Healing in peri‐implant gap with BMP‐2 and systemic bisphosphonate is dependent on BMP‐2 dose—A canine study

The bone–implant interface of cementless orthopedic implants can be described as a series of uneven sized gaps with discontinuous areas of direct bone–implant contact. Bridging these voids and crevices by addition of an anabolic stimulus to increase new bone formation can potentially improve osseointegration of implants. Bone morphogenetic protein 2 (BMP‐2) stimulates osteoblast formation to increase new bone formation but also indirectly stimulates osteoclast activity. In this experiment, we investigate the hypothesis that osseointegration, defined as mechanical push‐out and histomorphometry, depends on the dose of BMP‐2 when delivered as an anabolic agent with systemic administration of the anti‐resorptive agent zoledronate to curb an increase in osteoclast activity. Four porous coated titanium implants (one with each of three doses of surface‐applied BMP‐2 (15 µg; 60 µg; 240 µg) and untreated) surrounded by a 0.75 mm empty gap, were inserted into the distal femurs of each of twelve canines. Zoledronate IV (0.1 mg/kg) was administered 10 days into the observation period of 4 weeks. Bone–implant specimens were evaluated by mechanical push‐out test and histomorphometry. The 15 µg implants had the best fixation on all mechanical parameters and largest surface area covered with new bone compared to the untreated, 60 and 240 µg implants, as well as the highest volume of new bone in the implant gap compared to 60 and 240 µg implants. The results in a canine implant model demonstrated that a narrow range of BMP‐2 doses have opposite effects in bridging an empty peri‐implant gap with bone, when combined with systemic zoledronate. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1406–1414, 2018.

     

Dose-Dependent Resorption of Allograft by rhBMP-2 Uncompensated by New Bone Formation—A Canine Study With Implants and Zoledronate

Background

Impacted bone allograft is used to restore lost bone in total joint arthroplasties. Bone morphogenetic proteins (BMPs) can induce new bone formation to improve allograft incorporation, but they simultaneously invoke a seemingly dose-dependent allograft resorption mediated by osteoclasts. Bisphosphonates effectively inhibit osteoclast activity. Predicting allograft resorption when augmented with bone morphogenetic protein 2 (BMP-2), we intended to investigate whether a balanced bone metabolism was achievable within a range of BMP-2 doses with systemic zoledronate treatment.

Linoleic acid and dihomogammalinolenic acid inhibit leukotriene B4 formation and stimulate the formation of their 15-lipoxygenase products by human neutrophilsin vitro. Evidence of formation of antiinflammatory compounds

Enzymatic transformation of then-6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA) by the 5-lipoxygenase (LO) enzyme results in the formation of leukotrienes (LTs) including leukotriene B₄ (LTB₄), which is a potent mediator of inflammation. The purpose of the present study was to determine the effect of othern-6 fatty acids on the formation of LTB₄ by human neutrophils and to determine if thesen-6 fatty acids themselves may be transformed into products with antiinflammatory capacity. Purified neutrophils isolated from heparinized human venous blood were incubated with A23187 (5 M) and different concentrations (0–100 M) of then-6 fatty acids linoleic acid (LA) and dihomo-gammalinolenic acid (DGLA). LO products were determined by use of quantitative reversed-phase high performance liquid chromatography (RP-HPLC) and mass spectrometry. The formation of LTB₄ was dose dependently inhibited by both LA (IC₅₀=45 M) and DGLA (IC₅₀=40M). This inhibition of LTB₄ formation was associated with a dose dependent increase in the formation of the respective 15-LO products of LA (13-hydroxy-octadecadienoic acid; 13-HODE) and DGLA (15-hydroxy-eicosatrienoic acid; 15-HETrE). To determine whether these 15-LO products themselves might inhibit LTB₄ formation, neutrophils were incubated with 13-HODE and 15-HETrE. Both 15-LO products lead to a dose-dependent inhibition of LTB₄ formation (IC₅₀=7.5 M and IC₅₀=0.2 M). For comparison the 15-LO product of AA, 15-hydroxy-eicosatetraenoic acid (15-HETE), also inhibited LTB₄ formation (IC₅₀=0.75 M). The results show that the addition of LA and DGLA to neutrophils results in an inhibition of LTB₄ formation and simultaneously to the formation of 13-HODE and 15-HETrE, that also inhibits LTB₄ formation. Therefore, dietary supplementation or topical application of LA and DGLA or preferentially their respective 15-LO products, may have a therapeutic effect in inflammatroy diseases in which LTs are suspected to play a pathogenic role.     

A practical guide to the sublingual immunotherapy tablet adverse event profile: implications for clinical practice

Objectives: Treatment with allergy immunotherapy improves allergic rhinoconjunctivitis, but can also improve comorbidities associated with allergic rhinitis such as asthma. Sublingual immunotherapy (SLIT)-tablets are a convenient and efficacious method of allergy immunotherapy. They are self-administered after the first tablet has been provided under medical supervision. Therapy may elicit local reactions or, rarely, systemic allergic reactions. The objective of this report is to inform healthcare practitioners about the safety and tolerability profile of SLIT-tablets and use this information to provide practical guidance that may inform patients regarding potential adverse reactions and how to manage them.

Methods: Pooled analyses of safety data from completed randomized, multicenter, double-blind, placebo-controlled phase 2 and phase 3 US and EU trials of timothy grass, short ragweed, and SQ house dust mite SLIT-tablets were conducted to characterize safety and tolerability.

Results: SLIT-tablets are generally well tolerated. No life-threatening events, serious systemic allergic reactions, or events that compromised the airway have been reported. The most common treatment-related adverse events (AEs) are oral site reactions, most of which begin on day 1 of treatment, recur for less than 2 weeks, and resolve after approximately 30–60 minutes. Systemic allergic reactions have been managed with conventional pharmacotherapy. Reactions treated with epinephrine are uncommon, but have been reported. Treatment of AEs, treatment discontinuation considerations, and patient FAQs regarding SLIT-tablet safety/tolerability are discussed.

Conclusions: This report gives healthcare providers valuable information to educate patients regarding what to expect in terms of SLIT-tablet safety and tolerability. Practical guidance is also provided to ensure proper treatment of any adverse reactions.     

No association of DPP6 with amyotrophic lateral sclerosis in an Italian population

We have attempted to replicate a recently reported association of polymorphism rs10260404, in the Dipeptidyl-peptidase 6 gene (DPP6), with susceptibility to amyotrophic lateral sclerosis (ALS) in a large independent Italian cohort of 904 cases and 1036 controls. Minor allele frequency was 0.38 in cases and 0.39 in controls and no evidence of association with ALS was observed (P = 0.638). Our negative results agree with those recently reported in additional Polish and Italian cohorts.     

A comparison of preplan transrectal ultrasound with preplan-CT in assessing volume and number of seeds needed for real-time ultrasound-based intra-operative planning in prostate 125I seed implantation

PurposeIntra-operative (real-time) treatment planning has been adapted by many institutions for low–dose rate prostate brachytherapy. Although this allows dosimetric planning to be done during the procedure, preplan imaging to obtain a prostate volume is essential to identify the number of seeds to ensure adequate volume coverage. Currently, there is no consensus regarding the most appropriate imaging to obtain this information. We conducted a retrospective study to compare how volumes obtained from preplan CT (p-CT) scans or preplan transrectal ultrasound (p-TRUS) correlated with real-time ultrasound and postimplant CT volumes and the difference in accuracy of seed estimation between these techniques.Methods and MaterialsNinety-two patients underwent ¹²⁵I permanent seed implants at Thomas Jefferson University Hospital between February 2002 and August 2008. Fifty-one patients underwent p-TRUS before intra-operative planning and 41 patients were evaluated by p-CT.ResultsThe median difference in volume between preimplant imaging and the intra-operative planning ultrasound was 3.59 and 5.2 cc for patients who underwent p-TRUS and p-CT, respectively. p-TRUS volumes more closely correlated with real-time intra-operative volumes (R = 0.84 in all patients and R = 0.91 in hormone-naïve patients) vs. p-CT (R = 0.82). The median number of seeds wasted using p-CT was 18 vs. 7 using volumes derived from p-TRUS.ConclusionsThe number of seeds ordered could be more accurately obtained from p-TRUS volumes, and this translated into less seed wastage. Our findings indicate that p-TRUS is a more accurate and an economically superior alternative to p-CT imaging in the era of real-time ultrasound planning.     

Pyoderma gangrenosum and tumour necrosis factor alpha inhibitors: A semi‐systematic review

Pyoderma gangrenosum (PG) is a rare ulcerative skin disease that presents a therapeutic challenge. Tumour necrosis factor alpha (TNFα) inhibitors have been reported to successfully control PG. Our aim was to systematically evaluate and compare the clinical effectiveness of TNFα inhibitors in adults with PG. A literature search including databases such as PubMed, Embase, Scopus, and Web of Science was conducted, using search terms related to PG and TNFα inhibitors. Studies and case reports were included if patients were diagnosed with PG, over the age of 18 and administered TNFα inhibitor. A total of 3212 unique citations were identified resulting in 222 articles describing 356 patients being included in our study. The study we report found an 87% (95% CI: 83%‐90%) response rate and a 67% (95% CI: 62%‐72%) complete response rate to TNFα inhibitors. No statistically significant differences in the response rates (P = 0.6159) or complete response rates (P = 0.0773) to infliximab, adalimumab, and etanercept were found. In our study TNFα inhibitors demonstrated significant effectiveness with response and complete response rates supporting the use of TNFα inhibitors to treat PG in adults. Our study suggests that there is no significant difference in effectiveness among infliximab, adalimumab, and etanercept.     

Development and regulation of porcine pancreatic function

Summary A surgical and experimental procedure was developed to enable the collection of pure and inactivated pancreatic juice during the growth of the pig. Studies have shown that, during the suckling period, both the basal and the secretory responses to suckling are low, if present at all. After weaning, basal levels of the total exocrine secretion, total protein, amylase, and trypsin, respectively, increase slightly, while the postprandial levels of total protein, amylase, trypsin, lipase, colipase, and carboxylester lipase, respectively, increase markedly. The pancreatic juice enzyme composition changes qualitatively and the antibacterial activity of the pancreatic juice also significantly increases. Piglet age appeared to be of minor importance, since weaning at either 4 or 6 wk of age gave the same results. Secretin and CCK administered together in supraphysiological doses only significantly affect exocrine function from 3–4 wk of age. However, CCK may also affect the exocrine pancreas indirectly via reflexes initiated intraduodenally. Milk consumption in the suckling pig leads to a postprandial increase in glucose levels but not insulin. Milk, appears to be able to regulate the exocrine pancreas to produce only the amount and type of enzymes required for digestion. Thus, milk components or digestive products may affect pancreas function regulation. Studies show that enterostatin, the procolipase activation peptide, may inhibit pancreatic secretion mediated indirectly through the GI tract. Pancreastatin, an endocrine peptide, inhibits both insulin secretion and protein and trypsin secretion to pancreatic juice. In hypoinsulinemic (alloxan + streptozotocin diabetes) pigs (15–20 kg), no postprandial pancreatic juice response is seen, although CCK 33 + secretin can stimulate pancreatic secretion. Hypoinsulinemic pigs have a reduced capacity for glucose tissue utilization, suggesting that tissue metabolism and exocrine pancreas secretion are related.     

Tumor initiating but differentiated luminal-like breast cancer cells are highly invasive in the absence of basal-like activity

The majority of human breast cancers exhibit luminal epithelial differentiation. However, most aggressive behavior, including invasion and purported cancer stem cell activity, are considered characteristics of basal-like cells. We asked the following questions: Must luminal-like breast cancer cells become basal-like to initiate tumors or to invade? Could luminally differentiated cells within a basally initiated hierarchy also be tumorigenic? To answer these questions, we used rare and mutually exclusive lineage markers to isolate subsets of luminal-like and basal-like cells from human breast tumors. We enriched for populations with or without prominent basal-like traits from individual tumors or single cell cloning from cell lines and recovered cells with a luminal-like phenotype. Tumor cells with basal-like traits mimicked phenotypic and functional behavior associated with stem cells assessed by gene expression, mammosphere formation and lineage markers. Luminal-like cells without basal-like traits, surprisingly, were fully capable of initiating invasive tumors in NOD SCID gamma (NSG) mice. In fact, these phenotypically pure luminal-like cells generated larger and more invasive tumors than their basal-like counterparts. The tumorigenicity and invasive potential of the luminal-like cancer cells relied strongly on the expression of the gene GCNT1, which encodes a key glycosyltransferase controlling O-glycan branching. These findings demonstrate that basal-like cells, as defined currently, are not a requirement for breast tumor aggressiveness, and that within a single tumor there are multiple “stem-like” cells with tumorigenic potential casting some doubt on the hypothesis of hierarchical or differentiative loss of tumorigenicity.