Partial weight-bearing following ankle fracture: what's the actual load in early recovery?

PURPOSE: This study investigates the learning efficacy for partial weight load before discharge as well as the impact of biofeedback during the learning process. METHODS: We monitored weight-bearing in 57 patients who had surgery for ankle fractures. Continuous measurements without and with biofeedback were performed in the early postoperative stage in order to, first, assess how well these patients could apply what they have learned before being discharged, and second, to examine the influence of biofeedback. RESULTS: Using conventional teaching methods, only about one-third of patients (36.8% on the ground and 29.2% on the stairs) were able to maintain a satisfactory load. One-fourth of the patients did not place any weight on their leg, which was shown to be due to excessive pain at the time of the measurement (p < 0.05). A further one-fourth loaded inadequately low, while the remainder loaded excessively. Patients benefited significantly from the activation of audio-visual biofeedback in real time. As a result, loads in a target zone between 15 and 30 kg could be significantly increased (p < 0.05). CONCLUSION: We conclude that the majority of ankle fracture patients were unable to learn partial weight bearing in the early postoperative stage using traditional techniques. Additionally, each patient's ability to carry out a given loading varied. Using an audio-visual real-time biofeedback modality led to significantly improved performance. These findings support the proposed utility of audiovisual feedback in early rehabilitation. With the use of outpatient real-time biofeedback systems, therapists will be able to respond specifically to the needs of each individual patient. TRIAL REGISTRATION: Trial registration: DRKS00031136, Registered 01.02.2023 - Retrospectively registered, https://www.drks.de/DRKS00031136.

Continuous real-time biofeedback in orthosis improves partial weight bearing on stairs.

INTRODUCTION: Climbing up and down stairs with crutches is a particular challenge. The current study evaluates a commercially available insole orthosis device for weighing an affected limb and for biofeedback training of gait. This study was done on healthy, asymptomatic individuals before applying to the intended postoperative patient. The outcomes should demonstrate whether a continuous real-time biofeedback (BF) system is more effective on stairs than the current protocol involving a bathroom scale. MATERIALS AND METHODS: 59 healthy test subjects received both crutches and an orthosis and learned to apply a 3-point gait with a partial load of 20 kg using a bathroom scale. Thereafter, the participants were asked to complete an up-and-down course, first without (control group) and then with (test group) an audio-visual real-time biofeedback (BF). Compliance was evaluated using an insole pressure measurement system. RESULTS: Using the conventional therapy technique, 36.6% of the steps up and 39.1% of the steps down in the control group were loaded with < 20 kg. By activating continuous biofeedback, steps with < 20 kg could be increased significantly to 61.1% upstairs (p < 0.001) and 66.1% downstairs (p < 0.001). All subgroups profited from the BF system, independent of age, gender, side relieved, dominant or non-dominant side. CONCLUSIONS: Traditional training without biofeedback led to poor performance for partial weight bearing on stairs, even among young and healthy individuals. However, continuous real-time biofeedback clearly improved compliance, indicating its potential to enhance training and support future research in patient populations.

Can elderly individuals perform partial weight bearing on their lower limbs? A prospective cohort study using ambulatory real-time biofeedback.

BACKGROUND: Partial weight bearing in an orthosis and with forearm crutches is a widespread and well-accepted therapeutic principle after an injury of the lower extremity during early rehabilitation. Complying may be challenging to do under these circumstances, especially for elderly people. This study compares the spatiotemporal parameters and peak loads performed by a group of older participants before and after activating real-time biofeedback (BF) to determine whether they benefit from a biofeedback. METHODS: Twenty-four healthy subjects between 61 and 80 years learned how to walk using forearm crutches in a lower leg orthosis while performing a weight of 20 kg using a bathroom scale with the aim of loading in a zone between 15 and 30 kg. After that, they completed a course that was on level ground (50 m) and another course on stairs (11 steps). They did a walk without BF first, and then with BF. Each step was given a maximum load, which was determined and statistically checked. In addition, spatiotemporal parameters were collected. RESULTS: The classical teaching method with a bathroom scale was ineffective. Only 32.3% of the loads could be adequately carried by a person on level ground in the 15-30 kg target zone. On the stairs, it was 48.2% and 34.3%, respectively. Thus, on level ground, 52.7% of loads exceeded 30 kg. Downstairs it was 46.4%, and upstairs it was 41.6%. Subjects clearly benefit from activated biofeedback. Biofeedback significantly reduced missteps > 30 kg in every course. The loads decreased significantly to 25.0% on level ground, to 23.0% upstairs, and to 24.4% downstairs. At the same time, speed and stride length decreased per course while total time increased. CONCLUSION: Partial weight bearing is more complex and difficult for the elderly. These study results may help better understand 3-point gait in older adults in an outpatient setting. When partial weight bearing is recommended, special follow-up attention must be given for this group. Age-based therapy strategies can be developed and monitored with the assistance of ambulatory biofeedback devices. Trial registration Retrospectively registered, https://www.drks.de/DRKS00031136 .

The effect of perioperative hemadsorption in patients operated for acute infective endocarditis-A randomized controlled study.

Patients operated for infective endocarditis (IE) are at high risk of developing an excessive systemic hyperinflammatory state, resulting in systemic inflammatory response syndrome and septic shock. Hemoadsorption (HA) by cytokine adsorbers has been successfully applied to remove inflammatory mediators. This randomized controlled trial investigates the effect of perioperative HA therapy on inflammatory parameters and hemodynamic status in patients operated for IE. A total of 20 patients were randomly assigned to either HA therapy or the control group. HA therapy was initiated intraoperatively and continued for 24 hours postoperatively. Cytokine levels (IL-6, IL-1b, TNF-α), leukocytes, C-reactive protein (CRP), and Procalcitonin (PCT) as well as catecholamine support, and volume requirement were compared between both groups. Operative procedures included aortic (n = 7), mitral (n = 6), and multiple valve surgery (n = 7). All patients survived to discharge. No significant differences concerning median cytokine levels (IL-6 and TNF-α) were observed between both groups. CRP and PCT baseline levels were significantly higher in the HA group (59.5 vs. 26.3 mg/dL, P = .029 and 0.17 vs. 0.05 µg/L, P = .015) equalizing after surgery. Patients in the HA group required significantly higher doses of vasopressors (0.093 vs. 0.025 µg/kg/min norepinephrine, P = .029) at 12 hours postoperatively as well as significantly more overall volume replacement (7217 vs. 4185 mL at 12 hours, P = .015; 12 021 vs. 4850 mL at 48 hours, P = .015). HA therapy did neither result in a reduction of inflammatory parameters nor result in an improvement of hemodynamic parameters in patients operated for IE. For a more targeted use of HA therapy, appropriate selection criteria are required.

Clinical process optimization of transfemoral transcatheter aortic valve implantation.

Background: The avoidance of prolonged hospital stay is a major goal in the management of transcatheter aortic valve implantation (TAVI) - medically and economically. Materials & methods: We compared the time range of the preprocedural length of stay in 2014/2015 with 2016/2017, after the implementation of the TAVI coordinator in 2016. This included restructured pathways for screening and pre-interventional diagnosis, performed examinations during the inpatient stay and major outcome variables. Results: After 2016, we observed a significant reduction in preprocedural length of stay (admission to procedure) compared with 2014/2015 (11.3 ± 7.9 vs 7.5 ± 5.6 days, p = 0.001). There was no difference in other major outcome variables. Conclusion: The introduction of the TAVI coordinator caused a shortening of preprocedural length of stay.

Shoulder joint replacement can improve quality of life and outcome in patients with dysmelia: a case series.

BACKGROUND: Arthroplasty is a proven treatment option for glenohumeral osteoarthritis. Common indications include primary or posttraumatic osteoarthritis, avascular necrosis of the humeral head, rotator cuff tear arthropathy and rheumatoid osteoarthritis. Arthroplasty is rarely performed among patients with glenohumeral dysmelia. An overuse of the upper limb in patients with thalidomide-induced phocomelia and people with similar congenital deformities like dysmelia results in premature wear of the shoulder joint. This study aims to evaluate our experience with cases of glenohumeral osteoarthritis caused by dysmelia and treated with arthroplasty. To date, few reports on the outcome of shoulder arthroplasty exist on this particular patient group. CASE PRESENTATION: We included four dysmelic patients (five shoulders) with substantial glenoid dysplasia in a prospective database after approval by the local ethics committee. Once conservative treatment options had been exhausted, the patients were treated with shoulder arthroplasty and assessed clinically and radiographically before and after surgery. The mean patient age at the time of surgery was 50.4 years. The minimum follow-up time was 24 months (24-91 months). All patients experienced a considerable improvement of range of motion (ROM) and a relief of pain. No intra- or postoperative complications appeared. CONCLUSION: Patients with dysmelia have acceptable short and mid-term results with resurfacing hemiarthroplasty. It is an effective although somewhat complicated method to relieve pain and improve movement. Long-term performance of arthroplasty in patients with dysmelia remains to be seen, particularly with regard to the remaining problem of the altered and often deficient glenoid.

The TNF family member 4-1BBL sustains inflammation by interacting with TLR signaling components during late-phase activation.

Activation of Toll-like receptor (TLR)-dependent signaling leads to the expression of genes encoding proinflammatory factors, such as tumor necrosis factor-α (TNF-α), and this proinflammatory gene expression is sustained for the duration of the inflammatory response. TLR4-mediated inflammation, which occurs in two phases, depends on the TNF family member 4-1BB ligand (4-1BBL) to sustain TNF-α production during late-phase signaling. We showed that Toll-interleukin-1 receptor (TIR) domain-containing adaptor protein (TIRAP) and the kinase IRAK2 interacted with 4-1BBL to mediate late-phase TLR4 signaling. Expression of 4-1bbl depended on early TLR4 signaling that also induced Tnf expression, and 4-1BBL translocated to the plasma membrane, where it interacted with TLR4 to mediate late-phase signaling. TLR4-4-1BBL-mediated signaling depended on TIRAP and IRAK2, as well as a complex consisting of the E3 ubiquitin ligase TRAF6 (TNF receptor-associated factor 6), the kinase TAK1 (transforming growth factor-ß-activated kinase 1), and the adaptor protein TAB1 (TAK-binding protein 1). Inhibition of this late-phase pathway reduced the extent of TNF-α production by mouse macrophages exposed to the TLR4 ligand lipopolysaccharide (LPS) and ameliorated LPS-induced sepsis in mice. Together, these data suggest that TIRAP and IRAK2 are critical for the sustained inflammatory response that is mediated by late-phase signaling by the TLR-4-1BBL complex.

A potential suppressive effect of natural antisense IL-1ß RNA on lipopolysaccharide-induced IL-1ß expression.

Although more than half of genomic loci are believed to have antisense transcription, whether antisense transcription is involved in cytokine expression has not been studied. In this study, we show that some loci of innate immunity related genes do have antisense transcripts. We investigated the effect of several antisense RNAs, including anti-4-1BBL, anti-p100, and anti-IL-1ß, on their cognate sense gene's expression in macrophages. We found that overexpression of antisense IL-1ß transcript suppressed IL-1ß expression. Anti-IL-1ß is complementary to the sequence in the 5' upstream region of the IL-1ß promoter. Its mediated inhibition of IL-1ß production occurred at the transcriptional level. Anti-IL-1ß did not alter the methylation status of the IL-1ß promoter. However, chromatin immunoprecipitation assays revealed that the anti-IL-1ß transcript can change the chromatin structure of the IL-1ß promoter by decreasing H3K4 trimethylation on the promoter, which is at least part of the mechanism underlying the reduced binding of RNA polymerase II to the IL-1ß promoter upon anti-IL-1ß expression. Our data suggest that some antisense transcripts of innate immunity-related genes play a role by regulating cytokine expression.

The LPS2 mutation in TRIF is atheroprotective in hyperlipidemic low density lipoprotein receptor knockout mice.

Signaling through MyD88, an adaptor utilized by all TLRs except TLR3, is pro-atherogenic; however, it is unknown whether signaling through TIR-domain-containing adaptor-inducing interferon-ß (TRIF), an adaptor used only by TLRs 3 and 4, is relevant to atherosclerosis. We determined that the TRIF(Lps2) lack-of-function mutation was atheroprotective in hyperlipidemic low density lipoprotein (LDL) receptor knockout (LDLr(-/-)) mice. LDLr(-/-) mice were crossed with either TRIF(Lps2) or TLR3 knockout mice. After feeding an atherogenic diet for 10-15 wks, atherosclerotic lesions in the heart sinus and aorta were quantitated. LDLr(-/-) mice with TRIF(Lps2) were significantly protected from atherosclerosis. TRIF(Lps2) led to a reduction in cytokines secreted from peritoneal macrophages (M) in response to hyperlipidemia. Moreover, heart sinus valves from hyperlipidemic LDLr(-/-) TRIF(Lps2) mice had significantly fewer lesional M. However, LDLr(-/-) mice deficient in TLR3 showed some enhancement of disease. Collectively, these data suggest that hyperlipidemia resulting in endogenous activation of the TRIF signaling pathway from TLR4 leads to pro-atherogenic events.

Atherosclerosis induced by endogenous and exogenous toll-like receptor (TLR)1 or TLR6 agonists.

Atherosclerosis is a chronic inflammatory vascular disease. Toll-like receptors (TLRs) are major initiators of inflammation. TLR2 promotes atherosclerosis in LDL receptor (LDLr)-deficient mice fed a high-fat diet (HFD). TLR2 forms heterodimers with TLR1 or TLR6 to enable inflammatory responses in the presence of distinct ligands. Here we asked whether TLR1 and/or TLR6 are required. We studied atherosclerotic disease using either TLR1- or TLR6-deficient mice. Deficiency of TLR1 or TLR6 did not diminish HFD-driven disease. When HFD-fed LDLr-deficient mice were challenged with Pam3 or MALP2, specific exogenous ligands of TLR2/1 or TLR2/6, respectively, atherosclerotic lesions developed with remarkable intensity in the abdominal segment of the descending aorta. In contrast to atherosclerosis induced by the endogenous agonists, these lesions were diminished by deficiency of either TLR1 or TLR6. The endogenous ligand(s) that arise from consumption of a HFD and promote disease via TLR2 are unknown. Either TLR1 or TLR6 are redundant for this endogenous ligand detection, or they are both irrelevant to endogenous ligand detection. However, the exogenous ligands Pam3 and MALP2 promote severe abdominal atherosclerosis in the descending aorta that is dependent on TLR1 and TLR6, respectively.

The use of small molecule probes to study spatially separated stimulus-induced signaling pathways.

Simultaneous activation of signaling pathways requires dynamic assembly of higher-order protein complexes at the cytoplasmic domains of membrane-associated receptors in a stimulus-specific manner. Here, using the paradigm of cellular activation through cytokine and innate immune receptors, we demonstrate the proof-of-principle application of small molecule probes for the dissection of receptor-proximal signaling processes, such as activation of the transcription factor NF-κB and the protein kinase p38.

Monocyte tissue factor-dependent activation of coagulation in hypercholesterolemic mice and monkeys is inhibited by simvastatin.

Hypercholesterolemia is a major risk factor for atherosclerosis. It also is associated with platelet hyperactivity, which increases morbidity and mortality from cardiovascular disease. However, the mechanisms by which hypercholesterolemia produces a procoagulant state remain undefined. Atherosclerosis is associated with accumulation of oxidized lipoproteins within atherosclerotic lesions. Small quantities of oxidized lipoproteins are also present in the circulation of patients with coronary artery disease. We therefore hypothesized that hypercholesterolemia leads to elevated levels of oxidized LDL (oxLDL) in plasma and that this induces expression of the procoagulant protein tissue factor (TF) in monocytes. In support of this hypothesis, we report here that oxLDL induced TF expression in human monocytic cells and monocytes. In addition, patients with familial hypercholesterolemia had elevated levels of plasma microparticle (MP) TF activity. Furthermore, a high-fat diet induced a time-dependent increase in plasma MP TF activity and activation of coagulation in both LDL receptor-deficient mice and African green monkeys. Genetic deficiency of TF in bone marrow cells reduced coagulation in hypercholesterolemic mice, consistent with a major role for monocyte-derived TF in the activation of coagulation. Similarly, a deficiency of either TLR4 or TLR6 reduced levels of MP TF activity. Simvastatin treatment of hypercholesterolemic mice and monkeys reduced oxLDL, monocyte TF expression, MP TF activity, activation of coagulation, and inflammation, without affecting total cholesterol levels. Our results suggest that the prothrombotic state associated with hypercholesterolemia is caused by oxLDL-mediated induction of TF expression in monocytes via engagement of a TLR4/TLR6 complex.

MyD88 deficiency attenuates angiotensin II-induced abdominal aortic aneurysm formation independent of signaling through Toll-like receptors 2 and 4.

OBJECTIVE: The purpose of this study was to determine whether myeloid differentiation factor 88 (MyD88) and its related Toll-like receptors (TLRs) 2 and 4 contributed to the development of angiotensin II (AngII)-induced abdominal aortic aneurysms (AAAs) and atherosclerosis. METHODS AND RESULTS: AngII was infused into either apoE(-/-) or LDL receptor (LDLR)(-/-) male mice that were either MyD88(+/+) or (-/-). MyD88 deficiency profoundly reduced AngII-induced AAAs and atherosclerosis in both strains. To define whether deficiency of specific TLRs had similar effects, AngII was infused into LDLR(-/-) mice that were also deficient in either TLR2 or TLR4. TLR2 deficiency had no effect on AAA development but inhibited atherosclerosis. In contrast, TLR4 deficiency attenuated both AAAs and atherosclerosis. To resolve whether MyD88 and TLR4 exerted their effects through cells of hematopoietic lineage, LDLR(-/-) mice were lethally irradiated and repopulated with bone marrow-derived cells from either MyD88 or TLR4 strains. MyD88 deficiency in bone marrow-derived cells profoundly reduced both AngII-induced AAAs and atherosclerosis. However, TLR4 deficiency in bone marrow-derived cells had no effect on either pathology. CONCLUSIONS: These studies demonstrate that MyD88 deficiency in leukocytes profoundly reduces AngII-induced AAAs and atherosclerosis via mechanisms independent of either TLR2 or TLR4.

Knockout of toll-like receptor-2 attenuates both the proinflammatory state of diabetes and incipient diabetic nephropathy.

OBJECTIVE: Type 1 diabetes (T1DM) is a proinflammatory state and confers an increased risk for vascular complications. Toll-like receptors (TLR) could participate in diabetic vasculopathies. Whether TLR activation contributes to the proinflammatory state of T1DM and the pathogenesis of diabetic nephropathy remains unknown. METHODS AND RESULTS: We induced T1DM in TLR2 knockout mice (TLR2-/-) and wild-type littermates (C57BL/6J-WT) using streptozotocin (STZ). Fasting blood, peritoneal macrophages, and kidneys were obtained for flow cytometry, Western blot, microscopy, and cytokine assays at 6 and 14 weeks after induction of diabetes. Macrophage TLR2 expression and MyD88-dependent signaling were increased in diabetic mice (WT+STZ) compared with nondiabetic WT mice. These biomarkers were attenuated in diabetic TLR2-/- macrophages. WT+STZ mice showed increased kidney:body weight ratio due to cell hypertrophy, increased albuminuria, decreased kidney nephrin, podocin, and podocyte number and increased transforming growth factor-ß and laminin compared with WT mice. Nephrin, podocin, and podocyte number and effacement were restored, and transforming growth factor-ß and laminin levels were decreased in TLR2-/-+ STZ mice kidneys versus WT+STZ. Peritoneal and kidney macrophages were predominantly M1 phenotype in WT+STZ mice; this was attenuated in TLR2-/-+STZ mice. CONCLUSIONS: These data support a role for TLR2 in promoting inflammation and early changes of incipient diabetic nephropathy, in addition to albuminuria and podocyte loss.

Knockout of toll-like receptor-4 attenuates the pro-inflammatory state of diabetes.

Type 1 diabetes (T1DM) is associated with increased vascular complications and is a pro-inflammatory state. Recent findings have shown increased TLR2 and 4 expression, signaling, ligands, and functional activation in T1DM subjects compared to controls and further accentuated in T1DM with microvascular complications. Thus, the aim of this study was to examine if genetic deficiency of TLR4 attenuates the increased inflammation associated with T1DM using the streptozotocin-induced diabetic mouse model. C57BL/6 and TLR4(-/-) mice were obtained and studied in the native state and following induction of diabetes using streptozotocin. Diabetic (WT+STZ) mice had increased expression of both TLR2 and TLR4, while TLR4(-/-) STZ mice had increased expression only of TLR2, but not TLR4 compared to the non-diabetic mice TLR2 expression was significantly increased with STZ-induced diabetes and was unaffected by knockout of TLR4. Also, levels of MyD88, IRAK-1 protein phosphorylation, Trif, IRF3, and NF-κB activity were significantly reduced in TLR4(-/-) +STZ mice compared to the WT+STZ mice. WT+STZ mice exhibited significantly increased levels of serum and macrophage IL-1ß, IL-6, KC/IL-8, IP-10, MCP-1, IFN beta and TNF-α compared to WT mice and this was significantly attenuated in TLR4(-/-) +STZ mice (P<0.01). Thus, TLR4 contributes to the pro-inflammatory state and TLR4KO attenuates inflammation in diabetes.

Epithelial p38alpha controls immune cell recruitment in the colonic mucosa.

Intestinal epithelial cells (IECs) compose the first barrier against microorganisms in the gastrointestinal tract. Although the NF-kappaB pathway in IECs was recently shown to be essential for epithelial integrity and intestinal immune homeostasis, the roles of other inflammatory signaling pathways in immune responses in IECs are still largely unknown. Here we show that p38alpha in IECs is critical for chemokine expression, subsequent immune cell recruitment into the intestinal mucosa, and clearance of the infected pathogen. Mice with p38alpha deletion in IECs suffer from a sustained bacterial burden after inoculation with Citrobacter rodentium. These animals are normal in epithelial integrity and immune cell function, but fail to recruit CD4(+) T cells into colonic mucosal lesions. The expression of chemokines in IECs is impaired, which appears to be responsible for the impaired T cell recruitment. Thus, p38alpha in IECs contributes to the host immune responses against enteric bacteria by the recruitment of immune cells.

Emerging role of Toll-like receptors in atherosclerosis.

Atherosclerosis is inflammation of the vessel wall of the arterial tree. This inflammation arises at specific areas that experience disturbed blood flow such as bifurcations and the lesser curvature of the aortic arch. Although all endothelial cells are exposed to comparable levels of circulating plasma cholesterol, only endothelial cells overlaying lesions display an inflamed phenotype. This occurs even in the absence of any additional exacerbating disease factors because blood flow controls the expression of Toll-like receptors (TLR), which are initiators of cellular activation and inflammation. TLR2- and 4-expression exert an overall proatherogenic effect in hyperlipidemic mice. TLR activation of the endothelium promotes lipid accumulation and leukocyte accumulation within lesions.

Increased endothelial expression of Toll-like receptor 2 at sites of disturbed blood flow exacerbates early atherogenic events.

Toll-like receptors (TLRs) are pattern recognition receptors of innate immunity. TLRs initiate inflammatory pathways that may exacerbate chronic inflammatory diseases like atherosclerosis. En face laser scanning confocal microscopy (LSCM) of isolated aortic segments revealed the distribution of intimal TLR2 expression and the atheroprotective outcomes resulting from a TLR2 deficiency. TLR2 expression was restricted to endothelial cells in regions of disturbed blood flow, such as the lesser curvature region, in atherosclerosis-prone, low-density lipoprotein receptor-deficient (LDLr(-/-)) mice. Diet-induced hyperlipidemia in LDLr(-/-) mice increased this regional endothelial TLR2 expression. Bone marrow (BM) reconstitution of LDLr(-/-) and LDLr(-/-)TLR2(-/-) mice created chimeric mice with green fluorescent protein (GFP) expression in BM-derived cells (BMGFP(+)). Lesser curvature BMGFP(+) leukocyte accumulation, lipid accumulation, foam cell generation and endothelial cell injury were all increased by hyperlipidemia, whereas hyperlipidemic double mutant BMGFP(+)LDLr(-/-)TLR2(-/-) mice had reduced BMGFP(+) leukocyte accumulation, lipid accumulation, foam cells, and endothelial cell injury. This is the first report of in vivo site-specific expression of endothelial cell TLR2. Expression of this receptor on endothelial cells contributed to early atherosclerotic processes in lesion-prone areas of the mouse aorta.

TLR2 in murine atherosclerosis.

Atherosclerosis was once thought to be solely a disease of lipid accumulation in the vessel wall. It does involve lipid accumulation, but inflammation appears to be an important driving factor. Consequently, our laboratory undertook to examine the role(s) of TLRs, and especially TLR2, in murine models of atherosclerosis.