Alpha1-antitrypsin protects beta-cells from apoptosis

Beta-cell apoptosis appears to represent a key event in the pathogenesis of type 1 diabetes. Previous studies have demonstrated that administration of the serine proteinase inhibitor alpha1-antitrypsin (AAT) prevents type 1 diabetes development in NOD mice and prolongs islet allograft survival in rodents; yet the mechanisms underlying this therapeutic benefit remain largely unclear. Herein we describe novel findings indicating that AAT significantly reduces cytokine- and streptozotocin (STZ)-induced beta-cell apoptosis. Specifically, strong antiapoptotic activities for AAT (Prolastin, human) were observed when murine insulinoma cells (MIN6) were exposed to tumor necrosis factor-alpha. In a second model system involving STZ-induced beta-cell apoptosis, treatment of MIN6 cells with AAT similarly induced a significant increase in cellular viability and a reduction in apoptosis. Importantly, in both model systems, treatment with AAT completely abolished induced caspase-3 activity. In terms of its activities in vivo, treatment of C57BL/6 mice with AAT prevented STZ-induced diabetes and, in agreement with the in vitro analyses, supported the concept of a mechanism involving the disruption of beta-cell apoptosis. These results propose a novel biological function for this molecule and suggest it may represent an effective candidate for attempts seeking to prevent or reverse type 1 diabetes.     

Antimicrobial photodynamic therapy combined with conventional endodontic treatment to eliminate root canal biofilm infection

BACKGROUND AND OBJECTIVE: To compare the effectiveness of antimicrobial photodynamic therapy (PDT), standard endodontic treatment and the combined treatment to eliminate bacterial biofilms present in infected root canals. STUDY DESIGN/MATERIALS AND METHODS: Ten single-rooted freshly extracted human teeth were inoculated with stable bioluminescent Gram-negative bacteria, Proteus mirabilis and Pseudomonas aeruginosa to form 3-day biofilms in prepared root canals. Bioluminescence imaging was used to serially quantify bacterial burdens. PDT employed a conjugate between polyethylenimine and chlorin(e6) as the photosensitizer (PS) and 660-nm diode laser light delivered into the root canal via a 200-micro fiber, and this was compared and combined with standard endodontic treatment using mechanical debridement and antiseptic irrigation. RESULTS: Endodontic therapy alone reduced bacterial bioluminescence by 90% while PDT alone reduced bioluminescence by 95%. The combination reduced bioluminescence by >98%, and importantly the bacterial regrowth observed 24 hours after treatment was much less for the combination (P<0.0005) than for either single treatment. CONCLUSIONS: Bioluminescence imaging is an efficient way to monitor endodontic therapy. Antimicrobial PDT may have a role to play in optimized endodontic therapy.     

Distinct effects of surgical denervation on hepatic perfusion, bowel ischemia, and oxidative stress in brain dead and living donor porcine models.

The liver function and perfusion following brain death is mainly influenced by the sympathetic nerves and hormones. We examined the specific influence of surgical liver denervation on systemic and hepatic perfusion parameters, bowel ischemia and oxidative stress in hemodynamically stable BD and control (living donor [LD]) pigs. Brain death was induced in 8 pigs via saline infusion into the balloon of an epidural Tieman-catheter (1 mL/15 minutes) and compared to the control group (n = 6) over 4 hours. At 2 hours postoperatively, complete liver denervation was initiated. We analyzed systemic cardiocirculatory parameters (mean arterial pressure, aortic flow, bowel ischemia (endotoxin, and endotoxin-neutralizing capacity) and oxidative stress (total glutathione in erythrocytes [tGSH(E)]) and compared them to local/hepatic perfusion parameters (hepatic artery and portal venous flow, liver blood flow index, and microperfusion), local bowel ischemia (intramucosal pH [pHi] of stomach [pHi(S)]/colon[pHi(C)]), and liver oxidative stress (glutathione [rGSH(L), GSSG(L)]). Following brain death, the parameters including mean arterial pressure, aortic flow, pHi, endotoxin, and tGSH(E) showed no significant changes at 2 hours. Portal venous flow and microperfusion were decreased significantly and hepatic arterial buffer response was ineffective. Hepatic oxidative stress was increased in BD animals (decrease rGSH(L), increase GSSG(L)). Surgical denervation/manipulation increased portal venous flow significantly, hepatic arterial buffer response became effective, and stomach pHi decreased (BD and LD groups). Hepatic oxidative stress was reduced in the BD group (increase rGSH(L)/GSSG(L); P < 0.001) while it was increased in the LD group (decrease rGSH(L)/GSSG(L); P < 0.001). In conclusion, denervation reduces hepatic oxidative stress in BD only in contrast to the LD. The reciprocal effect of denervation depends on the state of neural activation and postulates a potential benefit of surgical denervation before organ harvesting in brain death.     

Bilateral plasmacytoma of the breast: a case report

Plasmacytoma of the breast is a rare condition that may occur as a solitary finding or in association with multiple myeloma. Of the cases of plasmacytoma of the breast that have been described, nearly half have been bilateral. We report a case of bilateral plasmacytoma of the breast detected on a routine screening mammogram in a patient with a recent diagnosis of multiple myeloma.     

Electron beam sterilization does not have a detrimental effect on the ability of extracellular matrix scaffolds to support in vivo ligament healing

Extracellular matrix (ECM) scaffolds have been used to enhance anterior cruciate ligament (ACL) repair in large animal models. To translate this technology to clinical care, identifying a method which effectively sterilizes the material without significantly impairing in vivo function is desirable. Sixteen Yorkshire pigs underwent ACL transection and were randomly assigned to bridge‐enhanced ACL repair—primary suture repair of the ACL with addition of autologous blood soaked ECM scaffold—with either (i) an aseptically processed ECM scaffold, or (ii) an electron beam irradiated ECM scaffold. Primary outcome measures included sterility of the scaffold and biomechanical properties of the scaffold itself and the repaired ligament at 8 weeks after surgery. Scaffolds treated with 15 kGy electron beam irradiation had no bacterial or fungal growth noted, while aseptically processed scaffolds had bacterial growth in all tested samples. The mean biomechanical properties of the scaffold and healing ligament were lower in the electron beam group; however, differences were not statistically significant. Electron beam irradiation was able to effectively sterilize the scaffolds. In addition, this technique had only a minimal impact on the in vivo function of the scaffolds when used for ligament healing in the porcine model. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1015–1023, 2015.     

Is patient age associated with risk of malignancy in a ≥4 cm cytologically benign thyroid nodule?

BackgroundCurrent data regarding the risk of malignancy in a large thyroid nodule with benign fine-needle aspiration biopsy(FNAB) is conflicting. We investigated the impact of patient age on the risk of malignancy in nodules≥4 cm with benign cytology.MethodsWe performed a single-institution retrospective review of patients who underwent surgery from 07/2008–08/2019 for a cytologically benign thyroid nodule ≥4 cm. The relationship between malignant histopathology and patient and ultrasound features was assessed with multivariable logistic regression.ResultsOf 474 nodules identified, 25(5.3%) were malignant on final pathology. In patients <55 years old, 21/273(7.7%) nodules were malignant, compared to 4/201(2.0%) in patients ≥55. Patient age ≥55 was independently associated with significantly lower risk of malignancy(OR:0.2,95%CI:0.1–0.7,p = 0.011). Increasing nodule size >4 cm and high-risk ultrasound features were not associated with risk of malignancy(OR:1.0,95%CI:0.7–1.4,p = 0.980, and OR:9.6,95%CI:0.9–107.8,p = 0.066, respectively).ConclusionsPatients <55 years old are 3.7-fold more likely to have a falsely benign FNA biopsy in a nodule≥4 cm.     

Evaluation of fluorodeoxyglucose positron emission tomography imaging in metastatic transitional cell carcinoma with and without prior chemotherapy

INTRODUCTION: This study was designed to determine the value of fluorodeoxyglucose (FDG) positron emission tomography (PET) in the evaluation of metastatic transitional cell carcinoma (TCC). METHODS: Fifty-eight FDG PET scans were performed on 46 consecutive patients with TCC. Results were correlated with radiologic, pathologic, and histologic findings in these patients and the sensitivity of PET for detecting malignancy in untreated TCC patients (n = 48) was compared to the sensitivity in patients who had undergone prior chemotherapy (n = 10). RESULTS: Of 48 scans in patients who had no prior systemic chemotherapy, 10 had increased uptake in proven metastatic TCC lesions and 3 PET studies failed to reveal metastatic TCC (sensitivity 76.9%). In patients free of metastatic disease, 33 revealed no abnormal uptake and 1 study revealed a suspicious area in a patient free of metastases (specificity = 97.1%). However, in 10 patients imaged after receiving chemotherapy, the sensitivity fell to 50% for the detection of histologically confirmed residual/recurrent tumor by PET. CONCLUSIONS: FDG PET detects increased metabolic activity. After chemotherapy, viable cancer cells may still be present but with a diminished metabolic rate. As a result, PET imaging is often useful in the evaluation of untreated metastatic TCC metastasis but should be interpreted with caution in patients who have received prior chemotherapy.     

The association of red blood cell n‐3 and n‐6 fatty acids with bone mineral density and hip fracture risk in the women's health initiative

Omega‐3 (n‐3) and omega‐6 (n‐6) polyunsaturated fatty acids (PUFA) in red blood cells (RBCs) are an objective indicator of PUFA status and may be related to hip fracture risk. The primary objective of this study was to examine RBC PUFAs as predictors of hip fracture risk in postmenopausal women. A nested case‐control study (n = 400 pairs) was completed within the Women's Health Initiative (WHI) using 201 incident hip fracture cases from the Bone Mineral Density (BMD) cohort, along with 199 additional incident hip fracture cases randomly selected from the WHI Observational Study. Cases were 1:1 matched on age, race, and hormone use with non–hip fracture controls. Stored baseline RBCs were analyzed for fatty acids using gas chromatography. After removing degraded samples, 324 matched pairs were included in statistical analyses. Stratified Cox proportional hazard models were constructed according to case‐control pair status; risk of fracture was estimated for tertiles of RBC PUFA. In adjusted hazard models, lower hip fracture risk was associated with higher RBC α‐linolenic acid (tertile 3 [T3] hazard ratio [HR]: 0.44; 95% confidence interval [CI], 0.23–0.85; p for linear trend 0.0154), eicosapentaenoic acid (T3 HR: 0.46; 95% CI, 0.24–0.87; p for linear trend 0.0181), and total n‐3 PUFAs (T3 HR: 0.55; 95% CI, 0.30–1.01; p for linear trend 0.0492). Conversely, hip fracture nearly doubled with the highest RBC n‐6/n‐3 ratio (T3 HR: 1.96; 95% CI, 1.03–3.70; p for linear trend 0.0399). RBC PUFAs were not associated with BMD. RBC PUFAs were indicative of dietary intake of marine n‐3 PUFAs (Spearman's rho = 0.45, p < 0.0001), total n‐6 PUFAs (rho = 0.17, p < 0.0001) and linoleic acid (rho = 0.09, p < 0.05). These results suggest that higher RBC α‐linolenic acid, as well as eicosapentaenoic acid and total n‐3 PUFAs, may predict lower hip fracture risk. Contrastingly, a higher RBC n‐6/n‐3 ratio may predict higher hip fracture risk in postmenopausal women. © 2013 American Society for Bone and Mineral Research.