functional channels. Methods Cx43 was characterized by RT-qPCR, Western blotting, and immunohistochemistry (IHC). Electrophysiology experiments, Lucifer Yellow (LY) uptake, electroporation in situ and scrape loading assay were performed to test the functionality of GJs. Results T/C-28a2 cells express Cx43. Electrophysiology experiments and LY uptake confirmed the capacity of these cells to communicate through GJ channels, although these cells contain significant levels of active c-Src kinase, presumably due to their immortalization with the Simian Virus 40 large T antigen. The results were validated using primary chondrocytes (PC). Conclusions These results reveal that the T/C-28a2 line may provide a useful in vitro model for the study of Cx43 function and cell communication to understand the physiology of chondrocytes and cartilage.

In clinical practice, fracture healing is evaluated by clinical judgment in combination with conventional radiography. Due to limited resolution, radiographs don't provide detailed information regarding the bone micro-architecture and bone strength. Recently, assessment of in vivo bone density, architectural and mechanical properties at the microscale became possible using high resolution peripheral quantitative computed tomography (HR-pQCT) in combination with micro finite element analysis (μFEA). So far, such techniques have been used mainly to study intact bone. The aim of this study was to explore whether these techniques can also be used to assess changes in bone density, micro-architecture and bone stiffness during fracture healing. Therefore, the fracture region in eighteen women, aged 50 years or older with a stable distal radius fracture, was scanned using HR-pQCT at 1-2 (baseline), 3-4, 6-8 and 12 weeks post-fracture. At 1-2 and 12 weeks post-fracture the distal radius at the contra-lateral side was also scanned as control. Standard bone density, micro-architectural and geometric parameters were calculated and bone stiffness in compression, torsion and bending was assessed using μFEA. A linear mixed effect model with time post-fracture as fixed effect was used to detect significant (p-value ≤ 0.05) changes from baseline. Wrist pain and function were scored using the patient-rated wrist evaluation (PRWE) questionnaire. Correlations between the bone parameters and the PRWE score were calculated by Spearman's correlation coefficient. At the fracture site, total and trabecular bone density increased by 11% and 20%, respectively, at 6-8 weeks, whereas cortical density was decreased by 4%. Trabecular thickness increased by 23-31% at 6-8 and 12 weeks and the intertrabecular area became blurred, indicating intertrabecular bone formation. Compared to baseline, calculated bone stiffness in compression, torsion and bending was increased by 31% after 12 weeks. A moderate negative correlation was found between the stiffness and the PRWE score. No changes were observed at the contra-lateral side. The results demonstrate that it is feasible to assess clinically relevant and significant longitudinal changes in bone density, micro-architecture and mechanical properties at the fracture region during the healing process of stable distal radius fractures using HR-pQCT.KeywordsFracture healing; Distal radius; HR-pQC

Background Around 5 to 15% of all scaphoid fractures result in nonunion. Treatment of long-lasting scaphoid nonunion remains a challenge for the treating surgeon. Healing of scaphoid nonunion is essential for prevention of scaphoid nonunion advanced collapse and the subsequent predictable pattern of radiocarpal osteoarthritis. Purpose The purpose of this study was to investigate the feasibility of fixation of the scaphoid nonunion with a volar angular stable miniplate and cancellous bone grafting. We hypothesized that this technique could be successful, even in patients with previous surgery for nonunion and in patients with a long duration of nonunion. Patients and Methods A total of 21 patients enrolled in a single-center prospective cohort study. Healing of nonunion was assessed on multiplanar computed tomography scan of the wrist at a 3-month interval. Functional outcome was assessed by measuring grip strength, range of motion, and by means of the patient-rated wrist and hand evaluation (PRWHE) questionnaire. Results During follow-up, 19 out of 21 patients (90%) showed radiological healing of the nonunion. The range of motion did not improve significantly. Postoperative PRWHE scores decreased by 34 points. Healing occurred regardless of the length of time of the nonunion (range: 6–183 months) and regardless of previous surgery (38% of patients). Conclusion Volar angular stable miniplate fixation with autologous cancellous bone grafting is a successful technique for the treatment of chronic unstable scaphoid nonunion, even in patients with long-lasting nonunion and in patients who underwent previous surgery for a scaphoid fracture. Rotational interfragmentary stability might be an important determining factor for the successful treatment of unstable scaphoid nonunion. Level of Evidence Level IV.

The time required to observe changes in participant evaluation of continuing medical education (CME) courses in surgical fields is unclear. We investigated the time required to observe changes in participant evaluation of an orthopaedic course after educational redesign using aggregate course-level data obtained from 1359 participants who attended one of 23 AO Davos Courses over a 5-year period between 2007 and 2011. Participants evaluated courses using two previously validated, 5-point Likert scales based on content and faculty performance, and we compared results between groups that underwent educational redesign incorporating serial needs assessment, problem-based learning, and faculty training initiatives (Masters Course), and those that did not (Non-Masters Course). Average scores for the usefulness and relevancy of a course and faculty performance were significantly higher for redesigned courses (p < 0.0001) and evaluations were significantly improved for both groups after faculty training was formalised in 2009 (p < 0.001). In summary, educational redesign incorporating serial needs assessment, problem-based learning, and faculty training initiatives were associated with improvement in participant evaluation, but these changes required 4-5 years to become evident.