Paul W. Ackermann

Does Rehabilitation Matter in Patients With Femoral Neck Fracture and Cognitive Impairment? A Prospective Study of 246 Patients

UNLABELLEDnAl-Ani AN, Flodin L, Söderqvist A, Ackermann P, Samnegård E, Dalén N, Sääf M, Cederholm T, Hedström M. Does rehabilitation matter in patients with femoral neck fracture and cognitive impairment? A prospective study of 246 patients.nnnOBJECTIVEnTo identify factors associated with preserved walking ability and Katz activities of daily living (ADLs) index at 4-month and 12-month follow-up in cognitively impaired patients with femoral neck fracture.nnnDESIGNnPopulation-based cohort study.nnnSETTINGnA multicenter study of the Stockholm Hip Fracture Group including 4 university hospitals.nnnPARTICIPANTSnConsecutive patients (N=246) with femoral neck fracture, older than 65 years (mean, 84y; 72% women) with cognitive impairment (known dementia or low [0-2 points] score) in Short Portable Mental Status Questionnaire [0-10 points]) and able to walk before the fracture.nnnINTERVENTIONSnNot applicable.nnnMAIN OUTCOME MEASUREnWalking ability and ADLs index at 4-month and 12-month follow-up.nnnRESULTSnSignificant predictors of preserved walking ability at 12-month follow-up were discharge to rehabilitation unit (odds ratio [OR]=2.83; confidence interval [CI], 1.1-7.26; P=.03) and walking ability before the fracture (OR=8.98; CI, 3.52-22.93; P<.001), while type of surgery was not (P=.197). Analyses were adjusted for age, sex, American Society of Anesthesiologists score, fracture type, and surgical method. Corresponding predictors of preserved Katz ADLs index at 12-month follow-up, after adjustment for age and sex, were discharge to rehabilitation unit (OR=5.33; CI, 1.44-19.65; P=.012) and ADLs index before fracture (OR=2.51; CI, 1.8-3.5; P<.001), while type of surgery was not (P=.376).nnnCONCLUSIONSnDischarge to rehabilitation unit, a factor we can influence, was associated with preserved walking ability and ADLs index in cognitively impaired patients with hip fracture.

Type 2 diabetes impairs tendon repair after injury in a rat model

Type 2 diabetes adversely affects the properties of native connective tissue. The underlying mechanisms, however, by which diabetes alters connective tissue metabolism, especially tendon, are poorly defined. The aim of this study was to determine the effect of type 2 diabetes on the mechanical, histological, and molecular properties of the intact and healing Achilles tendon. The right Achilles tendon was transected in 11 male diabetic Goto-Kakizaki (GK) and 10 age- and sex-matched Wistar control rats, while the left Achilles tendon was left intact. At 2 wk postinjury the intact and injured tendons were assessed by biomechanical testing and histology. The gene expression of collagen I and III, biglycan, versican, MMP-13, and MMP-3 was measured by quantitative RT-PCR, and their protein distribution was studied by immunohistochemistry. Intact tendons exhibited only small differences between the groups. In injured tendons, however, a significantly smaller transverse area and lower stiffness was found in diabetic GK compared with Wistar control rats. This correlated with impaired structural organization of collagen fibers and a reduced expression of collagen I and III in the injured tendons of the diabetic GK compared with Wistar control. Moreover, MMP-3 gene expression was downregulated in the injured diabetic GK tendons compared with injured Wistar controls. Our results indicate that in a rat model of diabetes tendon healing is impaired mainly due to altered expression of collagen and MMPs reflecting decreased degradation of matrix proteins and impaired tissue remodeling. Further our data suggest that therapeutic modulation of collagens or MMPs might be targets for new regenerative approaches in operated, injured, or maybe also degenerative tendon diseases in diabetes.

Neuronal regulation of tendon homoeostasis

The regulation of tendon homoeostasis, including adaptation to loading, is still not fully understood. Accumulating data, however, demonstrates that in addition to afferent (sensory) functions, the nervous system, via efferent pathways which are associated with through specific neuronal mediators plays an active role in regulating pain, inflammation and tendon homeostasis. This neuronal regulation of intact‐, healing‐ and tendinopathic tendons has been shown to be mediated by three major groups of molecules including opioid, autonomic and excitatory glutamatergic neuroregulators. In intact healthy tendons the neuromediators are found in the surrounding structures: paratenon, endotenon and epitenon, whereas the proper tendon itself is practically devoid of neurovascular supply. This neuroanatomy reflects that normal tendon homoeostasis is regulated from the tendon surroundings. After injury and during tendon repair, however, there is extensive nerve ingrowth into the tendon proper, followed by a time‐dependent emergence of sensory, autonomic and glutamatergic mediators, which amplify and fine‐tune inflammation and regulate tendon regeneration. In tendinopathic condition, excessive and protracted presence of sensory and glutamatergic neuromediators has been identified, suggesting involvement in inflammatory, nociceptive and hypertrophic (degenerative) tissue responses. Under experimental and clinical conditions of impaired (e.g. diabetes) as well as excessive (e.g. tendinopathy) neuromediator release, dysfunctional tendon homoeostasis develops resulting in chronic pain and gradual degeneration. Thus there is a prospect that in the future pharmacotherapy and tissue engineering approaches targeting neuronal mediators and their receptors may prove to be effective therapies for painful, degenerative and traumatic tendon disorders.

Compression therapy promotes proliferative repair during rat Achilles tendon immobilization

Achilles tendon ruptures are treated with an initial period of immobilization, which obstructs the healing process partly by a reduction of blood circulation. Intermittent pneumatic compression (IPC) has been proposed to enhance tendon repair by stimulation of blood flow. We hypothesized that daily IPC treatment can counteract the deficits caused by 2 weeks of immobilization post tendon rupture. Forty‐eight Sprague‐Dawley SD) rats, all subjected to blunt Achilles tendon transection, were divided in three equal groups. Group A was allowed free cage activity, whereas groups B–C were immobilized at the operated hindleg. Group C received daily IPC treatment. Two weeks postrupture the rats were euthanatized and the tendons analyzed with tensile testing and histological assessments of collagen organization and collagen III‐LI occurrence. Immobilization significantly reduced maximum force, energy uptake, stiffness, tendon length, transverse area, stress, organized collagen diameter and collagen III‐LI occurrence by respectively 80, 75, 77, 22, 47, 65, 49, and 83% compared to free mobilization. IPC treatment improved maximum force 65%, energy 168%, organized collagen diameter 50%, tendon length 25%, and collagen III‐LI occurrence 150% compared to immobilization only. The results confirm that immobilization impairs healing after tendon rupture and furthermore demonstrate that IPC‐treatment can enhance proliferative tendon repair by counteracting biomechanical and morphological deficits caused by immobilization.

Expressional changes in growth and inflammatory mediators during Achilles tendon repair in diabetic rats: new insights into a possible basis for compromised healing

Dysregulation of growth and inflammatory mediators might contribute to defective tissue homeostasis and healing, as commonly observed in sedentary lifestyles and in conditions such as diabetes mellitus type-2. The present study aims to assess expression changes in growth and inflammatory mediators in the intact and healing Achilles tendon of type-2 diabetic rats. The study utilized 11 male diabetic Goto-Kakizaki (GK) and 10 age- and sex-matched Wistar control rats. The right Achilles tendon was transected in all animals, whereas the left Achilles tendon remained intact. At 2xa0weeks post-injury, intact and injured tendons were assessed for gene expression for VEGF, Tβ-4, TGF-β1, IGF-1, COX-2, iNOS, HIF-1α, and IL-1β by quantitative reverse transcription plus the polymerase chain reaction, and their protein distribution was studied by immunolocalization. In injured tendons of diabetic GK rats, VEGF and Tβ-4 mRNA and corresponding protein levels were significantly down-regulated compared with those of injured Wistar controls. Compared with intact tendons of diabetic GK rats, TGF-β1, IGF-1, and COX-2 RNA levels were higher, whereas iNOS mRNA levels were lower in injured tendons of diabetic GK rats. Within Wistar controls, healing at 2xa0weeks post-injury led to significantly down-regulated VEGF and iNOS mRNA levels in injured tendons, whereas TGF-β1 and HIF-1α mRNA levels increased compared with intact tendons. Thus, dysregulation of inflammatory and growth mediators occurs in type-2 diabetes injured tendons. Our data suggest that therapeutic modulation of Tβ-4 and VEGF represent a new regenerative approach in operated, injured, or degenerative tendon diseases in diabetes.

Ageing, deep vein thrombosis and male gender predict poor outcome after acute Achilles tendon rupture

AIMSnPatients with an acute Achilles tendon rupture (ATR) take a long time to heal, have a high incidence of deep vein thrombosis (DVT) and widely variable functional outcomes. This variation in outcome may be explained by a lack of knowledge of adverse factors, and a subsequent shortage of appropriate interventions.nnnPATIENTS AND METHODSnA total of 111 patients (95 men, 16 women; mean age 40.3, standard deviation 8.4) with an acute total ATR were prospectively assessed. At one year post-operatively a uniform outcome score, Achilles Combined Outcome Score (ACOS), was obtained by combining three validated, independent, outcome measures: Achilles tendon Total Rupture Score, heel-rise height test, and limb symmetry heel-rise height. Predictors of ACOS included treatment; gender; age; smoking; body mass index; time to surgery; physical activity level pre- and post-injury; symptoms; quality of life and incidence of DVT.nnnRESULTSnThere were three independent variables that correlated significantly with the dichotomised outcome score (ACOS), while there was no correlation with other factors. An age of less than 40 years old was the strongest independent predictor of a good outcome one year after ATR (odds ratio (OR) 0.20, 95% confidence interval (CI) 0.08 to 0.51), followed by female gender (OR) 4.18, 95% CI 1.01 to 17.24). Notably, patients who did not have a DVT while immobilised post-operatively had a better outcome (OR 0.31, 95% CI 0.12 to 0.80).nnnCONCLUSIONnOver the age of 40 years, male gender and having a DVT while immobilised are independent negative predictors of outcome in patients with an acute ATR. Cite this article: Bone Joint J 2016;98-B:1635-41.

Additive effects of nutritional supplementation, together with bisphosphonates, on bone mineral density after hip fracture: a 12-month randomized controlled study

Background After a hip fracture, a catabolic state develops, with increased bone loss during the first year. The aim of this study was to evaluate the effects of postoperative treatment with calcium, vitamin D, and bisphosphonates (alone or together) with nutritional supplementation on total hip and total body bone mineral density (BMD). Methods Seventy-nine patients (56 women), with a mean age of 79 years (range, 61–96 years) and with a recent hip fracture, who were ambulatory before fracture and without severe cognitive impairment, were included. Patients were randomized to treatment with bisphosphonates (risedronate 35 mg weekly) for 12 months (B; n=28), treatment with bisphosphonates along with nutritional supplementation (40 g protein, 600 kcal daily) for the first 6 months (BN; n=26), or to controls (C; n=25). All participants received calcium (1,000 mg) and vitamin D3 (800 IU) daily. Total hip and total body BMD were assessed with dual-energy X-ray absorptiometry at baseline, 6, and 12 months. Marker of bone resorption C-terminal telopeptide of collagen I and 25-hydroxy vitamin D were analyzed in serum. Results Analysis of complete cases (70/79 at 6 months and 67/79 at 12 months) showed an increase in total hip BMD of 0.7% in the BN group, whereas the B and C groups lost 1.1% and 2.4% of BMD, respectively, between baseline and 6 months (P=0.071, between groups). There was no change in total body BMD between baseline and 12 months in the BN group, whereas the B group and C group both lost BMD, with C losing more than B (P=0.009). Intention-to-treat analysis was in concordance with the complete cases analyses. Conclusion Protein-and energy-rich supplementation in addition to calcium, vitamin D, and bisphosphonate therapy had additive effects on total body BMD and total hip BMD among elderly hip fracture patients.

Compromised Neurotrophic and Angiogenic Regenerative Capability during Tendon Healing in a Rat Model of Type-II Diabetes

Metabolic diseases such as diabetes mellitus type-II (DM-II) may increase the risk of suffering painful connective tissue disorders and tendon ruptures. The pathomechanisms, however, by which diabetes adversely affects connective tissue matrix metabolism and regeneration, still need better definition. Our aim was to study the effect of DM-II on expressional changes of neuro- and angiotrophic mediators and receptors in intact and healing Achilles tendon. The right Achilles tendon was transected in 5 male DM-II Goto-Kakizaki (GK) and 4 age-matched Wistar control rats. The left Achilles tendons were left intact. At week 2 post-injury, NGF, BDNF, TSP, and receptors TrkA, TrkB and Nk1 gene expression was studied by quantitative RT-PCR (qRT-PCR) and their protein distribution by immunohistochemistry in intact and injured tendons. The expression of tendon-related markers, Scleraxis (SCX) and Tenomodulin (TNMD), was evaluated by qRT-PCR in intact and injured tendons. Injured tendons of diabetic GK rats exhibited significantly down-regulated Ngf and Tsp1 mRNA and corresponding protein levels, and down-regulated Trka gene expression compared to injured Wistar controls. Intact tendons of DM-II GK rats displayed reduced mRNA levels for Ngf, Tsp1 and Trkb compared to corresponding intact non-diabetic tendons. Up-regulated Scx and Tnmd gene expression was observed in injured tendons of normal and diabetic GK rats compared to intact Wistar controls. However, these molecules were not up-regulated in injured DM-II GK rats compared to their corresponding controls. Our results suggest that DM-II has detrimental effects on neuro- and angiotrophic pathways, and such effects may reflect the compromised repair seen in diabetic Achilles tendon. Thus, novel approaches for regeneration of injured, including tendinopathic, and surgically repaired diabetic tendons may include therapeutic molecular modulation of neurotrophic pathways such as NGF and its receptors.

Tendinopathy I: Understanding Epidemiology, Pathology, Healing, and Treatment

Abstract Tendinopathy is a disorder increasing in prevalence and its treatment involves a huge effort from patient and therapist. Despite the extent of the disorder-targeted therapies has been limited due to lack of knowledge of the underlying pathophysiology. Repetitive loading and intrinsic risk factors, such as genetic variants of matrix proteins, neuronal dysregulation, and metabolic disorders contribute to the development of tendinopathy. Tendinosis is a fibrotic, failed healing response associated with pathological vessel and sensory nerve ingrowth. Aberrant sensory nerve sprouting may partly cause nociception and partly, by release of neuronal mediators contribute to causing the fibrosis. Eccentric exercise should be the basis of treatment, and can be combined with other modalities of treatment with less scientific evidence. Novel targeted therapies are emerging, for example, mini-operative procedures, but multicenter trials are needed to prove their clinical effectiveness.

Exercise training ameliorates matrix metalloproteinases 2 and 9 messenger RNA expression and mitigates adverse left ventricular remodeling in streptozotocin-induced diabetic rats☆

BACKGROUNDnThe aim was to investigate whether exercise training (ExT) would ameliorate expression of key genes for myocardial morphostructure and mitigate adverse left ventricular (LV) remodeling in experimental type 1 diabetes (T1D).nnnMETHODS AND RESULTSnMale Wistar rats were divided into four groups: sedentary control (SC, n=9), trained control (TC, n=13), sedentary diabetic (SD, n=20), and trained diabetic (TD, n=17). T1D was induced by 40 mg/kg streptozotocin (single dose, i.v.). Training program consisted of 4-week treadmill running (60 min/day, 5 days/wk). Structure of the LV was evaluated using histomorphometric techniques. Gene expression changes of LV collagens I and III, metalloproteinases (MMPs) 2 and 9, and transforming growth factor-β1 were detected by reverse transcriptase quantitative polymerase chain reaction. Compared with SC, SD rats presented LV eccentric remodeling, myocyte hypertrophy, and fibrosis, whereas TD animals showed normal LV geometry and collagen content but thinner myocytes. Expression of collagens and type I/III collagen messenger RNA (mRNA) ratio were diminished in diabetic hearts compared with SC. MMP-2 gene was down-regulated in SD, whereas TD group showed decreased MMP-9 mRNA levels and MMP-2 expression comparable to that of SC rats.nnnCONCLUSIONSnAttenuation of MMP-2 down-regulation and reduction in MMP-9 mRNA expression may constitute an underlying mechanism by which ExT counteracts progression of adverse LV remodeling in T1D.