Elevated plasma levels of TIMP-1 in patients with rotator cuff tear

Background and purpose

Extracellular matrix remodeling is altered in rotator cuff tears, partly due to altered expression of matrix metalloproteinases (MMPs) and their inhibitors. It is unclear whether this altered expression can be traced as changes in plasma protein levels. We measured the plasma levels of MMPs and their tissue inhibitors (TIMPs) in patients with rotator cuff tears and related changes in the pattern of MMP and TIMP levels to the extent of the rotator cuff tear.

Methods

Blood samples were collected from 17 patients, median age 61 (39–77) years, with sonographically verified rotator cuff tears (partial- or full-thickness). These were compared with 16 age- and sex-matched control individuals with sonographically intact rotator cuffs. Plasma levels of MMPs and TIMPs were measured simultaneously using Luminex technology and ELISA.

Results

The plasma levels of TIMP-1 were elevated in patients with rotator cuff tears, especially in those with full-thickness tears. The levels of TIMP-1, TIMP-3, and MMP-9 were higher in patients with full-thickness tears than in those with partial-thickness tears, but only the TIMP-1 levels were significantly different from those in the controls.

Interpretation

The observed elevation of TIMP-1 in plasma might reflect local pathological processes in or around the rotator cuff, or a genetic predisposition in these patients. That the levels of TIMP-1 and of certain MMPs were found to differ significantly between partial and full-thickness tears may reflect the extent of the lesion or different etiology and pathomechanisms.The subacromial pain syndrome includes a range of disorders from reversible inflammation to massive rotator cuff tearing (Shindle et al. 2011). The etiology appears to be multifactorial, and several anatomic structures may be involved. Repetitive damage of the supraspinatus tendon by mechanical wear from the coraco-acromial ligament and the anterior acromion was described by Neer 1972, and for a long time it was considered the major cause of cuff tearing (Neer 1983). Others have reported age-related tendon degeneration, associated with alterations in extracellular matrix remodeling as a contributing factor (Lo et al. 2004, Millar et al. 2009, Pasternak and Aspenberg 2009, Shindle et al. 2011). Histopathological changes associated with rotator cuff tendinosis have been documented, but it is unclear whether they are a result of a subacromial impingement or an endogenous process, and whether tendinosis might predispose to tendon tears (Lo et al. 2004).Regardless of whether mechanical or degenerative factors initiates tearing, there are alterations in the cellular and extracellular matrix (Gwilym et al. 2009). It has been suggested that genetic factors may influence apoptosis or regeneration (Gwilym et al. 2009, Shindle et al. 2011). Still, the molecular changes associated with rotator cuff tearing are largely unknown (Lo et al. 2004, Garofalo et al. 2011). Turnover of the extracellular matrix (ECM) is mediated by matrix metalloproteinases (MMPs), a family of at least 24 zinc-dependent endopeptidases. The MMPs are classified according to their main degradative activity, into for example collagenases, gelatinases, and stromelysins (Pasternak and Aspenberg 2009). Their activity is regulated by endogenous inhibitors: tissue inhibitors of metalloproteinases (TIMPs). There are 4 known TIMPs, which reversibly inhibit all MMPs by 1:1 interaction with the zinc-binding site (Lo et al. 2004, Pasternak and Aspenberg 2009). MMP production is induced by factors such as cytokines and tumor necrosis factor-α. MMPs are secreted by connective tissue and inflammatory cells and then activated in the extracellular space (Garofalo et al. 2011). The composition of the ECM is dependent on the balance between MMPs and TIMPs (Lo et al. 2004, Pasternak and Aspenberg 2009, Garofalo et al. 2011). Levels of MMP mRNA and TIMP mRNA were found to be altered in biopsies from torn rotator cuff tendon (Lo et al. 2004). It is not known, however, whether these changes are causative or whether they are secondary to tendon tearing.Studies on MMP and TIMP levels in patients with rotator cuff syndrome and cuff tears have used samples collected at surgery from the subacromial bursa, synovial fluid, or the tendons (Lo et al. 2004, Lakemeier et al. 2010, Shindle et al. 2011). To date, there have been no data on systemic levels. Alterations in MMP and TIMP levels in systemic blood samples have been identified in other musculoskeletal diseases such as Dupuytren’s disease, ankylosing spondylitis, and fracture non-union, suggesting that alterations associated with rotator cuff disease may also be measurable systemically (Ulrich et al. 2003, Henle et al. 2005, Pasternak and Aspenberg 2009). In osteoarthritis, circulating MMP-3 has been suggested to be a marker of disease severity and has been used as a prognostic tool (Lohmander et al. 2005).We measured plasma levels of MMPs and TIMPs in patients with rotator cuff tears and compared partial- and full-thickness tears, in order to find disease-associated changes in the expression patterns of MMP and TIMP.     

Epidemiology of adult ankle fractures in Sweden between 1987 and 2004: a population-based study of 91,410 Swedish inpatients

Background and purpose

Previous national epidemiological data on the characteristics and trends of patients with ankle fractures have been limited. We therefore analyzed data on Swedish inpatients with ankle fractures in this nationwide population study, based on data from 1987 through 2004.

Patients and methods

Data on all inpatients aged 15 years and older with ankle fracture were extracted from the Swedish National Patient Register for the period 1987–2004.

Results

We identified 91,410 hospital admissions with ankle fracture, corresponding to an annual incidence rate of 71 per 10⁵ person-years. During the study period, the number of hospital admissions increased by 0.2% annually, mainly from increase in fracture incidence in the elderly women. Mean age at admission was 45 (SD 19) years for men and 58 (18) for women. The major mechanism of injury was falling at the same level (64%).

Interpretation

This nationwide study of inpatients with ankle fractures showed an increase in fracture incidence, particularly in elderly women.Ankle fractures are among the most common fractures treated in orthopaedic surgery today. They are also a significant source of morbidity in both the young and the elderly (Donaldson et al. 1990, Jones et al. 1994, van Staa et al. 2001). Previous epidemiological studies have shown trends of increasing incidence over time, mainly in elderly women (Bengnér et al. 1986, Daly et al. 1987, Baron et al. 1996, Kannus et al. 1996, Court-Brown et al. 1998, van Staa et al. 2001, Kannus et al. 2002). However, most of these studies have included limited numbers of patients, and mostly originated from single hospitals or limited areas.Basic epidemiological data such as incidence, fracture type, age and sex distribution, mechanisms of injury, and surgical procedures can provide estimates when discussing disease burden and in the planning and provision of healthcare.The purpose of this study was to perform an epidemiological analysis of all adult ankle fractures requiring hospital admission in Sweden from 1997 through 2004, including incidence, causes of fracture, surgical procedures, patient characteristics, and trends over time.     

Influence of intraluminal thrombus on structural and cellular composition of abdominal aortic aneurysm wall

INTRODUCTION: It has been suggested that the intraluminal thrombus of abdominal aortic aneurysm (AAA) affects the underlying vessel wall. Aneurysm enlargement has been associated with growth of thrombus, and rupture has been proposed to occur after bleeding into the thrombus. To examine how thrombus affects the vessel wall, we compared the morphology of aneurysm wall covered with thrombus with wall segments exposed to flowing blood.Material and methods Sixteen patients (14 men, 2 women; age range, 56-79 years) undergoing elective repair of AAA, where computed tomography scans showed thrombus and segments of the aneurysm wall exposed to flowing blood, were included in the study. Specimens from the aneurysm were taken for light and electron microscopy. Masson trichrome staining was performed for wall thickness determination and demonstration of collagen, and Weigert-van Gieson staining for elastin. The cellular composition was analyzed by immunohistochemistry with antibodies against CD3 for T cells, CD4 for T helper cells, CD8 for T cytotoxic cells, CD20 for B cells, CD68 for macrophages, and smooth muscle alpha-actin for smooth muscle cells (SMCs). Caspase-3 staining and TUNEL analysis were performed to evaluate apoptosis. RESULTS: The aneurysm wall covered with thrombus was thinner and contained fewer elastin fibers, and the few that were found were often fragmented. This part of the wall also contained fewer SMCs and more apoptotic nuclei than the wall exposed to flowing blood. Clusters of inflammatory cells were detected in the media of the aneurysm wall and in higher numbers in the parts covered with thrombus. Electron microscopy showed that the aneurysm wall without thrombus contained a dense collagenous matrix with differentiated SMCs. In the segment covered with thrombus, SMCs were more dedifferentiated (synthetic) and apoptotic or necrotic. There were also an increased number of inflammatory cells located in close contact with SMCs in various stages of apoptosis. CONCLUSION: The aneurysm wall covered with thrombus is thinner and shows more frequent signs of inflammation, apoptosis of SMCs, and degraded extracellular matrix. These findings suggest that thrombus formation and accumulation of inflammatory cells may perturb the structural integrity and stability of the vessel wall and thereby increase the risk for aneurysm rupture.     

Effects of ejaculation by penile vibratory stimulation on bladder capacity in men with spinal cord lesions

PURPOSE: We examined the effects of ejaculation by penile vibratory stimulation on bladder capacity in men with spinal cord lesions. MATERIAL AND METHODS: Included in our study were 14 men with spinal cord lesions from C4 to T7 with detrusor hyperreflexia. Cystometry was performed before and immediately after ejaculation by penile vibratory stimulation to establish baseline conditions and repeated after 1 month of ejaculation by penile vibratory stimulation every third day. The third cystometry study was done after 1 month of ejaculation by penile vibratory stimulation every third day at home to determine any long-term effects of treatment. This third cystometry was performed 72 hours after the last ejaculation to exclude any acute effects of ejaculation by penile vibratory stimulation on detrusor hyperreflexia. In addition, 1 to 3 days later ejaculation was induced by penile vibratory stimulation and immediately followed by cystometry to examine whether it was possible to achieve an acute effect as well as a potential long-term effect. RESULTS: Baseline urodynamic investigations revealed bladder hyperreflexia and external sphincter dyssynergia in all individuals. There was no statistically significant difference in bladder capacity at leak point before and immediately after ejaculation by penile vibratory stimulation. However, after 4 weeks of frequent penile vibratory stimulation treatment bladder capacity at leak point increased significantly from a median of 190 ml. (range 17 to 700) at baseline to 293 (range 30 to 700) (Wilcoxon signed rank test p = 0.03). Furthermore, there was a trend toward decreased intravesical pressure during the filling phase. CONCLUSIONS: Ejaculation by penile vibratory stimulation was associated with a significant increase in bladder capacity at leak point after 4 weeks of frequent treatment. This finding may have implications in the management of incontinence in men with spinal cord lesions.     

Prevention of Secondary Insults in Neurointensive Care of Traumatic Brain Injury

Background: Secondary insults/complications have a major impact on the prognosis after traumatic brain injury (TBI). The aim was to study the occurrence and prognostic value of secondary insults occurring in TBI patients, during standardized neurointensive care (NIC) dedicated to avoiding secondary insults. Material and Methods: 154 patients, 17-79 years, with acute head trauma and pathologic CT, treated during a 2-year period at the NIC unit were studied. The occurrence of defined secondary insults (standard and severe) was recorded during the 1st week of NIC from bedside surveillance charts containing one value per hour and parameter (intracranial pressure, cerebral perfusion pressure, systolic blood pressure, PaO₂, temperature, and blood glucose). The data set was analyzed using univariate and multivariate logistic regression with favorable outcome as the response variable. Both admission variables (Glasgow Coma Scale Motor Score [GCS M], CT class, Injury Severity Score [ISS], age, and gender) and secondary insult variables were included as explanatory variables. Results: In total, 1,570 insults were identified (320 severe). In the univariate analysis, the sum of all insults, blood glucose, GCS M, CT class, and ISS showed significant effects on outcome (p < 0.05). In the multiple regression analysis, GCS M was the only significant explanatory variable. Conclusions: The occurrence of secondary insults in the NIC unit was not negligible, despite the fact that major efforts were made to avoid them. The sum score of all insult categories and high blood glucose had a statistically significant effect on favorable outcome in the univariate analysis, but secondary insults did not add any prognostic information to the neurologic grade in the multivariate analysis. This finding indicates that the insults that occurred were related to the degree of primary injury/neurologic grade.     

Fluorine-18-fluorodeoxyglucose positron emission tomography in the preoperative assessment of thyroid nodules in an endemic goiter area

BACKGROUND: The aim of this study was to evaluate the usefulness of fluorine-18-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) in the preoperative assessment of suspicious thyroid nodules. METHODS: A total of 43 patients were examined before surgical resection. In all patients, imaging was obtained at 70 minutes after the intravenous administration of 180 MBq (18)F-FDG. Standard uptake values (SUVs) were calculated. RESULTS: A total of 16 patients with thyroid carcinomas (11 papillary, 3 follicular, 2 anaplastic), 23 thyroid adenomas (11 microfollicular, 10 Hurthle cell, 2 macrofollicular), and 4 patients with degenerative goiter were found. (18)F-FDG uptake in Hurthle cell adenoma, thyroid cancer, microfollicular adenoma, degenerative goiter, and macrofollicular adenoma was 4.4 +/- 2.2, 3.7 +/- 1.9, 1.6 +/- 0.3, 1.2 +/- 0.2, and 0.9 +/- 0.1, respectively. Significant differences were observed between thyroid carcinomas and both microfollicular adenomas and degenerative goiters (P < 0.05), and between Hurthle cell adenomas and both microfollicular adenomas as well as degenerative goiter (P < 0.05). For diagnosis of thyroid carcinoma, 100% sensitivity, 63% specificity, and 100% negative predictive value was found when a cutoff value for SUV of 2 was used. CONCLUSIONS: Our results indicate that thyroid carcinomas, in contrast to most benign thyroid nodules, demonstrate significantly increased glucose metabolism. (18)F-FDG PET is unlikely to differentiate successfully all benign tumors from malignant tumors, but it can help select patients who need surgery, especially if cytology is inconclusive or malignancy cannot be excluded.     

Effects of immediate switch from cyclosporine microemulsion to tacrolimus at first acute rejection in renal allograft recipients

BACKGROUND: A number of institutions have reported favorable results in renal transplant patients after conversion from cyclosporine (CsA) to tacrolimus at the time of acute rejection, but no prospective, controlled study has been performed to date. Here, we report the first randomized study comparing patients whose therapy was changed at a first episode of acute rejection to tacrolimus with those who were maintained on CsA microemulsion (ME). METHODS: This 3-month, prospective, open, multicenter, parallel-group study was conducted at 15 centers in seven European countries. In total, 119 renal graft recipients experiencing a first biopsy-proven acute rejection episode while receiving CsA-ME were randomized (1:1) to start tacrolimus-based therapy (n=61) or to continue CsA-ME-based therapy (n=58). RESULTS: Baseline characteristics were comparable for both groups. The initial rejection episode responded to steroid treatment in 93.4% (tacrolimus) and 63.8% (CsA-ME) (P=0.001), respectively. In patients at risk, the incidence of recurrent rejection events within 3 months was significantly lower with tacrolimus therapy (5/57, 8.8%) compared with CsA-ME therapy (15/44, 34.1%) (P=0.002). Patient and graft survival were similar in both study groups 3 months after randomization. The most frequently reported adverse events were increased serum creatinine (29.5% vs. 22.4%), hypertension (24.6% vs. 22.4%), and urinary tract infection (18.0% vs. 20.7%) for tacrolimus versus CsA-ME. Tremor was more common in tacrolimus treated-patients (17.4% vs. 2.1%, P=0.011). CONCLUSIONS: Early conversion to tacrolimus therapy benefited the resolution of acute rejection episodes and significantly reduced the risk of recurrent rejection compared with continuation of CsA-ME.     

Successful open reduction of a 5-month-old hip dislocation associated with a femoral head fracture

The long-term prognosis after open reduction of neglected posterior hip dislocations is poor; as such, primary arthroplasty is recommended by a number of authors. We present a patient with a 5-month-old posterior hip dislocation with concomitant paralysis of the sciatic nerve who had an open reduction. At a follow-up of 3.5 years, the patient has normal function with no signs of arthrosis. Magnetic resonance imaging scans, however, revealed partial avascular necrosis of the femoral head. A discussion based on the literature shows the uniqueness of this case.     

Anxiety, Depression and Health-Related Quality of Life after Jejunoileal Bypass: A 25-Year Follow-up Study of 20 Female Patients

Background: Jejunoileal (JI) bypass was a widely performed operation for morbid obesity in the 1970s.The aim of this study was to investigate the long-term status for mental and physical health after weight loss induced by this operation. Methods: 20 female patients (age 48-80 y, BMI 23-75 kg/m²) were interviewed 25 years after JI bypass. The Hospital Anxiety and Depression Scale (HAD) and Short Form 36 (SF-36) were used. Scores from the Norwegian female population, and published scores for morbidly obese patients were used for comparison. An assessment was made on whether present demographic and clinical factors influenced the scores. Results: Anxiety and depression scores, and scores for physical functioning, bodily pain, vitality and mental health on the SF-36 were similar to scores in the Norwegian female population used for comparison. The scores from the patient sample were much better than scores published for morbidly obese patients, and implies that weight loss induced by the operation has been of great benefit on mental health and health-related quality of life. Anxiety and depression symptoms improved; however, being socially handicapped by the stools had a negative impact on HAD and SF-36 scores. Conclusion: These results suggest that 25 years after the JI bypass most of these patients have a similar level of mental and physical health as the general Norwegian female population. For individuals with bothersome side-effect(s) of the operation, a negative impact is seen.