A humanised tissue‐engineered bone model allows species‐specific breast cancer‐related bone metastasis in vivo

Bone metastases frequently occur in the advanced stages of breast cancer. At this stage, the disease is deemed incurable. To date, the mechanisms of breast cancer‐related metastasis to bone are poorly understood. This may be attributed to the lack of appropriate animal models to investigate the complex cancer cell–bone interactions. In this study, two established tissue‐engineered bone constructs (TEBCs) were applied to a breast cancer‐related metastasis model. A cylindrical medical‐grade polycaprolactone‐tricalcium phosphate scaffold produced by fused deposition modelling (scaffold 1) was compared with a tubular calcium phosphate‐coated polycaprolactone scaffold fabricated by solution electrospinning (scaffold 2) for their potential to generate ectopic humanised bone in NOD/SCID mice. While scaffold 1 was found not suitable to generate a sufficient amount of ectopic bone tissue due to poor ectopic integration, scaffold 2 showed excellent integration into the host tissue, leading to bone formation. To mimic breast cancer cell colonisation to the bone, MDA‐MB‐231, SUM1315, and MDA‐MB‐231BO breast cancer cells were cultured in polyethylene glycol‐based hydrogels and implanted adjacent to the TEBCs. Histological analysis indicated that the breast cancer cells induced an osteoclastic reaction in the TEBCs, demonstrating analogies to breast cancer‐related bone metastasis seen in patients.     

Challenges and remediation for Patient Safety Indicators in the transition to ICD-10-CM

Reporting of hospital adverse events relies on Patient Safety Indicators (PSIs) using International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM) codes. The US transition to ICD-10-CM in 2015 could result in erroneous comparisons of PSIs. Using the General Equivalent Mappings (GEMs), we compared the accuracy of ICD-9-CM coded PSIs against recommended ICD-10-CM codes from the Centers for Medicaid/Medicare Services (CMS). We further predict their impact in a cohort of 38 644 patients (1 446 581 visits and 399 hospitals). We compared the predicted results to the published PSI related ICD-10-CM diagnosis codes. We provide the first report of substantial hospital safety reporting errors with five direct comparisons from the 23 types of PSIs (transfusion and anesthesia related PSIs). One PSI was excluded from the comparison between code sets due to reorganization, while 15 additional PSIs were inaccurate to a lesser degree due to the complexity of the coding translation. The ICD-10-CM translations proposed by CMS pose impending risks for (1) comparing safety incidents, (2) inflating the number of PSIs, and (3) increasing the variability of calculations attributable to the abundance of coding system translations. Ethical organizations addressing ‘data-, process-, and system-focused’ improvements could be penalized using the new ICD-10-CM Agency for Healthcare Research and Quality PSIs because of apparent increases in PSIs bearing the same PSI identifier and label, yet calculated differently. Here we investigate which PSIs would reliably transition between ICD-9-CM and ICD-10-CM, and those at risk of under-reporting and over-reporting adverse events while the frequency of these adverse events remain unchanged.     

Primary structure and biological activity of human brain-derived neurotrophic factor

Brain-derived neurotrophic factor (BDNF) is a 27-kDa basic protein of noncovalently linked 13.5-kD subunits related to nerve growth factor and is produced by the central nervous system (CNS). BDNF has been shown to promote the survival of neurons located in or directly connected with the CNS and is likely to function in adjusting the cell number within neuronal populations to the need of this projection field. Here we describe the primary structure of a human BDNF cDNA, the biological activities of pure recombinant human BDNF, and the tissue distribution of rat BDNF. BDNF mRNA can be found in some peripheral tissues as well as in the CNS, and recombinant human BDNF is a potent neurotrophic factor for primary peripheral sensory neurons.     

Free radicals alter ionic calcium levels and membrane phospholipids in cultured rat ventricular myocytes

Oxygen-derived free radicals have been implicated in damage to membrane phospholipids leading to alterations in membrane function. The purpose of this study was to investigate alterations in intracellular ionic calcium (Ca2+) levels and Ca2+ transients, cellular morphology, conjugated diene levels, arachidonate release, and lactate dehydrogenase release resulting from the exposure of cultured neonatal rat ventricular myocytes to a xanthine oxidase catalyzed free radical generating system capable of producing superoxide and hydroxyl radicals. The ability of alpha-tocopherol to prevent alterations due to free radical exposure was investigated. For measurements of Ca2+, myocytes grown on coverslips for 3-4 days were loaded with fura-2/AM and studied by microspectrofluorometry. Control myocytes superfused with a physiological buffer or buffer containing purine and iron-loaded transferrin exhibited Ca2+ transients associated with spontaneous contractions. For control, buffer perfused myocytes (n = 4), the fura-2 340/380 ratios were 0.5 +/- 0.1 (mean +/- S.E.) and 1.6 +/- 0.03 at the minimum and maximum, respectively, of the Ca2+ transient, after 1 h of perfusion. Exposure to the free radical generating solution (n = 14) altered intracellular Ca2+. The 340/380 minimum ratio was 639% of the control value after approximately 30-70 mins with cessation of normal Ca2+ transients. Bleb development was associated with increased Ca2+. Myocytes reperfused with control medium continued to exhibit an elevated minimum fura-2 ratio at 687% of control. Myocytes pretreated with 10 microM alpha-tocopherol (n = 13) for 18-24 h and exposed to free radicals did not exhibit increases in intracellular Ca2+, having a minimum 340/380 ratio of 0.5 +/- 0.1 after 60-90 mins, and although myocytes often ceased contracting, they resumed spontaneous Ca2+ transients with control medium reperfusion and also maintained normal structure. Exposure of myocyte cultures to free radical generating solutions resulted in increased levels of conjugated dienes and increased release of [3H]arachidonate and lactate dehydrogenase compared to control values after 1 h. alpha-Tocopherol treatment attenuated the increase in conjugated diene levels, and the release of [3H]arachidonate and lactate dehydrogenase. Thus, free radicals alter intracellular Ca2+, conjugated dienes and membrane structure indicating their ability to induce altered ionic homeostasis in association with myocardial membrane damage. alpha-Tocopherol decreased free radical mediated injury.     

Concepts of rehabilitation for the management of low back pain

This chapter develops rehabilitation principles for the clinical and occupational management of non-specific low back pain (LBP). Rehabilitation has traditionally been a secondary intervention, which focused on permanent impairment, but this is inappropriate for LBP. Most patients with LBP do not have any irremediable impairment and long-term incapacity is not inevitable: given the right care, support and opportunity, most should be able to return to work. Rehabilitation should then address obstacles to recovery and barriers to (return to) work. Rehabilitation should not be a separate, second stage after 'treatment' is complete: rehabilitation principles should be integral to clinical and occupational management. It should be possible to reduce sickness absence and long-term incapacity due to LBP by at least 30-50%, but this will require a fundamental shift in management culture.     

Long-term efficacy of sertraline as a treatment for cholestatic pruritus in patients with primary biliary cirrhosis

OBJECTIVES: Generalized pruritus is a common complication of cholestatic liver diseases, although its pathogenesis remains elusive. Current treatments are often inadequate and may be poorly tolerated, so the clinician is sometimes faced with a patient in misery and no good therapeutic options. Because, in our experience, several patients with primary biliary cirrhosis (PBC) claimed that sertraline had improved their pruritus, we sought to determine whether sertraline use was associated with changes in pruritus medications or self-reported severity of pruritus in a large cohort of patients with PBC. METHODS: The self-reported severity of pruritus was followed prospectively in 40 patients with PBC for a mean of 7.5 +/- 1.3 yr. These data were then retrospectively examined to determine the effect of sertraline on pruritus in all subjects who had received sertraline at some time during the study. RESULTS: For 28 of 32 patients with pruritus, itching was stable or fluctuated slightly over the follow-up period. No patient experienced rapid progression of pruritus, and four patients experienced a sustained resolution of their pruritus. Ten subjects started sertraline and continued it long enough (>6 months) to determine its lasting effect on pruritus. Three of these individuals did not have significant pruritus before or after sertraline. Of the seven patients with pruritus, six (86%) recorded a significant reduction or resolution of pruritus in their weekly diaries and also decreased or completely stopped other medications for pruritus. CONCLUSIONS: Sertraline use is associated with an improvement in cholestatic pruritus. This novel observation implies that serotonergic fibers are important in regulating the perception of itch.