Integrating molecular and radiological screening tools during community-based active case-finding for tuberculosis and COVID-19 in southern Africa.

OBJECTIVES: To evaluate diagnostic yield and feasibility of integrating testing for TB and COVID-19 using molecular and radiological screening tools during community-based active case-finding (ACF). METHODS: Community-based participants with presumed TB and/or COVID-19 were recruited using a mobile clinic. Participants underwent simultaneous point-of-care (POC) testing for TB (sputum; Xpert Ultra) and COVID-19 (nasopharyngeal swabs; Xpert SARS-CoV-2). Sputum culture and SARS-CoV-2 RT-PCR served as reference standards. Participants underwent ultra-portable POC chest radiography with computer-aided detection (CAD). TB infectiousness was evaluated using smear microscopy, cough aerosol sampling studies (CASS), and chest radiographic cavity detection. Feasibility of POC testing was evaluated via user-appraisals. RESULTS: Six hundred and one participants were enrolled, with 144/601 (24.0%) reporting symptoms suggestive of TB and/or COVID-19. 16/144 (11.1%) participants tested positive for TB, while 10/144 (6.9%) tested positive for COVID-19 (2/144 [1.4%] had concurrent TB/COVID-19). Seven (7/16 [43.8%]) individuals with TB were probably infectious. Test-specific sensitivity and specificity (95% CI) were: Xpert Ultra 75.0% (42.8-94.5) and 96.9% (92.4-99.2); Xpert SARS-CoV-2 66.7% (22.3-95.7) and 97.1% (92.7-99.2). Area under the curve (AUC) for CAD4TB was 0.90 (0.82-0.97). User appraisals indicated POC Xpert to have 'good' user-friendliness. CONCLUSIONS: Integrating TB/COVID-19 screening during community-based ACF using POC molecular and radiological tools is feasible, has a high diagnostic yield, and can identity probably infectious persons.

The tourniquet's effects on skeletal muscle during total knee arthroplasty.

This study investigates the impact of perioperative tourniquet on skeletal muscle cells during total knee arthroplasty (TKA) and its effects on the gene expression of apoptotic, inflammatory, and angiogenic pathways. The randomized controlled trial included 44 patients undergoing TKA. The patients were randomized to undergo surgery with (n = 23) or without (n = 21) tourniquet. The tourniquet was inflated before skin incision and deflated before wound closure in the tourniquet group. Biopsies from the lateral vastus muscle were obtained from both groups before wound closure and 8 weeks after surgery. The messenger ribonucleic acid (mRNA) expression and protein levels of angiopoietin-like 4 (ANGPTL4), Hypoxia-inducible Factor 1α, and Vascular Endothelial Growth Factor Alpha (VEGF-A) in the biopsies were examined by reverse transcription-quantitative polymerase chain reaction and tissue microarray, respectively. Differences in mean values (ΔCt for mRNA expression and staining positivity for protein expression) were compared with t-tests. The apoptotic marker BID and the angiogenic marker VEGF-A were significantly lower in the tourniquet group compared to the control group (p = 0.03, p = 0.047). However, there was a significant upregulation of VEGF-A 8 weeks after surgery in the tourniquet group compared to perioperative biopsies (p = 0.002), indicating persistent changes. A significant upregulation in protein expression of the angiogenic marker ANGPTL4 was found perioperatively in the tourniquet group (p = 0.02). Our results demonstrate that the angiogenic gene expression is significantly altered by the tourniquet, the effects of which might contribute to postoperative interstitial edema, increased pain, and decreased muscle strength. These effects could lead to delayed rehabilitation and ultimately reduced patient satisfaction after TKA.

SARS-CoV-2 Viral Replication Persists in the Human Lung for Several Weeks after Symptom Onset.

Rationale: In the upper respiratory tract, replicating (culturable) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is recoverable for ∼4-8 days after symptom onset, but there is a paucity of data about the frequency and duration of replicating virus in the lower respiratory tract (i.e., the human lung).Objectives: We undertook lung tissue sampling (needle biopsy) shortly after death in 42 mechanically ventilated decedents during the Beta and Delta waves. An independent group of 18 ambulatory patients served as a control group.Methods: Lung biopsy cores from decedents underwent viral culture, histopathological analysis, electron microscopy, transcriptomic profiling, and immunohistochemistry.Measurements and Main Results: Thirty-eight percent (16 of 42) of mechanically ventilated decedents had culturable virus in the lung for a median of 15 days (persisting for up to 4 wk) after symptom onset. Lung viral culture positivity was not associated with comorbidities or steroid use. Delta but not Beta variant lung culture positivity was associated with accelerated death and secondary bacterial infection (P < 0.05). Nasopharyngeal culture was negative in 23.1% (6 of 26) of decedents despite lung culture positivity. This hitherto undescribed biophenotype of lung-specific persisting viral replication was associated with an enhanced transcriptomic pulmonary proinflammatory response but with concurrent viral culture positivity.Conclusions: Concurrent rather than sequential active viral replication continues to drive a heightened proinflammatory response in the human lung beyond the second week of illness and was associated with variant-specific increased mortality and morbidity. These findings have potential implications for the design of interventional strategies and clinical management of patients with severe coronavirus disease (COVID-19).

Cerebral revascularization surgery reduces cerebrovascular events in children with sickle cell disease and moyamoya syndrome: Results of the stroke in sickle cell revascularization surgery retrospective study.

BACKGROUND: Recent studies suggest that cerebral revascularization surgery may be a safe and effective therapy to reduce stroke risk in patients with sickle cell disease and moyamoya syndrome (SCD-MMS). METHODS: We performed a multicenter, retrospective study of children with SCD-MMS treated with conservative management alone (conservative group)-chronic blood transfusion and/or hydroxyurea-versus conservative management plus surgical revascularization (surgery group). We monitored cerebrovascular event (CVE) rates-a composite of strokes and transient ischemic attacks. Multivariable logistic regression was used to compare CVE occurrence and multivariable Poisson regression was used to compare incidence rates between groups. Covariates in multivariable models included age at treatment start, age at moyamoya diagnosis, antiplatelet use, CVE history, and the risk period length. RESULTS: We identified 141 patients with SCD-MMS, 78 (55.3%) in the surgery group and 63 (44.7%) in the conservative group. Compared with the conservative group, preoperatively the surgery group had a younger age at moyamoya diagnosis, worse baseline modified Rankin scale scores, and increased prevalence of CVEs. Despite more severe pretreatment disease, the surgery group had reduced odds of new CVEs after surgery (odds ratio = 0.27, 95% confidence interval [CI] = 0.08-0.94, p = .040). Furthermore, comparing surgery group patients during presurgical versus postsurgical periods, CVEs odds were significantly reduced after surgery (odds ratio = 0.22, 95% CI = 0.08-0.58, p = .002). CONCLUSIONS: When added to conservative management, cerebral revascularization surgery appears to reduce the risk of CVEs in patients with SCD-MMS. A prospective study will be needed to validate these findings.

Combination laser interstitial thermal therapy plus stereotactic radiotherapy increases time to progression for biopsy-proven recurrent brain metastases.

Background: Improved survival for patients with brain metastases has been accompanied by a rise in tumor recurrence after stereotactic radiotherapy (SRT). Laser interstitial thermal therapy (LITT) has emerged as an effective treatment for SRT failures as an alternative to open resection or repeat SRT. We aimed to evaluate the efficacy of LITT followed by SRT (LITT+SRT) in recurrent brain metastases. Methods: A multicenter, retrospective study was performed of patients who underwent treatment for biopsy-proven brain metastasis recurrence after SRT at an academic medical center. Patients were stratified by "planned LITT+SRT" versus "LITT alone" versus "repeat SRT alone." Index lesion progression was determined by modified Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Results: Fifty-five patients met inclusion criteria, with a median follow-up of 7.3 months (range: 1.0-30.5), age of 60 years (range: 37-86), Karnofsky Performance Status (KPS) of 80 (range: 60-100), and pre-LITT/biopsy contrast-enhancing volume of 5.7 cc (range: 0.7-19.4). Thirty-eight percent of patients underwent LITT+SRT, 45% LITT alone, and 16% SRT alone. Median time to index lesion progression (29.8, 7.5, and 3.7 months [P = .022]) was significantly improved with LITT+SRT. When controlling for age in a multivariate analysis, patients treated with LITT+SRT remained significantly less likely to have index lesion progression (P = .004). Conclusions: These data suggest that LITT+SRT is superior to LITT or repeat SRT alone for treatment of biopsy-proven brain metastasis recurrence after SRT failure. Prospective trials are warranted to validate the efficacy of using combination LITT+SRT for treatment of recurrent brain metastases.

Decentralising paediatric hearing services through district healthcare screening in Western Cape province, South Africa.

BACKGROUND: Childhood hearing loss is a global epidemic most prevalent in low- and middle-income countries where hearing healthcare services are often inaccessible. Referrals for primary care services to central hospitals add to growing lists and delays the time-sensitive treatment of childhood hearing loss. AIM: To compare a centralised tertiary model of hearing healthcare with a decentralised model through district hearing screening for children in the Western Cape province, South Africa. SETTING: A central paediatric tertiary hospital in Cape Town and a district hospital in the South Peninsula region. METHODS: A pragmatic quasi-experimental study design was used with a 7-month control period at a tertiary hospital (June 2019 to December 2019). Decentralising was measured by attendance rates, travelling distance, number of referrals to the tertiary hospital and hearing outcomes. There were 315 children in the tertiary group and 158 in the district group. Data were collected from patient records and an electronic database at the tertiary hospital. RESULTS: Attendance rate at the district hospital was significantly higher (p 0.001). Travel distance to the district hospital was significantly shorter (p 0.001). Number of referrals to the tertiary hospital decreased significantly during the intervention period (p 0.001). Most children in both the tertiary and district groups (78.7% and 80.4%, respectively) passed initial hearing screening bilaterally. CONCLUSION: Hearing screening should be conducted at the appropriate level of care to increase access, reduce patient travelling distances and associated costs and reduce the burden on tertiary-level hospitals.

Can Achilles tendon xanthoma be distinguished from Achilles tendinopathy using Dixon method MRI? A cross-sectional exploratory study.

BACKGROUND: Familial hypercholesterolemia is a genetic condition characterized by life-long elevations of plasma low-density lipoprotein cholesterol. In addition to life-threatening cardiovascular complications, intratendinous cholesterol deposits (xanthomas) can lead to pain and tendon thickening, particularly in the Achilles. Clinical detection of xanthomas currently relies upon visual assessment and palpation, or ultrasound-based measures of tendon thickening or echotexture. Misdiagnosis of xanthoma can delay the commencement of potentially life-saving lipid-lowering therapy. Our primary purpose was to determine whether analysis of separated fat and water magnetic resonance images may be able to differentiate between xanthomatic and nonxanthomatic Achilles tendons through quantification of intratendinous fat content. The main hypothesis was that Achilles tendon xanthomas will demonstrate greater lipid content than Achilles tendinopathy or healthy control tendons. METHODS: Bilateral MRI scans of Achilles tendons from 30 participants (n = 10 Achilles tendon xanthoma, n = 10 Achilles overuse tendinopathy, n = 10 healthy controls) were analyzed for total lipid content using the Dixon method of fat and water signal separation. Secondary outcome measures included tendon water content, as well as ultrasound characterization of tendon tissue organization and thickness. RESULTS: Fat content was greater in Achilles tendon xanthomas compared to the tendinopathy (p < 0.0001) and control groups (p < 0.0001). Water content was also greater in Achilles tendon xanthomas compared to the tendinopathy (p < 0.0001) and control groups (p = 0.0002). Ultrasound tissue characterization revealed worse tissue organization in Achilles tendon xanthoma tendons compared to Achilles tendinopathy (p < 0.05) but demonstrated largely overlapping distributions. Achilles tendon xanthoma tendons were, on average, significantly thicker than the tendons of the other two groups (p < 0.01 and p < 0.001, respectively). CONCLUSION: MRI-derived measures of Achilles tendon fat content may be able to distinguish xanthomas from control and tendinopathic tissue. Dixon method MRI warrants further evaluation in an adequately powered study to develop and test clinically relevant diagnostic thresholds.

Feasibility study for supporting medication adherence for adults with cystic fibrosis: mixed-methods process evaluation.

OBJECTIVES: To undertake a process evaluation of an adherence support intervention for people with cystic fibrosis (PWCF), to assess its feasibility and acceptability. SETTING: Two UK cystic fibrosis (CF) units. PARTICIPANTS: Fourteen adult PWCF; three professionals delivering adherence support ('interventionists'); five multi-disciplinary CF team members. INTERVENTIONS: Nebuliser with data recording and transfer capability, linked to a software platform, and strategies to support adherence to nebulised treatments facilitated by interventionists over 5 months (± 1 month). PRIMARY AND SECONDARY MEASURES: Feasibility and acceptability of the intervention, assessed through semistructured interviews, questionnaires, fidelity assessments and click analytics. RESULTS: Interventionists were complimentary about the intervention and training. Key barriers to intervention feasibility and acceptability were identified. Interventionists had difficulty finding clinic space and time in normal working hours to conduct review visits. As a result, fewer than expected intervention visits were conducted and interviews indicated this may explain low adherence in some intervention arm participants. Adherence levels appeared to be >100% for some patients, due to inaccurate prescription data, particularly in patients with complex treatment regimens. Flatlines in adherence data at the start of the study were linked to device connectivity problems. Content and delivery quality fidelity were 100% and 60%-92%, respectively, indicating that interventionists needed to focus more on intervention 'active ingredients' during sessions. CONCLUSIONS: The process evaluation led to 14 key changes to intervention procedures to overcome barriers to intervention success. With the identified changes, it is feasible and acceptable to support medication adherence with this intervention. TRIAL REGISTRATION NUMBER: ISRCTN13076797; Results.

Adolescent combined hormonal contraceptives and surgical repair of anterior cruciate tears: a risky recommendation based on an unproven causal relationship.

A recent cross-sectional national USA registry of surgery to repair anterior cruciate ligament tears found that fewer adolescent women who reported using combined hormonal contraceptives (CHC) had the surgery. They reviewed a complex literature on ovarian steroidal relationships with connective tissues biology, physiology and clinical issues. They concluded, based on their data and that evidence shows the greatest gender imbalance for women's ACL injury during adolescence, that all adolescent athletic women should be treated with CHC to prevent ACL injury. We caution that this admonition is using association to imply causation, implies we understand the ovarian hormonal relationships with connective tissues while that remains unclear, the directive to use CHC in adolescent ignores the recent meta-analytic evidence that its use is associated with failure to achieve peak bone mass and that these authors have used erroneous inferential reasoning and ignored the other variables besides sex and age related to ACL injury and the convincing evidence that training strategies can prevent tears.

Diagnostic accuracy of ultrasound and MRI for Achilles tendon xanthoma in people with familial hypercholesterolemia: A systematic review.

BACKGROUND: Achilles tendon xanthoma (ATX) results from tendon thickening and subclinical inflammation triggered by hypercholesterolemia, and is associated with more severe coronary artery disease and a higher risk of cardiovascular events. The ability to detect ATX by clinical examination is limited, and diagnostic imaging, for instance, using ultrasonography or magnetic resonance imagine (MRI), may improve the identification of ATX. However, the accuracy of ultrasound (US) imaging or MRI in identifying ATX in people with familial hypercholesterolemia (FH) has not been systematically reviewed. OBJECTIVE: The objective of this study was to systematically review the accuracy of US imaging or MRI in diagnosing ATX in individuals with FH. METHODS: Searches in Medline, Embase, Cochrane Central, and Cochrane Database of Systematic Reviews on the Ovid platform from inception to April 15, 2018, were conducted to identify articles. Any study design that included US imaging or MRI of Achilles tendon xanthoma in people with FH, and that included a control group of non-FH participants with either normal or symptomatic Achilles tendons, was considered eligible. All of the included studies were reviewed according to the STAndards for the Reporting of Diagnostic accuracy (STARD) method. A qualitative synthesis of the included studies was undertaken. RESULTS: Fifteen studies with 699 patients with FH and 868 non-FH participants were included. Among the non-FH participants, 26 individuals had other documented Achilles tendon pathology (trauma or overuse). Evaluation with the STARD checklist suggested that the quality of evidence was low. US imaging and MRI may have acceptable sensitivity in detecting tendon thickening associated with ATX. There is a wide range in the suggested thickness thresholds and in the estimates of diagnostic accuracy. CONCLUSIONS: A small amount of low-quality evidence suggests that ultrasonography or MRI can improve clinicians' accuracy in identifying ATX in people with FH, thereby identifying those with more severe coronary artery disease.

The Viability of Percutaneous Bone-Anchored Hearing Systems in the HIV Population.

OBJECTIVE: To determine the viability of percutaneous bone-anchored hearing systems (BAHS), in terms of local soft tissue complications, in the HIV population. STUDY DESIGN: Retrospective folder review. SETTING: Two tertiary-level academic state hospitals in Cape Town, South Africa. PATIENTS: Twenty patients, of which six (30%) were HIV-positive. All HIV-positive patients had CD4 counts greater than 200, and were on highly-active antiretroviral therapy (HAART). INTERVENTION: Percutaneous BAHS implantation surgery was performed on all patients. MAIN OUTCOME MEASURE: Comparisons were made between HIV-positive and HIV-negative patients in terms of incidence of local soft tissue complications post-implantation. RESULTS: Soft tissue complications occurred in 50% of patients, and most were easily managed with topical treatment. No significant differences were found when comparing incidence of local soft tissue complications between HIV-positive and HIV-negative patients (p = 0.314). Similarly, surgical technique did not influence soft tissue complication incidence (p = 0.143). CONCLUSIONS: No significant differences in incidence of local soft tissue complications after percutaneous BAHS implantation were found between HIV-positive and HIV-negative patients. In a resource-constrained country like South Africa, where cost and time management are vital, these results indicate that the use of percutaneous BAHS implantation is a viable option, even in HIV-positive patients.

Angiopoietin-like 4 promotes angiogenesis in the tendon and is increased in cyclically loaded tendon fibroblasts.

KEY POINTS: Angiopoietin-like 4 (ANGPTL4) modulates tendon neovascularization. Cyclic loading stimulates the activity of transforming growth factor-ß and hypoxia-inducible factor 1α and thereby increases the expression and release of ANGPTL4 from human tendon cells. Targeting ANGPTL4 and its regulatory pathways is a potential avenue for regulating tendon vascularization to improve tendon healing or adaptation. ABSTRACT: The mechanisms that regulate angiogenic activity in injured or mechanically loaded tendons are poorly understood. The present study examined the potential role of angiopoietin-like 4 (ANGPTL4) in the angiogenic response of tendons subjected to repetitive mechanical loading or injury. Cyclic stretching of human tendon fibroblasts stimulated the expression and release of ANGPTL4 protein via transforming growth factor-ß (TGF-ß) and hypoxia-inducible factor 1α (HIF-1α) signalling, and the released ANGPTL4 was pro-angiogenic. Angiogenic activity was increased following ANGPTL4 injection into mouse patellar tendons, whereas the patellar tendons of ANGPTL4 knockout mice displayed reduced angiogenesis following injury. In human rotator cuff tendons, the expression of ANGPTL4 was correlated with the density of tendon endothelial cells. To our knowledge, this is the first study characterizing a role of ANGPTL4 in the tendon. ANGPTL4 may assist in the regulation of vascularity in the injured or mechanically loaded tendon. TGF-ß and HIF-1α comprise two signalling pathways that modulate the expression of ANGPTL4 by mechanically stimulated tendon fibroblasts and, in the future, these could be manipulated to influence tendon healing or adaptation.

Mechanism of mast cell adhesion to human tenocytes in vitro.

Mast cells and fibroblasts are two key players involved in many fibrotic and degenerative disorders. In the present study we examined the nature of binding interactions between human mast cells and tendon fibroblasts (tenocytes). In the mast cell-fibroblast co-culture model, mast cells were shown to spontaneously bind to tenocytes, in a process that was partially mediated by α5ß1 integrin receptors. The same receptors on mast cells significantly mediated binding of these cells to tissue culture plates in the presence of tenocyte-conditioned media; the tenocyte-derived fibronectin in the media was shown to also play a major role in these binding activities. Upon binding to tenocytes or tissue culture plates, mast cells acquired an elongated phenotype, which was dependent on α5ß1 integrin and tenocyte fibronectin. Additionally, tenocyte-derived fibronectin significantly enhanced mRNA expression of the adhesion molecule, THY1, by mast cells. Our data suggests that α5ß1 integrin mediates binding of mast cells to human tenocyte and to tenocyte-derived ECM proteins, in particular fibronectin.

Cyclic strain alters the expression and release of angiogenic factors by human tendon cells.

Angiogenesis is associated with the tissue changes underlying chronic overuse tendinopathy. We hypothesized that repetitive, cyclic loading of human tendon cells would lead to increased expression and activity of angiogenic factors. We subjected isolated human tendon cells to overuse tensile loading using an in vitro model (1 Hz, 10% equibiaxial strain). We found that mechanically stimulated human tendon cells released factors that promoted in vitro proliferation and tube formation by human umbilical vein endothelial cells (HUVEC). In response to cyclic strain, there was a transient increase in the expression of several angiogenic genes including ANGPTL4, FGF-2, COX-2, SPHK1, TGF-alpha, VEGF-A and VEGF-C, with no change in anti-angiogenic genes (BAI1, SERPINF1, THBS1 and 2, TIMP1-3). Cyclic strain also resulted in the extracellular release of ANGPTL4 protein by tendon cells. Our study is the first report demonstrating the induction of ANGPTL4 mRNA and release of ANGPTL4 protein in response to cyclic strain. Tenocytes may contribute to the upregulation of angiogenesis during the development of overuse tendinopathy.

Rotator cuff tear degeneration and cell apoptosis in smokers versus nonsmokers.

PURPOSE: The purpose of this study was to assess the effect of smoking on supraspinatus tendon degeneration, including cellular alterations, proliferation, and apoptosis of tendon cells. METHODS: Supraspinatus tendon samples of 10 smokers and 15 nonsmokers with full-thickness tears were compared, focusing on the severity of tendon histopathology including apoptosis (programmed cell death), cellularity, and proliferation. Immunohistochemistry was used to assess the density of apoptotic cells and proliferation. The extent of tendon degeneration was classified according to a revised version of the Bonar tendon histopathology score. RESULTS: The smokers were younger (P = .01). The symptom duration among smokers was longer (P < .05). The supraspinatus tendons from the smokers presented significantly more advanced degenerative changes (Bonar score, 13.5 [interquartile range, 1.4] v 9 [interquartile range, 3]; P < .001). The smokers' tendons showed increased density of apoptotic cells (0.108 [SE, 0.038] v 0.0107 [SE, 0.007]; P = .024) accompanied by reduced tenocyte density (P = .019) and upregulation of proliferative activity (P < .0001). CONCLUSIONS: Smoking is associated with worsened supraspinatus tendon histopathology and increased apoptosis. CLINICAL RELEVANCE: Pronounced degenerative changes, reduced tendon cellularity, and increased apoptosis may indicate reduced tendon healing capacity in smokers.

The seasonal variation of Achilles tendon ruptures in Vancouver, Canada: a retrospective study.

OBJECTIVE: To examine the seasonal distribution of tendon ruptures in a large cohort of patients from Vancouver, Canada. DESIGN: Retrospective chart review. SETTING: Acute Achilles tendon rupture cases that occurred from 1987 to 2010 at an academic hospital in Vancouver, Canada. Information was extracted from an orthopaedic database. PARTICIPANTS: No direct contact was made with the participants. The following information was extracted from the OrthoTrauma database: age, sex, date of injury and season (winter, spring, summer and autumn), date of surgery if date of injury was unknown and type of injury (sport related or non-sport related/unspecified). Only acute Achilles tendon rupture cases were included; chronic cases were excluded along with those that were conservatively managed. PRIMARY AND SECONDARY OUTCOMES: The primary outcome was to determine the seasonal pattern of Achilles tendon rupture. Secondary outcomes, such as differences in gender and mechanism of sport (non-sport vs sport related), were also assessed. RESULTS: There were 543 cases in total; 83% of the cases were men (average age 39.3) and 17% were women (average age 37.3). In total, 76% of cases were specified as sport related. The distribution of injuries varied significantly across seasons (χ(2), p<0.05), with significantly more cases occurring in spring. The increase in the number of cases in spring was due to sport-related injuries, whereas non-sport-related cases were distributed evenly throughout the year. CONCLUSIONS: The seasonality of sport-related Achilles tendon ruptures should be considered when developing preventive strategies and when timing their delivery.

Tendons--time to revisit inflammation.

It is currently widely accepted among clinicians that chronic tendinopathy is caused by a degenerative process devoid of inflammation. Current treatment strategies are focused on physical treatments, peritendinous or intratendinous injections of blood or blood products and interruption of painful stimuli. Results have been at best, moderately good and at worst a failure. The evidence for non-infammatory degenerative processes alone as the cause of tendinopathy is surprisingly weak. There is convincing evidence that the inflammatory response is a key component of chronic tendinopathy. Newer anti-inflammatory modalities may provide alternative potential opportunities in treating chronic tendinopathies and should be explored further.

Lower muscle regenerative potential in full-thickness supraspinatus tears compared to partial-thickness tears.

BACKGROUND AND PURPOSE: Rotator cuff tears are associated with secondary rotator cuff muscle pathology, which is definitive for the prognosis of rotator cuff repair. There is little information regarding the early histological and immunohistochemical nature of these muscle changes in humans. We analyzed muscle biopsies from patients with supraspinatus tendon tears. METHODS: Supraspinatus muscle biopsies were obtained from 24 patients undergoing arthroscopic repair of partial- or full-thickness supraspinatus tendon tears. Tissue was formalin-fixed and processed for histology (for assessment of fatty infiltration and other degenerative changes) or immunohistochemistry (to identify satellite cells (CD56+), proliferating cells (Ki67+), and myofibers containing predominantly type 1 or 2 myosin heavy chain (MHC)). Myofiber diameters and the relative content of MHC1 and MHC2 were determined morphometrically. RESULTS: Degenerative changes were present in both patient groups (partial and full-thickness tears). Patients with full-thickness tears had a reduced density of satellite cells, fewer proliferating cells, atrophy of MHC1+ and MHC2+ myofibers, and reduced MHC1 content. INTERPRETATION: Full-thickness tears show significantly reduced muscle proliferative capacity, myofiber atrophy, and loss of MHC1 content compared to partial-thickness supraspinatus tendon tears.

Substance P enhances collagen remodeling and MMP-3 expression by human tenocytes.

The loss of collagen organization is considered a hallmark histopathologic feature of tendinosis. At the cellular level, tenocytes have been shown to produce signal substances that were once thought to be restricted to neurons. One of the main neuropeptides implicated in tendinosis, substance P (SP), is known to influence collagen organization, particularly after injury. The aim of this study was to examine the influence of SP on collagen remodeling by primary human tendon cells cultured in vitro in three-dimensional collagen lattices. We found that SP stimulation led to an increased rate of collagen remodeling mediated via the neurokinin-1 receptor (NK-1 R), the preferred cell receptor for SP. Gene expression analysis showed that SP stimulation resulted in significant increases in MMP3, COL3A1 and ACTA2 mRNA levels in the collagen lattices. Furthermore, cyclic tensile loading of tendon cell cultures along with the administration of exogenous SP had an additive effect on MMP3 expression. Immunoblotting confirmed that SP increased MMP3 protein levels via the NK-1 R. This study indicates that SP, mediated via NK-1 R, increases collagen remodeling and leads to increased MMP3 mRNA and protein expression that is further enhanced by cyclic mechanical loading.