Infliximab restores the balance between pro- and anti-apoptotic proteins in regressing psoriatic lesions.

BACKGROUND: Psoriasis and psoriatic arthritis are treated very efficaciously with infliximab, a chimaeric human-murine antitumour necrosis factor (TNF)-α antibody. As we reported earlier, infliximab, besides its anti-inflammatory properties, induces a caspase-independent programmed cell death of psoriatic keratinocytes. OBJECTIVES: To elucidate this finding further, we investigated the epidermal expression of proteins involved in the mitochondria-dependent (intrinsic) pathway of cell death. METHODS: Quantification of proteins with pro- (p53, AIF, Bax) and anti-apoptotic functions (Bcl-2, Bcl-XL) and of NF-κB was performed by means of immunohistochemistry and digital image analysis of the staining of nonlesional skin and lesional psoriatic skin from patients treated with infliximab at weeks 0, 2 and 6. RESULTS: Serial biopsies from psoriatic plaques of samples taken at days 0, 5, 14 and 21 of therapy demonstrated a significant downregulation of anti-apoptotic proteins Bcl-2, Bcl-XL and NF-κB during treatment and, in parallel, a significant upregulation of pro-apoptotic proteins p53, Bax and AIF. These differences in expression correlated with decreases in epidermal thickness and clinical outcome (Psoriasis Area and Severity Index). At day 21, expression levels of apoptosis-related proteins in lesional skin approximated those found in nonlesional skin. CONCLUSIONS: Our data therefore suggest that TNF-targeting agents may induce the regression of psoriasis at least in part by normalizing the expression of apoptosis-related proteins in lesional keratinocytes.

Arthroscopic partial repair with versus without biodegradable subacromial spacer for patients with massive rotator cuff tears: a case-control study.

BACKGROUND: To investigate whether arthroscopic partial repair with the additional use of a biodegradable subacromial spacer would be proven better treatment for irreparable massive rotator cuff tears (MRCT) compared to single arthroscopic partial repair. METHODS: A matched-pairs case-control study of 32 patients suffering from irreparable MRCT who underwent an arthroscopic partial repair with (Group B: 16 patients) or without (Group A: 16 patients) InSpace Balloon (ISB®; Orthospace, Caesarea, Israel) implantation was conducted. For the clinical and functional assessment of the patients, the visual analog scale, Constant score, American Shoulder and Elbow Surgeons Shoulder Score (ASES), Range of Motion (RoM), and patients' satisfaction were obtained. RESULTS: The two groups were matched in all baseline demographic and clinical characteristics (n.s.). All mean final quantitative postoperative clinical and functional scores of group A (partial repair and ISB) and group B (single partial repair), as well as active RoM, were significantly improved (t test) in comparison with the mean preoperative values (p < 0.05). No significant differences were observed between the two groups in relation to the two success rate criteria (ASES minimal clinically important difference or MCID > 17, Constant score MCID > 10.4), as well as pain relief and RoM 12 months after surgery. CONCLUSION: Arthroscopic partial repair, either with or without ISB implantation, resulted in significantly improved clinical and functional short-term outcomes for the treatment of MRCT. Patients who were treated with combined partial repair and ISB implantation had a potential propensity toward better functional outcomes and higher patient satisfaction compared to the single-partial-repair-treated group. However, given that these differences were not significant, we feel that further studies are required to clarify the potential therapeutic value of ISB implantation in the treatment of irreparable MRCT. LEVEL OF EVIDENCE: Level III. CLINICAL TRIALS' REGISTRY: German Clinical Trials Register (WHO International Clinical Trials Registry Platform). ID number: DRKS00014725. Date of registration: 07/05/2018.

The role of endothelial cell apoptosis in the effect of etanercept in psoriasis.

BACKGROUND: Psoriasis is a chronic inflammatory skin disease associated with abnormal vascular expansion in the papillary dermis. Tumour necrosis factor (TNF)-α is a proinflammatory cytokine that can induce antiapoptotic proteins and endothelial cell activation factors in psoriasis. OBJECTIVES: The present study investigated the effect of the anti-TNF-α agent etanercept on the expression of endothelial nuclear factor-κB (NF-κB), angiogenic vascular endothelial growth factor (VEGF), endothelial cell marker CD31, antiangiogenic factor thrombospondin-1 (TSP-1), and antiapoptotic factors Bcl-2 and Bcl-xL in psoriasis. METHODS: Sixteen patients with moderate-to-severe psoriasis were included in the study and treated with etanercept 50 mg twice weekly subcutaneously for 12 weeks. Biopsies of lesional skin (baseline, weeks 3, 6 and 10) were obtained and immunohistochemically stained with antibodies for CD31, VEGF, TSP-1, NF-κB, Bcl-2 and Bcl-xL. Double immunofluorescence staining for VEGF and CD31 was evaluated with confocal laser microscopy. The terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelling (TUNEL) assay was applied for apoptosis detection. RESULTS: Etanercept caused a statistically significant time-dependent reduction in the number of dermal blood vessels, the number of CD31+ cells and VEGF in psoriatic lesions, with induction of endothelial cell apoptosis and statistically significant upregulation of TSP-1 in psoriatic vessels. Immunohistochemical analysis showed significant reduction of NF-κB, Bcl-2 and Bcl-xL expression in endothelial cells during treatment. These changes were accompanied by a marked clinical response. CONCLUSIONS: The present findings suggest that treatment with etanercept induces apoptosis, reduces apoptosis-inhibiting factors in psoriatic endothelial cells, and decreases angiogenesis in psoriatic skin.

Non-anatomic arthroscopic repair of massive rotator cuff tears versus anatomic complete arthroscopic repair: a case-control study.

PURPOSE: To investigate whether a non-anatomic arthroscopic repair of massive rotator cuff tear (RCT) produces satisfactory clinical outcomes comparable to those of an anatomic complete arthroscopic repair. METHODS: A retrospective case-control study (prospectively collected data, mean follow-up: 32.7 months ± 29.5; range 12-80 months) was conducted with patients with massive RCT who underwent either an anatomic complete arthroscopic repair (group A: 34 patients) or a non-anatomic arthroscopic repair (partial repair or medialized repair, group B: 30 patients). The rate of success was calculated primarily by the number of patients per group who achieved a minimal clinically important difference between the preoperative and postoperative values of (a) the American Shoulder and Elbow Surgeons Shoulder Score, (b) the constant score and (c) secondarily, the visual analogue scale (VAS-pain). Active range of motion (shoulder forward flexion, abduction, external rotation in 0° and 90° abduction), muscle strength and external rotation lag sign were also assessed. RESULTS: No significant statistical differences amongst groups were found concerning the baseline demographic and clinical characteristics. All postoperative clinical and functional scores were significantly improved in both groups (p < 0.001). According to our primary and secondary success rate criteria, both treatments were found to be successful, whereas there was no significant difference amongst them. CONCLUSIONS: Non-anatomic arthroscopic repair of massive RCT illustrated satisfactory outcomes, which are not significantly different from those reported after an anatomic complete arthroscopic repair.

Fetal tachycardia: is digitalis still the first-line therapy?

Medical treatment of fetal tachycardias has substantially improved neonatal outcome over the past years. Digitalis has been often used as first-line therapy in these cases, and more recently the use of several newer agents have been reported. We present four cases of fetal tachycardia with a favorable neonatal outcome after successful treatment with digitalis. Rapid transplacental digitalization appears to be an effective and reliable treatment option for fetal tachycardia, particularly in non-hydropic fetuses. In hydropic fetuses, however, digitalis alone appears to be less effective and administration of a second drug is usually needed.