Research Spotlight

Posted March 15th 2016

Midterm clinical outcomes following arthroscopic transosseous rotator cuff repair.

Brody Flanagin M.D.

Brody Flanagin, M.D.

Flanagin, B. A., R. Garofalo, E. Y. Lo, L. Feher, A. Castagna, H. Qin and S. G. Krishnan (2016). “Midterm clinical outcomes following arthroscopic transosseous rotator cuff repair.” Int J Shoulder Surg 10(1): 3-9.

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PURPOSE: Arthroscopic transosseous (TO) rotator cuff repair has recently emerged as a new option for surgical treatment of symptomatic rotator cuff tears. Limited data is available regarding outcomes using this technique. This study evaluated midterm clinical outcomes following a novel arthroscopic TO (anchorless) rotator cuff repair technique. MATERIALS AND METHODS: A consecutive series of 107 patients and 109 shoulders underwent arthroscopic TO (anchorless) rotator cuff repair for a symptomatic full-thickness tear. Pre and postoperative range of motion (ROM) was compared at an average of 11.8 months. Postoperative outcome scores were obtained at an average of 38.0 months. Statistical analysis was performed to compare pre and postoperative ROM data. Univariate analysis was performed using Student’s t-test to compare the effect of other clinical characteristics on final outcome. RESULTS: Statistically significant improvements were noted in forward flexion, external rotation and internal rotation (P < 0.0001). Average postoperative subjective shoulder value was 93.7, simple shoulder test 11.6, and American Shoulder and Elbow Surgeons (ASES) score 94.6. According to ASES scores, results for the 109 shoulders available for final follow-up were excellent in 95 (87.1%), good in 8 (7.3%), fair in 3 (2.8%), and poor in 3 (2.8%). There was no difference in ROM or outcome scores in patients who underwent a concomitant biceps procedure (tenodesis or tenotomy) compared with those who did not. Furthermore, there was no significant difference in outcome between patients who underwent either biceps tenodesis or tenotomy. Age, history of injury preceding the onset of pain, tear size, number of TO tunnels required to perform the repair, and presence of fatty infiltration did not correlate with postoperative ROM or subjective outcome measures at final follow-up. Two complications and four failures were noted. CONCLUSIONS: Arthroscopic TO rotator cuff repair technique leads to statistically significant midterm improvement in ROM and satisfactory midterm subjective outcome scores with low complication/failure rates in patients with average medium-sized rotator cuff tears with minimal fatty infiltration. Further work is required to evaluate radiographic healing rates with this technique and to compare outcomes following suture anchor repair. Level of evidence: Level IV.

Posted March 15th 2016

Dietary Betaine Supplementation Increases Fgf21 Levels to Improve Glucose Homeostasis and Reduce Hepatic Lipid Accumulation in Mice.

Teodoro Bottiglieri Ph.D.

Teodoro Bottiglieri, Ph.D.

Ejaz, A., L. Martinez-Guino, A. B. Goldfine, F. Ribas-Aulinas, V. De Nigris, S. Ribo, A. Gonzalez-Franquesa, P. M. Garcia-Roves, E. Li, J. M. Dreyfuss, W. Gall, J. K. Kim, T. Bottiglieri, F. Villarroya, R. E. Gerszten, M. E. Patti and C. Lerin (2016). “Dietary Betaine Supplementation Increases Fgf21 Levels to Improve Glucose Homeostasis and Reduce Hepatic Lipid Accumulation in Mice.” Diabetes. Feb 8. [Epub ahead of print]

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Identifying markers of human insulin resistance may permit development of new approaches for treatment and prevention of type 2 diabetes. To this end, we analyzed the fasting plasma metabolome in metabolically characterized human volunteers across a spectrum of insulin resistance. We demonstrate that plasma betaine levels are reduced in insulin resistant humans, and correlate closely with insulin sensitivity. Moreover, betaine administration to diet-induced obese mice prevents the development of impaired glucose homeostasis, reduces hepatic lipid accumulation, increases white adipose oxidative capacity, and enhances whole-body energy expenditure. In parallel with these beneficial metabolic effects, betaine supplementation robustly increased hepatic and circulating Fgf21 levels. Betaine administration failed to improve glucose homeostasis and liver fat content in Fgf21-/- mice, demonstrating that Fgf21 is necessary for betaine’s beneficial effects. Together, these data indicate that dietary betaine increases Fgf21 levels to improve metabolic health in mice, and suggest that betaine supplementation merits further investigation as a supplement for treatment or prevention of type 2 diabetes in humans.

Posted March 15th 2016

Application of the 1, 3-beta-d-Glucan (Fungitell) Assay in the Diagnosis of Invasive Fungal Infections.

Tuan Tran M.D.

Tuan Tran, M.D.

Tran, T. and S. G. Beal (2016). “Application of the 1, 3-beta-d-Glucan (Fungitell) Assay in the Diagnosis of Invasive Fungal Infections.” Arch Pathol Lab Med 140(2): 181-185.

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With the high mortality rate associated with invasive fungal infections, methods for timely detection and diagnosis are necessary for appropriate and effective treatment. Testing for 1, 3-beta-d-glucan, a cell wall component of many medically important fungi, can be a useful adjunct in diagnosing such infections. The Fungitell assay (Associates of Cape Cod, East Falmouth, Massachusetts) is a US Food and Drug Administration-approved laboratory test that quantitatively measures 1,3-beta-d-glucan levels and is widely available for clinical use as a relatively noninvasive method to aid in detecting the presence of invasive fungal infections. Numerous studies have evaluated its performance in clinical settings, and results have, overall, been favorable. It is not without its drawbacks, however, and the test must be interpreted and applied with care. Ordering practices are also widely variable among clinicians, and official guidelines have not been readily available. We present the details of this test and aim to propose evidence-based guidance for its use.

Posted March 15th 2016

Mannose receptor-mediated delivery of moss-made alpha-galactosidase A efficiently corrects enzyme deficiency in Fabry mice.

Raphael Schiffmann M.D.

Raphael Schiffmann, M.D.

Shen, J. S., A. Busch, T. S. Day, X. L. Meng, C. I. Yu, P. Dabrowska-Schlepp, B. Fode, H. Niederkruger, S. Forni, S. Chen, R. Schiffmann, T. Frischmuth and A. Schaaf (2016). “Mannose receptor-mediated delivery of moss-made alpha-galactosidase A efficiently corrects enzyme deficiency in Fabry mice.” J Inherit Metab Dis 39(2): 293-303.

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Enzyme replacement therapy (ERT) is an effective treatment for several lysosomal storage disorders (LSDs). Intravenously infused enzymes are taken up by tissues through either the mannose 6-phosphate receptor (M6PR) or the mannose receptor (MR). It is generally believed that M6PR-mediated endocytosis is a key mechanism for ERT in treating LSDs that affect the non-macrophage cells of visceral organs. However, the therapeutic efficacy of MR-mediated delivery of mannose-terminated enzymes in these diseases has not been fully evaluated. We tested the effectiveness of a non-phosphorylated alpha-galactosidase A produced from moss (referred to as moss-aGal) in vitro and in a mouse model of Fabry disease. Endocytosis of moss-aGal was MR-dependent. Compared to agalsidase alfa, a phosphorylated form of alpha-galactosidase A, moss-aGal was more preferentially targeted to the kidney. Cellular localization of moss-aGal and agalsidase alfa in the heart and kidney was essentially identical. A single injection of moss-aGal led to clearance of accumulated substrate in the heart and kidney to an extent comparable to that achieved by agalsidase alfa. This study suggested that mannose-terminated enzymes may be sufficiently effective for some LSDs in which non-macrophage cells are affected, and that M6P residues may not always be a prerequisite for ERT as previously considered.

Posted March 15th 2016

T follicular helper (Tfh) cells in lupus: Activation and involvement in SLE pathogenesis.

Hideki Ueno M.D.

Hideki Ueno, M.D.

Blanco, P., H. Ueno and N. Schmitt (2016). “T follicular helper (Tfh) cells in lupus: Activation and involvement in SLE pathogenesis.” Eur J Immunol 46(2): 281-290.

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Systemic lupus erythematosus (SLE) is a chronic systemic inflammatory autoimmune disease characterized by a breakdown of tolerance to self. The autoantibodies generated in SLE are directed against nuclear components, with which they form immune complexes (ICs). ICs play key roles in organ and tissue damage, as well as in the activation of the innate and adaptive immune system during the disease course. Therefore, it is of prime importance to understand the mechanisms responsible for the development of B cells producing these pathogenic autoantibodies. There is compelling evidence that T follicular helper (Tfh) cells play a fundamental role in this process. In this review, we will summarize the current knowledge regarding the involvement of Tfh cells in SLE pathogenesis, and discuss potential strategies to target Tfh cells and/or molecules as a therapeutic modality of SLE.