Impact of monopolar radiofrequency energy on subchondral bone viability

The purpose of this study was to analyze the impact of monopolar radiofrequency energy treatment on subchondral bone viability. The femoral grooves of six chinchilla bastard rabbits were exposed bilaterally to monopolar radiofrequency energy for 2, 4 and 8 s, creating a total of 36 defects. An intravital fluorescence bone-labeling technique characterized the process of subchondral bone mineralization within the 3 months following exposure to radiofrequency energy and was analyzed by widefield epifluorescence optical sectioning microscopy using an ApoTome. After 2 s of radiofrequency energy exposure, regular fluorescence staining of the subchondral bone was evident in all samples when compared to untreated areas. The depth of osteonecrosis after 4 and 8 s of radiofrequency energy treatment averaged 126 and 942 µm at 22 days (P < .05; P < .01). The 4 s treatment group showed no osteonecrosis after 44 days whereas the depth of osteonecrosis extended from 519 µm at 44 days (P < .01), to 281 µm at 66 days (P < .01) and to 133 µm at 88 days (P < .05) after 8 s of radiofrequency energy application. Though radiofrequency energy may induce transient osteonecrosis in the superficial zone of the subchondral bone, the results of this study suggest that post-arthroscopic osteonecrosis appears to be of only modest risk given the current clinical application in humans

Current patch test results with the European baseline series and extensions to it from the 'European Surveillance System on Contact Allergy' network, 2007-2008

BACKGROUND: The pattern of contact sensitization to the supposedly most important allergens assembled in the baseline series differs between countries, presumably at least partly because of exposure differences. Objectives. To describe the prevalence of contact sensitization to allergens tested in consecutive patients in the years 2007 and 2008, and to discuss possible differences. METHODS: Data from the 39 departments in 11 European countries comprising the European Surveillance System on Contact Allergy network (www.essca-dc.org) in this period have been pooled and analysed according to common standards. RESULTS: Patch test results with the European baseline series, and country-specific or department-specific additions to it, obtained in 25 181 patients, showed marked international variation. Metals and fragrances are still the most frequent allergens across Europe. Some allergens tested nationally may be useful future additions to the European baseline series, for example methylisothiazolinone, whereas a few long-term components of the European baseline series, namely primin and clioquinol, no longer warrant routine testing. CONCLUSIONS: The present analysis points to 'excess' prevalences of specific contact sensitization in some countries, although interpretation must be cautious if only few, and possibly specialized, centres are representing one country. A comparison as presented may help to target in-depth research into possible causes of 'excess' exposure, and/or consideration of methodological issues, including modifications to the baseline series

Part II, Provider perspectives: should patients be activated to request evidence-based medicine? a qualitative study of the VA project to implement diuretics (VAPID)

<p>Abstract</p> <p>Background</p> <p>Hypertension guidelines recommend the use of thiazide diuretics as first-line therapy for uncomplicated hypertension, yet diuretics are under-prescribed, and hypertension is frequently inadequately treated. This qualitative evaluation of provider attitudes follows a randomized controlled trial of a patient activation strategy in which hypertensive patients received letters and incentives to discuss thiazides with their provider. The strategy prompted high discussion rates and enhanced thiazide-prescribing rates. Our objective was to interview providers to understand the effectiveness and acceptability of the intervention from their perspective, as well as the suitability of patient activation for more widespread guideline implementation.</p> <p>Methods</p> <p>Semi-structured phone interviews were conducted with 21 primary care providers. Interviews were transcribed verbatim and reviewed by the interviewer before being analyzed for content. Interviews were coded, and relevant themes and specific responses were identified, grouped, and compared.</p> <p>Results</p> <p>Of the 21 providers interviewed, 20 (95%) had a positive opinion of the intervention, and 18 of 20 (90%) thought the strategy was suitable for wider use. In explaining their opinions of the intervention, many providers discussed a positive effect on treatment, but they more often focused on the process of patient activation itself, describing how the intervention facilitated discussions by informing patients and making them more pro-active. Regarding effectiveness, providers suggested the intervention worked like a reminder, highlighted oversights, or changed their approach to hypertension management. Many providers also explained that the intervention 'aligned' patients' objectives with theirs, or made patients more likely to accept a change in medications. Negative aspects were mentioned infrequently, but concerns about the use of financial incentives were most common. Relevant barriers to initiating thiazide treatment included a hesitancy to switch medications if the patient was at or near goal blood pressure on a different anti-hypertensive.</p> <p>Conclusions</p> <p>Patient activation was acceptable to providers as a guideline implementation strategy, with considerable value placed on the activation process itself. By 'aligning' patients' objectives with those of their providers, this process also facilitated part of the effectiveness of the intervention. Patient activation shows promise for wider use as an implementation strategy, and should be tested in other areas of evidence-based medicine.</p> <p>Trial registration</p> <p>National Clinical Trial Registry number NCT00265538</p

The capsule polysaccharide structure and biogenesis for non-O1 Vibrio cholerae NRT36S: genes are embedded in the LPS region

BACKGROUND: In V. cholerae, the biogenesis of capsule polysaccharide is poorly understood. The elucidation of capsule structure and biogenesis is critical to understanding the evolution of surface polysaccharide and the internal relationship between the capsule and LPS in this species. V. cholerae serogroup O31 NRT36S, a human pathogen that produces a heat-stable enterotoxin (NAG-ST), is encapsulated. Here, we report the covalent structure and studies of the biogenesis of the capsule in V. cholerae NRT36S. RESULTS: The structure of the capsular (CPS) polysaccharide was determined by high resolution NMR spectroscopy and shown to be a complex structure with four residues in the repeating subunit. The gene cluster of capsule biogenesis was identified by transposon mutagenesis combined with whole genome sequencing data (GenBank accession DQ915177). The capsule gene cluster shared the same genetic locus as that of the O-antigen of lipopolysaccharide (LPS) biogenesis gene cluster. Other than V. cholerae O139, this is the first V. cholerae CPS for which a structure has been fully elucidated and the genetic locus responsible for biosynthesis identified. CONCLUSION: The co-location of CPS and LPS biosynthesis genes was unexpected, and would provide a mechanism for simultaneous emergence of new O and K antigens in a single strain. This, in turn, may be a key element for V. cholerae to evolve new strains that can escape immunologic detection by host populations

Origin and insertion of the medial patellofemoral ligament: a systematic review of anatomy.

PURPOSE: The medial patellofemoral ligament (MPFL) is the major medial soft-tissue stabiliser of the patella, originating from the medial femoral condyle and inserting onto the medial patella. The exact position reported in the literature varies. Understanding the true anatomical origin and insertion of the MPFL is critical to successful reconstruction. The purpose of this systematic review was to determine these locations. METHODS: A systematic search of published (AMED, CINAHL, MEDLINE, EMBASE, PubMed and Cochrane Library) and unpublished literature databases was conducted from their inception to the 3 February 2016. All papers investigating the anatomy of the MPFL were eligible. Methodological quality was assessed using a modified CASP tool. A narrative analysis approach was adopted to synthesise the findings. RESULTS: After screening and review of 2045 papers, a total of 67 studies investigating the relevant anatomy were included. From this, the origin appears to be from an area rather than (as previously reported) a single point on the medial femoral condyle. The weighted average length was 56 mm with an 'hourglass' shape, fanning out at both ligament ends. CONCLUSION: The MPFL is an hourglass-shaped structure running from a triangular space between the adductor tubercle, medial femoral epicondyle and gastrocnemius tubercle and inserts onto the superomedial aspect of the patella. Awareness of anatomy is critical for assessment, anatomical repair and successful surgical patellar stabilisation. LEVEL OF EVIDENCE: Systematic review of anatomical dissections and imaging studies, Level IV

TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions

Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n = 14), with the major allele correlated with later age at death (p = 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n = 75), again finding that the major allele associates with later age at death (p = 0.016), as well as later age at onset (p = 0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease

Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis

Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR, and SPINK1 variants were associated with pancreatitis risk. We now report two significant genome-wide associations identified and replicated at PRSS1-PRSS2 (1×10-12) and x-linked CLDN2 (p < 1×10-21) through a two-stage genome-wide study (Stage 1, 676 cases and 4507 controls; Stage 2, 910 cases and 4170 controls). The PRSS1 variant affects susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous male) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men – male hemizygous frequency is 0.26, female homozygote is 0.07

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development