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Injuries of the acromioclavicular joint (ACG) are among the most common shoulder injuries, especially in young men. A large number of biomechanical and clinical studies have led to significant improvements in diagnostics and surgery in recent years. In particular, the assessment of horizontal instability came into focus, so that the existing classification according to Rockwood was supplemented. Standard imaging includes bilateral Zanca imaging with weights and a modified Alexander imaging of both sides. In addition, sonography is increasingly used for the dynamic assessment of horizontal instabilities. While low-grade ACG injuries are treated conservatively, higher-grade injuries should be stabilized within the first 3 weeks. Numerous techniques are available for treatment, but anatomy should always be restored with regard to horizontal and vertical stability to avoid persistent injury. In terms of the different types of treatment, minimally invasive arthroscopically-assisted techniques seem to be superior to open procedures. If chronic, biological augmentation with allo- and autografts is the gold standard. [ABSTRACT FROM AUTHOR]

The pre-operative determination of infection plays a decisive role in non-union treatment. This study investigated in a large cohort the diagnostic potential of contrast-enhanced ultrasound (CEUS) as stand-alone method for the differentiation between aseptic and infected non-unions. Of 109 patients with lower extremity non-unions (tibia n = 78, femur n = 31) osseous perfusion with CEUS was prospectively assessed before revision surgery. The perfusion was quantified via time-intensity curves and peak enhancement (PE) (arbitrary unit [au]). Significant perfusion differences between aseptic and infected non-unions were evident (PE, p < 0.001). The sensitivity and specificity for the detection of infected tibial and femoral non-unions could be determined with 85.1% and 88.7% (cutoff PE: 81.2 au). CEUS illustrates tibial and femoral non-union perfusion in real time and discriminates reliably between aseptic and infected non-unions. Consequently, when CEUS is integrated into the diagnostic routine algorithm, non-union revision surgery can be planned more accurately as a single or multistep procedure. [ABSTRACT FROM AUTHOR]

Background: Muscle degeneration as a consequence of rotator cuff tears is mainly assessed by magnetic resonance imaging. Contrast-enhanced ultrasound (CEUS) is a new functional imaging method to assess microvascular perfusion as a fundamental parameter of muscle tissue vitality. In this cross-sectional study, the authors evaluated supraspinatus muscle perfusion after cuff repair and analyzed its association with functional shoulder outcome and the grade of echogenicity in B-mode ultrasound indicating fatty infiltration. Hypothesis: The authors expected reduced microperfusion of the operated versus the contralateral supraspinatus muscle and a correlation of the muscular microperfusion with functional shoulder outcome. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Patients who received unilateral repair of the supraspinatus tendon between 2009 and 2014 were invited for a single follow-up examination. Functional scores were assessed, including the Constant-Murley score and American Shoulder and Elbow Surgeons score. CEUS examination was performed bilaterally in an oblique sagittal plane of the supraspinatus fossa. Perfusion was quantified by the parameters wash-in perfusion index (WiPI) and peak enhancement via VueBox quantification software. The results of the Constant-Murley score, American Shoulder and Elbow Surgeons score, and perfusion parameters were referenced to the contralateral shoulder. Echogenicity of the supraspinatus muscle was classified with a 3-point scale as compared with the trapezius muscle. Results: Sixty-seven patients were available, with a mean follow-up of 38.0 ± 18.5 months. Functional assessment showed impaired shoulder function on the operated shoulder as compared with the contralateral side (relative Constant Score [CS], 80% ± 19%). CEUS revealed diminished perfusion on the operated shoulder (WiPI, 55.1% ± 40.2%, P < .001). A strong correlation could be demonstrated between the perfusion deficit and functional impairment (relative WiPI and CS: rs = .644, P < .001). Higher grade of echogenicity in B-mode ultrasound was associated with reduced perfusion. Conclusion: CEUS could visualize impaired supraspinatus muscle perfusion after rotator cuff repair as compared with the contralateral, healthy shoulder. With its ability to quantify microvascular perfusion as a surrogate parameter for muscle vitality and function, CEUS may serve as a quantitative method to evaluate rotator cuff muscles. [ABSTRACT FROM AUTHOR]

Background & Aims: In most cases celiac disease (CD) is successfully treated with a gluten-free diet (GFD). However, some patients become refractory to the GFD. Refractory CD (RCD) patients have an increased risk for developing enteropathy associated T-cell lymphoma and early diagnosis is therefore of importance. Currently, RCD diagnosis relies on endoscopy and adequate serological markers are lacking. Antibodies against glycoprotein-2 (GP2A) were described in Crohn's disease (CrD) and active CD but not in ulcerative colitis (UC), suggesting this is a specific marker for small intestinal lesions. Methods: Sera obtained from patients visiting our outpatient clinic for routine serological tests for diagnosis and/or follow-up of inflammatory bowel disease (n=78), active CD (n=45), GFD (n=34) and RCD (n=15) were analysed for GP2A titres. Results: Increased GP2A-IgA levels in CrD and active CD as compared to controls (p<0.001) and lack thereof in UC was confirmed. However, we could not confirm the association with small bowel localization within the CrD patient group. Within CD patients, we demonstrated a significant decrease of GP2A-IgA titres upon a GFD and increased levels in RCD patients as compared to patients on a GFD. Although GP2A-IgA was not associated with the degree of villous atrophy, GP2A-IgA levels were able to distinguish RCD patients from GFD patients (ROC AUC=0.79, p=0.002). Conclusion: Follow-up of GP2A-IgA titres in CD patients on a GFD may help to identify patients at risk for developing RCD. [ABSTRACT FROM AUTHOR]

A small fraction of coeliac disease (CD) patients have persistent villous atrophy despite strict adherence to a gluten-free diet. Some of these refractory CD (RCD) patients develop a clonal expansion of lymphocytes with an aberrant phenotype, referred to as RCD-type II (RCDII). Pathogenesis of active CD (ACD) has been shown to be related to gluten-specific immunity whereas the disease is no longer gluten driven in RCD. We therefore hypothesized that the immune response is differentially regulated by cytokines in ACD versus RCDII and investigated mucosal cytokine release after polyclonal stimulation of isolated mucosal lymphocytes. Secretion of the TH2 cytokine IL-13 was significantly higher in lamina propria leukocytes (LPLs) isolated from RCDII patients as compared to LPL from ACD patients (P = 0.05). In patients successfully treated with a gluten-free diet LPL-derived IL-13 production was also higher as compared to ACD patients (P = 0.02). IL-13 secretion correlated with other TH2 as well as TH1 cytokines but not with IL-10 secretion. Overall, the cytokine production pattern of LPL in RCDII showed more similarities with LPL isolated from GFD patients than from ACD patients. Our data suggest that different immunological processes are involved in RCDII and ACD with a potential role for IL-13. [ABSTRACT FROM AUTHOR]

Abstract: Aims: To test whether the genetic variant CCR5Δ32 in the CC-chemokine receptor 5, which is known to lead to CCR5 deficiency, is associated with mortality in type 2 diabetes patients. Methods: We examined the effect of presence or absence of the CCR5Δ32 on overall and cardiovascular mortality risk in the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) cohort, a type 2 diabetes patient cohort. Results: We studied 756 patients with a mean duration of follow-up of 5.4 (± 1.4) years. 194 patients died during follow up of which 83 were cardiovascular deaths. 144 subjects (19%) carried the CCR5Δ32 deletion. CCR5Δ32 carriers had an adjusted hazard ratio of 0.62 (95%CI: 0.40–0.96; p =0.03) for all-cause mortality and 0.63 (95%CI: 0.33–1.19; p =0.16) for cardiovascular mortality. Conclusions: The presence of CCR5Δ32 is associated with better survival in type 2 diabetes patients. These data suggest that it is worthwhile to explore the protective potential of pharmacological blockade of CCR5 in type 2 diabetic patients. [Copyright &y& Elsevier]

Protein serine/threonine phosphatase type 1 (PP1) has been found in all eukaryotes examined to date and is involved in the regulation of many cellular functions, including glycogen metabolism, muscle contraction, and mitosis. In Drosophila, four genes code for the catalytic subunit of PP1 (PP1c), three of which belong to he PP1α subtype. PP1α9C (flapwing) encodes the fourth PP1c gene and has a specific and nonredundant function as a nonmuscle myosin phosphatase. PP1α87B is the major form and contributes ~80% of the total PP1 activity. We describe the first mutant alleles of PP1α96A and show that PP1α96A is not ar essential gene, but seems to have a function in the regulation of nonmuscle myosin. We show that overexpression of the PP1α isozymes does not rescue semilethal PP1β9C mutants, whereas overexpression of either PP1α96A or PP1β9C does rescue a lethal PP1α87B mutant combination, showing that the lethality is due to a quantitative reduction in the level of PP1c. Overexpression of PP1β9C does not rescue a PP1α87B, PP1α96A double mutant, suggesting an essential PP1α-specific function in Drosophila. [ABSTRACT FROM AUTHOR]

Drosophila flapwing (flw) codes for serine/threonine protein phosphatase type 1β (PP1β). Regulation of nonmuscle myosin activity is the single essential flw function that is nonredundant with the three closely related PP1α genes. Flw is thought to dephosphorylate the nonmuscle myosin regulatory light chain, Spaghetti Squash (Sqh); this inactivates the nonmuscle myosin heavy chain, Zipper (Zip). Thus, strong flw mutants lead to hyperphosphorylation of Sqh and hyperactivation of nonmuscle myosin activity. Here, we show genetically that a Jun N-terminal kinase (JNK) mutant suppresses the semilethality of a strong flw allelle. Alleles of the JNK phosphatase puckered (puc) genetically enhance the weak allele flw¹, leading to severe wing defects. Introducing a mutant of the nonmuscle myosin-binding subunit (Mbs) further enhances this genetic interaction to lethality. We show that puc expression is upregulated in wing imaginal discs mutant for flw¹ and pucA251 and that this upregulation is modified by JNK and Zip. The level of phosphorylated (active) JNK is elevated in flw¹ enhanced by puc. Together, we show that disruption of nonmuscle myosin activates JNK and puc expression in wing imaginal discs. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article related to use of serum intestinal-fatty acid binding protein as a biomarker in the previous issue.

Supraspinatus (SSP) tendon tears represent a common indication for shoulder surgery. Yet, prediction of postoperative function and tendon retear remains challenging and primarily relies on morphologic magnetic resonance imaging (MRI)‐based parameters, supported by patients' demographic data like age, gender, and comorbidities. Considering continuously high retear rates, especially in patients with larger tears and negative prognostic factors, improved outcome prediction could be of high clinical value. Contrast‐enhanced ultrasound (CEUS) enables an assessment of dynamic perfusion of the SSP muscle. As a potential surrogate for muscle vitality, CEUS might reflect functional properties of the SSP and support improved outcome prediction after tendon repair. Fifty patients with isolated SSP tendon tears were prospectively enrolled. Preoperatively, SSP muscle perfusion was quantified by CEUS and conventional morphologic parameters like tear size, fatty infiltration, and tendon retraction were assessed by MRI. At six months follow‐up, shoulder function, tendon integrity, and muscle perfusion were reassessed. The predictive value of preoperative CEUS for postoperative shoulder function and tendon integrity was evaluated. 35 patients entered the statistical analysis. Preoperative CEUS‐based assessment of SSP perfusion significantly correlated with early postoperative shoulder function (Constant, r = 0.48, p < 0.018) and tendon retear (r = 0.67, p < 0.001). CEUS‐based subgroup analysis identified patients with exceptionally high, respectively low risk for tendon retear. CEUS‐based assessment of the SSP seemed to predict early shoulder function and tendon retear after SSP repair and allowed to identify patient subgroups with exceptionally high or low risk for tendon retear. © 2019 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 38:1150‐1158, 2020 [ABSTRACT FROM AUTHOR]

Muscle perfusion quantification by contrast-enhanced ultrasound (CEUS) may facilitate treatment decisions in musculoskeletal disorders. Translation into clinical routine relies on high intra-observer and inter-observer reliability and transferability between ultrasound devices to enable validation and multicenter studies. This study evaluates these aspects for deltoid muscle perfusion quantification, including possible multicenter study setups. One hundred sixty-six CEUS quantifications were conducted on 42 shoulders. Intra-observer reliability revealed a high intra-class correlation coefficient (ICC, r = 0.91) and low coefficient of variation (CV, 10.28%). Inter-observer reliability revealed an ICC of .84 and a CV of 17.1%, but these values decreased when different ultrasound devices were used (ICC = .60, CV = 18.6%). Re-evaluating subgroups with high sectional plane concordance significantly increased reliability (intra-observer: ICC = .97, CV = 5.49%, inter-observer/same device: ICC = .98, CV = 5.83%, varying devices: ICC = .78, CV = 9.8%). CEUS perfusion quantification of the deltoid seems applicable for multicenter studies, yet pooling different ultrasound devices remains critical. Sectional plane concordance appears to be crucial for reliability and transferability of CEUS muscle perfusion quantifications. [ABSTRACT FROM AUTHOR]

Rotator cuff tear including SSP (Supraspinatus) tendon tears are a very common and often painful condition with several therapeutic options such as tendon repair. Reflected by the high retear rates, the preoperative selection of patients suitable for surgery or conservative treatment, which often yields comparable results, remains difficult. Using contrast‐enhanced ultrasound (CEUS), it is possible to quantify the SSP muscle perfusion as a surrogate parameter for its vitality and healing capabilities. In this study, we enrolled 20 patients who underwent an SSP repair for a preoperative and two postoperative (6 months and 1 year) clinical and sonographic exams including CEUS. Along with functional improvement (p < 0.001, Constant score), we found a significant increase in CEUS‐assessed muscle perfusion after tendon repair (p < 0.001). Furthermore, weak preoperative muscle perfusion was associated with a higher risk of a retear (χ2 = 0.045) and a moderate trend toward lower postoperative shoulder function that did not reach significance (r = 0.435; p = 0.055, DASH score). If confirmed in larger studies, CEUS might be a valuable additional diagnostic method for a precise selection of patients who most likely profit from a tendon repair and those who can be treated conservatively with an equally good outcome. [ABSTRACT FROM AUTHOR]

Abstract: Aims: To investigate whether skin autofluorescence (AF), a non-invasive marker for advanced glycation end products (AGEs), is elevated in stable coronary artery disease (sCAD) and to investigate its relationship with serum levels of the soluble receptor for AGEs (sRAGE), neopterin and C-reactive protein (CRP). Methods and results: Skin AF and serum levels of sRAGE, neopterin and CRP were assessed in 63 sCAD patients (mean age: 64.7±10.5 years), comprising 78% males, 19% subjects with diabetes, and 22% current smokers and in 33 (mean age: 63.4±10.0 years) healthy non-diabetic and non-smoking age and gender matched controls. Skin AF was significantly increased in sCAD compared with controls, irrespective of diabetes, current smoking and renal function. Levels of sRAGE (standardized β: 0.43 (explaining 17% of variance in skin AF); P <0.001), neopterin (β: 0.36 (11%); P =0.003) and glucose (β: 0.29 (8%); P =0.0011) as well as current smoking (β: 0.26 (6%); P =0.024) were independently associated with skin AF (R 2 0.42), whereas the association of gender, former smoking, body mass index, CRP, lipids, creatinine clearance and pulse pressure with skin AF was not significant in this model. Conclusion: These data demonstrate that skin AF is elevated in sCAD and is related to sRAGE and neopterin, making it an easily applicable tool to improve our understanding of inflammatory and oxidative stress in cardiovascular disease. [Copyright &y& Elsevier]

Background: Protein phosphatase 1 (PP1) is involved in diverse cellular processes, and is targeted to substrates via interaction with many different protein binding partners. PP1 catalytic subunits (PP1c) fall into PP1α and PP1β subfamilies based on sequence analysis, however very few PP1c binding proteins have been demonstrated to discriminate between PP1α and PP1β. Results: URI (unconventional prefoldin RPB5 interactor) is a conserved molecular chaperone implicated in a variety of cellular processes, including the transcriptional response to nutrient signalling and maintenance of DNA integrity. We show that Drosophila Uri binds PP1α with much higher affinity than PP1β, and that this ability to discriminate between PP1c forms is conserved to humans. Most Uri is cytoplasmic, however we found some protein associated with active RNAPII on chromatin. We generated a uri loss of function allele, and show that uri is essential for viability in Drosophila. uri mutants have transcriptional defects, reduced cell viability and differentiation in the germline, and accumulate DNA damage in their nuclei. Conclusion: Uri is the first PP1α specific binding protein to be described in Drosophila. Uri protein plays a role in transcriptional regulation. Activity of uri is required to maintain DNA integrity and cell survival in normal development. [ABSTRACT FROM AUTHOR]

We previously identified Neuregulin1 (NRG1) as a gene contributing to the risk of developing schizophrenia. Furthermore, we showed that NRG1+/- mutant mice display behavioral abnormalities that are reversed by clozapine, an atypical antipsychotic drug used for the treatment of schizophrenia. We now present evidence that ErbB4 (v-erb-a erythroblastic leukemia viral oncogene homolog 4), the tyrosine kinase receptor for NRG1 in hippocampal neurons, interacts with two nonreceptor tyrosine kinases, Fyn and Pyk2 (proline-rich tyrosine kinase 2). NRG1 stimulation of cells expressing ErbB4 and Fyn leads to the association of Fyn with ErbB4 and consequent activation. Furthermore, we show that NRG1 signaling, through activation of Fyn and Pyk2 kinases, stimulates phosphorylation of Y1472 on the NR2B subunit of the NMDA receptor (NMDAR), a key regulatory site that modulates channel properties. NR2B Y1472 is hypophosphorylated in NRG1+/- mutant mice, and this defect can be reversed by clozapine at a dose that reverses their behavioral abnormalities. We also demonstrate that short-term synaptic plasticity is altered and theta-burst long-term potentiation is impaired in NRG1+/- mutant mice, and incubation of hippocampal slices from these mice with NRG1 reversed those effects. Attenuated NRG1 signaling through ErbB4 may contribute to the pathophysiology of schizophrenia through dysfunction of NMDAR modulation. Thus, our data support the glutamate hypothesis of schizophrenia. [ABSTRACT FROM AUTHOR]

Identifies two proteins that bind with high specificity to type 1 serine/threonine protein phosphatase (PP1). Development of an efficient and flexible strategy for conditional inactivation of PP1; Suppression of the phenotypes by coexpression of PP1; Demonstration of the use of PP1 inhibitors in a tissue-and developmental-specific manner to examine the developmental roles of PP1.

Purpose: To investigate whether occurance of early radiation effects in lung tissue depends on local dose only. Methods and Materials: Twenty-five percent, 50%, 66%, 88%, or 100% of the rat lung was irradiated using single fractions of 150-MeV protons. For all volumes, in-field and out-of-field dose–response curves were obtained 8 weeks after irradiation. The pathohistology of parenchymal inflammation, infiltrates, fibrosis, and vascular damage and the relative expression of proinflammatory cytokines interleukin (IL)-1α, transforming growth factor-β, IL-6, and tumor necrosis factor-α were assessed. Results: For all histologic endpoints, irradiated dose- and volume-dependent in-field and out-of-field effects were observed, albeit with different dynamics. Of note, the out-of-field effects for vascular damage were very similar to the in-field effects. Interestingly, only IL-6 showed a clear dose-dependent increase in expression both in-field and out-of-field, whereas the expression levels of IL-1α, transforming growth factor-β, and tumor necrosis factor-α were either very low or without a clear dose–volume relation. As such, none of the radiation effects studied depended only on local dose to the tissue. Conclusion: The effects of radiation to lung tissue do not only depend on local dose to that tissue. Especially at high-volume irradiation, lung damage seems to present globally rather than locally. The accuracy of predictive modeling may be improved by including nonlocal effects. [ABSTRACT FROM AUTHOR]