Statistical and clustering analysis of microseismicity from a Saskatchewan potash mine

Microseismicity is expected in potash mining due to the associated rock-mass response. This phenomenon is known, but not fully understood. To assess the safety and efficiency of mining operations, producers must quantitatively discern between normal and abnormal seismic activity. In this work, statistical aspects and clustering of microseismicity from a Saskatchewan, Canada, potash mine are analyzed and quantified. Specifically, the frequency-magnitude statistics display a rich behavior that deviates from the standard Gutenberg-Richter scaling for small magnitudes. To model the magnitude distribution, we consider two additional models, i.e., the tapered Pareto distribution and a mixture of the tapered Pareto and Pareto distributions to fit the bi-modal catalog data. To study the clustering aspects of the observed microseismicity, the nearest-neighbor distance (NND) method is applied. This allowed the identification of potential cluster characteristics in time, space, and magnitude domains. The implemented modeling approaches and obtained results will be used to further advance strategies and protocols for the safe and efficient operation of potash mines

Population Pharmacokinetic and Pharmacodynamic Modeling for Assessing Risk of Bisphosphonate-related Osteonecrosis of the Jaw

Objective: We hypothesized that patients with bisphosphonate (BP)-related osteonecrosis of the jaw (BRONJ) accumulate higher levels of BP in bone than those without BRONJ. Study Design: Using the Pmetrics package and published data, we designed a population pharmacokinetic model of pamidronate concentration in plasma and bone and derived a toxic bone BP threshold of 0.2 mmol/L. With the model, and using patient individual BP duration and bone mineral content estimated from lean body weight, we calculated bone BP levels in 153 subjects. Results: Mean bone BP in 69 BRONJ cases was higher than in 84 controls (0.20 vs 0.10 mmol/L, P \u3c 0.001), consistent with the toxic bone threshold of 0.2 mmol/L. BRONJ was also associated with longer duration BP therapy (5.3 vs 2.7 years, P \u3c 0.001), older age (76 vs 70 years, P \u3c 0.001), and Asian race (49% vs 14%, P \u3c 0.001). Conclusions: Our model accurately discriminated BRONJ cases from controls among patients on BP therapy. © 2013 Elsevier Inc

Non-exposed Bisphosphonate-related Osteonecrosis of the Jaw: A Critical Assessment of Current Definition, Staging, and Treatment Guidelines

Non-exposed bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a newly reported complication arising from bisphosphonate therapy that presents with atypical symptoms and no apparent mucosal fenestration or exposure of necrotic bone. The clinical observation of the presence of necrotic bone underneath normal epithelial coverage was not conclusive for the diagnosis of BRONJ based on current guidelines established by the American Association of Oral and Maxillofacial Surgeons (AAOMS) and the American Society for Bone and Mineral Research (ASBMR), which specify the presence of clinically exposed necrotic bone for more than 8weeks. Hence, the purpose of this review is to critically assess the current guidelines for diagnosis and management of BRONJ and propose a modified staging system and treatment guidelines to properly address the non-exposed variant of BRONJ lesions. © 2012 John Wiley & Sons A/S

Design, synthesis, and antimicrobial evaluation of a novel bone-targeting bisphosphonate-ciprofloxacin conjugate for the treatment of osteomyelitis biofilms

Osteomyelitis is a major problem worldwide and is devastating due to the potential for limb-threatening sequelae and mortality. Osteomyelitis pathogens are bone-attached biofilms, making antibiotic delivery challenging. Here we describe a novel osteoadsorptive bisphosphonate-ciprofloxacin conjugate (BV600022), utilizing a “target and release” chemical strategy, which demonstrated a significantly enhanced therapeutic index versus ciprofloxacin for the treatment of osteomyelitis in vivo. In vitro antimicrobial susceptibility testing of the conjugate against common osteomyelitis pathogens revealed an effective bactericidal profile and sustained release of the parent antibiotic over time. Efficacy and safety were demonstrated in an animal model of periprosthetic osteomyelitis, where a single dose of 10 mg/kg (15.6 μmol/kg) conjugate reduced the bacterial load by 99% and demonstrated nearly an order of magnitude greater activity than the parent antibiotic ciprofloxacin (30 mg/kg, 90.6 μmol/kg) given in multiple doses. Conjugates incorporating a bisphosphonate and an antibiotic for bone-targeted delivery to treat osteomyelitis biofilm pathogens constitute a promising approach to providing high bone-antimicrobial potency while minimizing systemic exposure

Histomorphology of healthy oral mucosa in untreated celiac patients: unexpected association with spongiosis.

BACKGROUND: The jejunal mucosa is the major site involved in celiac disease, but modifications have also been found in the gastric, rectal and esophageal mucosa. Few studies have focused on the histomorphological features of the oral mucosa in celiac disease patients. Our objectives were: (i) to assess the presence, quality and intensity of lymphocytic infiltrate in clinically healthy oral mucosa and its relation to celiac disease severity (villous height to crypt depth ratio); and (ii) to detect any other histological features connected to celiac disease. METHODS: Twenty-one untreated celiac disease patients (age range 13-68 years) with clinically healthy oral mucosa were enrolled and compared with 14 controls. Intestinal and oral biopsies were carried out and specimens were evaluated after staining with hematoxylin and eosin. RESULTS: Intra-epithelial lymphocyte B and T infiltrates of the oral mucosa were found to be similar in both groups; likewise, intensity of the lymphocytic infiltrate in the lamina propria was similar in both groups and was not related to intestinal damage; important signs of spongiosis were found to be more significantly present in celiac disease patients compared with controls (P = 0.0002). CONCLUSIONS: Our study showed that the healthy oral mucosa of untreated patients does not reflect the intestinal damage by celiac disease, but it is unexpectedly affected by spongiosis, as being detected for the first time in the literature. This latter feature could be related to gliadin ingestion and could contribute to explain the higher susceptibility of celiac disease patients to suffering from oral mucosa lesions

Real-time impedance-based monitoring of the growth and inhibition of osteomyelitis biofilm pathogen Staphylococcus aureus treated with novel bisphosphonate-fluoroquinolone antimicrobial conjugates

Osteomyelitis is a limb- and life-threatening orthopedic infection predominantly caused by Staphylococcus aureus biofilms. Bone infections are extremely challenging to treat clinically. Therefore, we have been designing, synthesizing, and testing novel antibiotic conjugates to target bone infections. This class of conjugates comprises bone-binding bisphosphonates as biochemical vectors for the delivery of antibiotic agents to bone minerals (hydroxyapatite). In the present study, we utilized a real-time impedance-based assay to study the growth of Staphylococcus aureus biofilms over time and to test the antimicrobial efficacy of our novel conjugates on the inhibition of biofilm growth in the presence and absence of hydroxyapatite. We tested early and newer generation quinolone antibiotics (ciprofloxacin, moxifloxacin, sitafloxacin, and nemonoxacin) and several bisphosphonate-conjugated versions of these antibiotics (bisphosphonate-carbamate-sitafloxacin (BCS), bisphosphonate-carbamate-nemonoxacin (BCN), etidronate-carbamate-ciprofloxacin (ECC), and etidronate-carbamate-moxifloxacin (ECX)) and found that they were able to inhibit Staphylococcus aureus biofilms in a dose-dependent manner. Among the conjugates, the greatest antimicrobial efficacy was observed for BCN with an MIC of 1.48 µg/mL. The conjugates demonstrated varying antimicrobial activity depending on the specific antibiotic used for conjugation, the type of bisphosphonate moiety, the chemical conjugation scheme, and the presence or absence of hydroxyapatite. The conjugates designed and tested in this study retained the bone-binding properties of the parent bisphosphonate moiety as confirmed using high-performance liquid chromatography. They also retained the antimicrobial activity of the parent antibiotic in the presence or absence of hydroxyapatite, albeit at lower levels due to the nature of their chemical modification. These findings will aid in the optimization and testing of this novel class of drugs for future applications to pharmacotherapy in osteomyelitis

Oral bisphosphonate-related osteonecrosis of the jaws in rheumatoid arthritis patients: a critical discussion and two case reports

<p>Abstract</p> <p>Background</p> <p>Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a clinical condition characterized by the presence of exposed bone in the maxillofacial region. Its pathogenesis is still undetermined, but may be associated with risk factors such as rheumatoid arthritis (RA). The aim of this paper is to report two unpublished cases of BRONJ in patients with RA and to conduct a literature review of similar clinical cases with a view to describe the main issues concerning these patients, including demographic characteristics and therapeutic approaches applied.</p> <p>Methods</p> <p>Two case reports of BRONJ involving RA patients were discussed</p> <p>Results</p> <p>Both patients were aging female taking alendronate for more than 3 years. Lesions were detected in stage II in posterior mandible with no clear trigger agent. The treatment applied consisted of antibiotics, oral rinses with chlorhexidine, drug discontinuation and surgical procedures. Complete healing of the lesions was achieved.</p> <p>Conclusions</p> <p>This paper brings to light the necessity for rheumatologists to be aware of the potential risk to their patients of developing BRONJ and to work together with dentists for the prevention and early detection of the lesions. Although some features seem to link RA with oral BRONJ and act as synergistic effects, more studies should be developed to support the scientific bases for this hypothesis.</p

Increased human defensine levels hint at an inflammatory etiology of bisphosphonate-associated osteonecrosis of the jaw: An immunohistological study

<p>Abstract</p> <p>Background</p> <p>Human β-defensins (hBD) are antimicrobial peptides that are an integral part of bone innate immunity. Recently, it could be shown that expression of hBD-1, -2 and -3 were upregulated in cases of osteomyelitis of the jaws. In order to gain insight into the possible impairment of hBD metabolism in bisphosphonate-associated osteonecrosis of the jaws (BONJ), the present exploratory study was designed so as to determine the qualitative and quantitative expression of afore mentioned hBDs in BONJ and infected osteoradionecrosis (ORN), both of which represent inflammatory bone diseases.</p> <p>Methods</p> <p>Bone samples were collected from patients with BONJ (n = 20) and ORN (n = 20). Non-infected healthy bone samples (n = 20) were included as controls. Immunohistological staining in an autostainer was carried out by the (Strept-ABC)-method against hBD-1,-2,-3. Specific positive vs. negative cell reaction of osteocytes (labeling index) near the border of bony resection was determined and counted for quantitative analysis. Number of vital osteocytes vs. empty osteocytes lacunae was compared between groups.</p> <p>Results</p> <p>hBD-1,-2 and -3 could be detected in BONJ as well as ORN and healthy bone samples. Immunoreactivity against hBD-2 and -3 was significantly higher in BONJ than in ORN and healthy jaw bone samples. Number of empty osteocyte lacunae was significantly higher in ORN compared with BONJ (<it>P </it>= 0.001).</p> <p>Conclusion</p> <p>Under the condition of BONJ an increased expression of hBD-1,-2,-3 is detectable, similarly to the recently described upregulation of defensins in chronically infected jaw bones. It remains still unclear how these findings may relate to the pathoetiology of these diseases and whether this is contributing to the development of BONJ and ORN or simply an after effect of the disease.</p