Correction: Aberrant iPSC-derived human astrocytes in Alzheimer's disease.

The original version of this Article contained an error in Fig. 1, in which a number of incorrect fluorescence images were inadvertently incorporated into the panel. This has been corrected in both the PDF and HTML versions of the Article.

Radiological criteria for atypical features of femur fractures: what we can learn when applied in a clinical study setting.

The paper focuses on the identification of atypical fractures (AFFs). This paper examines the concordance between objective classification and expert subjective review. We believe the paper adds critical information about how to apply the American Society of Bone and Mineral Research (ASBMR) criteria to diagnose AFFs and is of high interest to the field. INTRODUCTION: Assess American Society of Bone and Mineral Research (ASBMR) criteria for identifying atypical femoral fractures (AFFs). METHODS: Two orthopedic surgeons independently evaluated radiographs of 372 fractures, applying ASBMR criteria. We assessed ease of applying ASBMR criteria and whether criteria-based assessment matched qualitative expert assessment. RESULTS: There was up to 27% uncertainty about how to classify specific features. 84% of films were classified similarly for the presence of AFF according to ASBMR criteria; agreement increased to 94% after consensus meeting. Of 37 fractures categorized as AFFs based on ASBMR criteria, 23 (62.2%) were considered AFFs according to expert assessment (not relying on criteria). Only one (0.5%) femoral shaft fracture that did not meet ASBMR criteria was considered an AFF per expert assessment. The number of major ASBMR features present (four vs five) and whether there was periosteal or endosteal thickening ("beaking" or "flaring") played major roles in the discrepancies between ASBMR criteria-based and expert-based determinations. CONCLUSIONS: ASBMR AFF criteria were useful for reviewers but several features were difficult to interpret. Expert assessments did not agree with the ASBMR classification in almost one-third of cases, but rarely identified an AFF when a femoral shaft fracture did not meet ASBMR AFF criteria. Experts identified lateral cortical transverse fracture line and associated new-bone formation along with no or minimal comminution as crucial features necessary for the definition of atypical femoral fractures.

A proposal for an atypical femur fracture treatment and prevention clinical practice guideline.

The prevention as well as the treatment of atypical femur fractures (AFFs) remains controversial but there have been many clinical recommendations suggested. We have summarized these recommendations as well as expanded upon them in this paper. INTRODUCTION: The purpose of the paper was to develop a clinical practice guideline that both treats AFF and decreases the risk of AFF in patients requiring antiresorptive medications. Examples of these medications include bisphosphonates and denosumab for the treatment of osteoporosis. METHODS: A literature review looking for recommendations on AFF identification, management, and prevention was done. We also performed an updated review of clinical guidelines on AFF prevention and treatment that were developed for the Kaiser Permanente osteoporosis/fracture prevention team. RESULTS: Concise clinical practice guidelines are presented that can be applied in treatment of AFF as well as help reduce the risk of developing an AFF in patients requiring antiresorptive medications. These guidelines are based on using both typical fracture and AFF risk assessment to determine duration of antiresorptive of 3 to 5 years before consideration if a drug holiday is needed. Specific groups such as younger Asian women should be reassessed at 3 years with DXA and FRAX to see if a drug holiday is needed whereas patients at higher risk for typical fractures may be reassessed at 5 years of treatment. The DXA rescreening can now be accessed if focal or generalized lateral cortex changes are present that may indicate incomplete AFFs are present. If an incomplete AFF is discovered either by DXA or by other imaging studies, it is imperative to stop antiresorptive medications and to take additional measures to lower the risk of progression to a complete AFF. If complete AFF does occur, then antiresorptive medications should be stopped and additional measures should be taken to decrease the risk of developing an AFF on the contralateral femur. CONCLUSIONS: Clinical practice guidelines for the treatment and prevention of AFF will benefit clinicians who are frequently faced with having to make clinical decisions in patients requiring antiresorptive medications.

Aberrant iPSC-derived human astrocytes in Alzheimer's disease.

The pathological potential of human astroglia in Alzheimer's disease (AD) was analysed in vitro using induced pluripotent stem cell (iPSC) technology. Here, we report development of a human iPSC-derived astrocyte model created from healthy individuals and patients with either early-onset familial AD (FAD) or the late-onset sporadic form of AD (SAD). Our chemically defined and highly efficient model provides >95% homogeneous populations of human astrocytes within 30 days of differentiation from cortical neural progenitor cells (NPCs). All astrocytes expressed functional markers including glial fibrillary acidic protein (GFAP), excitatory amino acid transporter-1 (EAAT1), S100B and glutamine synthetase (GS) comparable to that of adult astrocytes in vivo. However, induced astrocytes derived from both SAD and FAD patients exhibit a pronounced pathological phenotype, with a significantly less complex morphological appearance, overall atrophic profiles and abnormal localisation of key functional astroglial markers. Furthermore, NPCs derived from identical patients did not show any differences, therefore, validating that remodelled astroglia are not as a result of defective neural intermediates. This work not only presents a novel model to study the mechanisms of human astrocytes in vitro, but also provides an ideal platform for further interrogation of early astroglial cell autonomous events in AD and the possibility of identification of novel therapeutic targets for the treatment of AD.

Sensitivity and specificity of radiographic characteristics in atypical femoral fractures.

Using the American Society for Bone and Mineral Research Task Force case definition for atypical femoral fractures, sensitivity and specificity of radiographic fracture characteristics were calculated. Fracture pattern was the most sensitive and specific characteristic. This suggests that some characteristics should be weighted more heavily when identifying these fractures. INTRODUCTION: To estimate the sensitivity and specificity of each radiographic criterion in the 2013 ASBMR atypical femoral fracture (AFF) case definition for distinguishing AFF from other subtrochanteric/diaphyseal fractures (non-AFF) among women enrolled in a large integrated health care organization. METHODS: Radiographs from 55 physician-confirmed AFFs and a sample of 39 non-AFFs were reviewed by four independent expert reviewers representing four medical specialties. One image per fracture was selected for review. Using a standardized data collection tool, based on the 2013 AFF case definition, reviewers indicated the presence or absence of the following characteristics viewable on radiograph: fracture pattern, comminution, periosteal and/or endosteal thickening, and cortical thickening. Sensitivity and specificity for each characteristic was calculated for each reviewer and summarized across reviewers with the mean and range. Agreement across reviewers was quantified using Fleiss's kappa (FK) statistic. RESULTS: The most sensitive factors distinguishing AFF from non-AFF were lateral cortex transverse fracture pattern (mean 93.6 %, range 85.5-98.2 %), medial cortex transverse or oblique fracture pattern (mean 84.1 %, range 72.7-98.2 %), and minimal/non-comminution (mean 93.2 %, range 89.1-98.2 %). Specificity was the greatest for lateral cortex transverse fracture pattern (mean 95.5 %, range 92.3-97.4 %). Agreement across reviewers was the highest for lateral cortex transverse fracture pattern (FK 0.83) and incomplete fracture through the lateral cortex only (FK 0.80). CONCLUSION: Lateral cortex transverse fracture pattern was the most sensitive and specific characteristic and the most highly agreed upon across reviewers. Other characteristics were less readily agreed upon across reviewers. Measurement of discrete combinations of individual characteristics may enhance sensitivity and/or specificity.

Ten-year hip fracture incidence rate trends in a large California population, 1997-2006.

UNLABELLED: Hip fractures are a large public health problem with significant negative impact on an individual's overall health and survival. But while the total numbers of persons affected by hip fractures may be anticipated to increase, incidence rates appear to be declining. INTRODUCTION: To describe annual hip fracture incidence rate trends in an integrated health-care organization over 1997-2006, during which a proactive bone health program was initiated program-wide and other secular trends occurred in the population. METHODS: For this ecologic trend study, we identified all men and women ≥45 years old as of January 1 of each year. Incident fractures for each year were identified using ICD-9 diagnosis codes 820-820.9, excluding all subjects who had fractures in prior years. Annual person-time at risk for hip fracture was determined from enrollment data. Sex- and age-specific and adjusted annual incidence rates were calculated. RESULTS: The overall annual hip fracture incidence rate for men declined from 1.52/1,000 person-years in 1997 to 1.29/1,000 person-years in 2006, a 15.3% (95% confidence interval [CI]=6.2-24.5) decrease. For women, incidence declined from 2.65/1,000 person-years in 1997 to 2.24/1,000 person-years in 2006, a 15.3% (95% CI=8.7-21.9) decrease. Among subjects aged 85 years or older, incidence rates for men declined from 27.0/1,000 to 18.9/1,000 person-years, and for women they declined from 32.7/1,000 to 27.1/1,000 person-years. CONCLUSION: Hip fracture incidence has been declining in all age groups over the past 10 years. While many factors may contribute to this decline, the results are consistent with a potential benefit of the active bone health intervention.

Fracture prevention in Kaiser Permanente Southern California.

The Kaiser Permanente Healthy Bones Program has used a systematic approach to address the osteoporosis/fracture care gaps. The article discusses the ten-step processes that utilize information technology and care managers to identify, risk stratify, treat, and then track our patients with care gaps. This program has led to 40+% reduction in the expected number of hip fractures in 2009 that we attribute to the increase in DXA screening followed by appropriate osteoporosis treatment.

Systems-based approaches to osteoporosis and fracture care: policy and research recommendations from the workgroups.

Participants in the conference selected to attend two different working group sessions. The working groups discussed different perspectives of system-based approaches to osteoporosis and fracture care. The group on postfracture case management recommended that nurse case managers be used to improve communication among patients, orthopaedic surgeons, and those providing ongoing clinical care. The hospital working group discussed the impact of and barriers to improved postfracture management in the hospital setting. The health systems group emphasized the difference between a closed system in which long-term benefits of interventions were more likely to be appreciated than in fee for service systems. The health information technology group discussed the advantages and challenges of electronic health records. The working group on consumer and provider education discussed interventions for both primary and secondary prevention of fractures. Recommendations were produced by most groups for improving postfracture care.

Glioma: what is the role of c-Myc, hsp90 and telomerase?

The continuous advancements in cancer research have contributed to the overwhelming evidence of the presence of telomerase in primary and secondary tumours together with hsp90 and c-Myc. This review will discuss the important role of telomerase together with hsp90 and c-Myc within the initiation and progression of gliomas. Also it will review the differential expression of these genes in the different grades of gliomas and the possibility of new treatments targeting these specific genes.

The Autosow raised miniature swine as a model for assessing the effects of dietary soy trypsin inhibitor.

Toxicological effects of dietary soy trypsin inhibitor (TI) were assessed in male miniature swine, a model chosen for its similarities to human digestive physiology and anatomy. The TI preparation was extracted from defatted raw soy flour. From 1 through 5 weeks of age, piglets were automatically fed either a TI liquid diet [Autosow TI group (ASTI)] or a control liquid diet [Autosow control group (ASC)]. From 6 to 39 weeks of age, these animals received either swine chow and TI or swine chow and control article. The TI diets were formulated to contain a TI activity of approximately 500 mg TI/100 g dry matter. A sow control (SC) group suckled from birth to 6 weeks of age and then fed as the ASC group with swine chow plus control article from 6 to 39 weeks of age. The SC piglets grew faster than ASC piglets during postnatal weeks 1 and 2; however, the ASC piglets were significantly heavier than the SC piglets (P=0.001) at 6 weeks of age. Compared with the ASC group, TI caused a moderate decrease in feed consumption and a moderate but reversible decrease in growth from 2 to 5 weeks of age, but not thereafter. Some control and TI-fed Autosow-reared piglets had loose stools until 6 weeks of age; the effect was significantly greater in the TI-fed group. Otherwise, all swine were active and had normal appearance and behavior.

alpha-Dicarbonyls increase in the postprandial period and reflect the degree of hyperglycemia.

OBJECTIVE: Chronic hyperglycemia is known to increase tissue glycation and diabetic complications, but controversy exists regarding the independent role of increased postprandial glucose excursions. To address this question, we have studied the effect of postprandial glycemic excursions (PPGEs) on levels of methylglyoxal (MG) and 3-deoxyglucosone (3-DG), two highly reactive precursors of advanced glycation end products (AGEs). RESEARCH DESIGN AND METHODS: We performed 4-month crossover studies on 21 subjects with type 1 diabetes and compared the effect of premeal insulin lispro or regular insulin on PPGEs and MG/3-DG excursions. PPGE was determined after standard test meal (STMs) and by frequent postprandial glucose monitoring. HbA1c and postprandial MG and D-lactate were measured by HPLC, whereas 3-DG was determined by gas chromatography/mass spectroscopy. RESULTS: Treatment with insulin lispro resulted in a highly significant reduction in PPGEs relative to the regular insulin-treated group (P = 0.0005). However, HbA1c levels were similar in the two groups, and no relationship was observed between HbA1c and PPGE (P = 0.93). Significant postprandial increases in MG, 3-DG, and D-lactate occurred after the STM. Excursions of MG and 3-DG were highly correlated with levels of PPGE (R = 0.55, P = 0.0002 and R = 0.61, P = 0.0004; respectively), whereas a significant inverse relationship was seen between PPGE and D-lactate excursions (R = 0.40, P = 0.01). Conversely, no correlation was observed between HbAlc and postprandial MG, 3-DG, or D-lactate levels. CONCLUSIONS: Increased production of MG and 3-DG occur with greater PPGE, whereas HbA1c does not reflect these differences. Reduced PPGE also leads to increased production of D-lactate, indicating a role for increased detoxification in reducing MG levels. The higher postprandial levels of MG and 3-DG observed with greater PPGE may provide a partial explanation for the adverse effects of glycemic lability and support the value of agents that reduce glucose excursions.

Surgical correction of extensor tendon subluxation and ulnar drift in the rheumatoid hand: long-term results.

Subluxation of the extensor digitorum communis tendons in the rheumatoid hand causes ulnar digital drift. If passively correctable, the digit may be realigned by soft tissue rebalancing and extensor centralization, which may preserve a more functional arc of motion than achieved with arthroplasty. A total of 71 centralization procedures were done in 15 rheumatoid patients with a mean age of 55 years and an average follow-up of 9 years. A distally based central-third strip of extensor tendon was used. Correction of ulnar drift deformity was from an average of 47 degrees preoperatively to 7.9 degrees postoperatively, and correction of active range of motion of the metacarpophalangeal joints was from an average of 38 degrees to 56.2 degrees. Reoperation and complication rates were low. This technique corrects and maintains ulnar drift in the rheumatoid hand. Range of motion at the metacarpophalangeal joint level is improved and converted to a more functional one by decreasing the extensor lag.

Cyclodextrin-modified biosensors: comparision of cyclodextrin-linked ferrocenes as mediators in sol-gel and screen-printed formats for sensing acetylcholine.

This work reports the comparison of a sol-gel and a screen-printed biosensor format using new mediators and a sensitive thin-film (ref. 1: P. Kataky and D. Parker, Analyst, 1996, 121, 1829) to enhance the sensitivity and stability of biosensors. The new mediators were per-alkylated cyclodextrin linked ferrocenes and a control, ferrocene aminocarboxylic acid. The thin film comprised a cocktail with polyurethane, plasticiser, lipophilic anion and a perethylated beta-CD. The analyte targeted was acetylcholine using the established horseradish peroxidase-choline-oxidase-acetylcholine esterase relay. The screen-printed electrode format showed a marked decrease in oxidation potential, the magnitude of the shift depended on the structure of the mediator and the membrane covering. Although lower oxidation-potentials were observed with the sol-gel format sensors, their response was more akin to aqueous solution behaviour. Electrocatalytic currents were observed suggesting a highly efficient electron transfer process.

Anaesthesia for strabismus surgery: a regional survey.

An increase in the demand by local surgeons for neuromuscular block during strabismus surgery, and the forced duction test in particular, led us to review the literature and conduct a regional survey of anaesthetic techniques used. A questionnaire was distributed to 379 anaesthetists in the region and 264 responses were received. The results demonstrated that 55% of paediatric patients and 66% of adult patients may have been operated on under suboptimal conditions; residual tone may have been present in the extraocular muscles during forced duction testing and strabismus correction.