Impaction bone grafting of the acetabulum at hip revision using a mix of bone chips and a biphasic porous ceramic bone graft substitute: Good outcome in 43 patients followed for a mean of 2 years

Background and purpose One of the greatest problems of revision hip arthroplasty is dealing with lost bone stock. Good results have been obtained with impaction grafting of allograft bone. However, there have been problems of infection, reproducibility, antigenicity, stability, availability of bone, and cost. Thus, alternatives to allograft have been sought. BoneSave is a biphasic porous ceramic specifically designed for use in impaction grafting. BoneSave is 80% tricalcium phosphate and 20% hydroxyapatite. Previous in vitro and in vivo studies have yielded good results using mixtures of allograft and BoneSave, when compared with allograft alone. This study is the first reported human clinical trial of BoneSave in impaction grafting

Preparation and Characterization of the Extracellular Domain of Human Sid-1

In C. elegans, the cell surface protein Sid-1 imports extracellular dsRNA into the cytosol of most non-neuronal cells, enabling systemic spread of RNA interference (RNAi) throughout the worm. Sid-1 homologs are found in many other animals, although for most a function for the protein has not yet been established. Sid-1 proteins are composed of an N-terminal extracellular domain (ECD) followed by 9–12 predicted transmembrane regions. We developed a baculovirus system to express and purify the ECD of the human Sid-1 protein SidT1. Recombinant SidT1 ECD is glycosylated and spontaneously assembles into a stable and discrete tetrameric structure. Electron microscopy (EM) and small angle x-ray scattering (SAXS) studies reveal that the SidT1 ECD tetramer is a compact, puck-shaped globular particle, which we hypothesize may control access of dsRNA to the transmembrane pore. These characterizations provide inroads towards understanding the mechanism of this unique RNA transport system from structural prospective

The Effect of Interpersonal Psychotherapy and other Psychodynamic Therapies versus ‘Treatment as Usual’ in Patients with Major Depressive Disorder

Major depressive disorder afflicts an estimated 17% of individuals during their lifetimes at tremendous suffering and costs. Interpersonal psychotherapy and other psychodynamic therapies may be effective interventions for major depressive disorder, but the effects have only had limited assessment in systematic reviews.Cochrane systematic review methodology with meta-analysis and trial sequential analysis of randomized trials comparing the effect of psychodynamic therapies versus ‘treatment as usual’ for major depressive disorder. To be included the participants had to be older than 17 years with a primary diagnosis of major depressive disorder. Altogether, we included six trials randomizing a total of 648 participants. Five trials assessed ‘interpersonal psychotherapy’ and only one trial assessed ‘psychodynamic psychotherapy’. All six trials had high risk of bias. Meta-analysis on all six trials showed that the psychodynamic interventions significantly reduced depressive symptoms on the 17-item Hamilton Rating Scale for Depression (mean difference −3.12 (95% confidence interval −4.39 to −1.86;P<0.00001), no heterogeneity) compared with ‘treatment as usual’. Trial sequential analysis confirmed this result.We did not find convincing evidence supporting or refuting the effect of interpersonal psychotherapy or psychodynamic therapy compared with ‘treatment as usual’ for patients with major depressive disorder. The potential beneficial effect seems small and effects on major outcomes are unknown. Randomized trials with low risk of systematic errors and low risk of random errors are needed

The EFF-1A Cytoplasmic Domain Influences Hypodermal Cell Fusions in C. elegans But Is Not Dependent on 14-3-3 Proteins.

BACKGROUND: Regulatory and biophysical mechanisms of cell-cell fusion are largely unknown despite the fundamental requirement for fused cells in eukaryotic development. Only two cellular fusogens that are not of clear recent viral origin have been identified to date, both in nematodes. One of these, EFF-1, is necessary for most cell fusions in Caenorhabditis elegans. Unregulated EFF-1 expression causes lethality due to ectopic fusion between cells not developmentally programmed to fuse, highlighting the necessity of tight fusogen regulation for proper development. Identifying factors that regulate EFF-1 and its paralog AFF-1 could lead to discovery of molecular mechanisms that control cell fusion upstream of the action of a membrane fusogen. Bioinformatic analysis of the EFF-1A isoform\u27s predicted cytoplasmic domain (endodomain) previously revealed two motifs that have high probabilities of interacting with 14-3-3 proteins when phosphorylated. Mutation of predicted phosphorylation sites within these motifs caused measurable loss of eff-1 gene function in cell fusion in vivo. Moreover, a human 14-3-3 isoform bound to EFF-1::GFP in vitro. We hypothesized that the two 14-3-3 proteins in C. elegans, PAR-5 and FTT-2, may regulate either localization or fusion-inducing activity of EFF-1. METHODOLOGY/PRINCIPAL FINDINGS: Timing of fusion events was slightly but significantly delayed in animals unable to produce full-length EFF-1A. Yet, mutagenesis and live imaging showed that phosphoserines in putative 14-3-3 binding sites are not essential for EFF-1::GFP accumulation at the membrane contact between fusion partner cells. Moreover, although the EFF-1A endodomain was required for normal rates of eff-1-dependent epidermal cell fusions, reduced levels of FTT-2 and PAR-5 did not visibly affect the function of wild-type EFF-1 in the hypodermis. CONCLUSIONS/SIGNIFICANCE: Deletion of the EFF-1A endodomain noticeably affects the timing of hypodermal cell fusions in vivo. However, prohibiting phosphorylation of candidate 14-3-3-binding sites does not impact localization of the fusogen. Hypodermal membrane fusion activity persists when 14-3-3 expression levels are reduced

Genetic Polymorphisms in the Hypothalamic Pathway in Relation to Subsequent Weight Change – The DiOGenes Study

BACKGROUND: Single nucleotide polymorphisms (SNPs) in genes encoding the components involved in the hypothalamic pathway may influence weight gain and dietary factors may modify their effects. AIM: We conducted a case-cohort study to investigate the associations of SNPs in candidate genes with weight change during an average of 6.8 years of follow-up and to examine the potential effect modification by glycemic index (GI) and protein intake. METHODS AND FINDINGS: Participants, aged 20-60 years at baseline, came from five European countries. Cases ('weight gainers') were selected from the total eligible cohort (n = 50,293) as those with the greatest unexplained annual weight gain (n = 5,584). A random subcohort (n = 6,566) was drawn with the intention to obtain an equal number of cases and noncases (n = 5,507). We genotyped 134 SNPs that captured all common genetic variation across the 15 candidate genes; 123 met the quality control criteria. Each SNP was tested for association with the risk of being a 'weight gainer' (logistic regression models) in the case-noncase data and with weight gain (linear regression models) in the random subcohort data. After accounting for multiple testing, none of the SNPs was significantly associated with weight change. Furthermore, we observed no significant effect modification by dietary factors, except for SNP rs7180849 in the neuromedin β gene (NMB). Carriers of the minor allele had a more pronounced weight gain at a higher GI (P = 2 x 10⁻⁷). CONCLUSIONS: We found no evidence of association between SNPs in the studied hypothalamic genes with weight change. The interaction between GI and NMB SNP rs7180849 needs further confirmation

The potential utility of B cell-directed biologic therapy in autoimmune diseases

Increasing awareness of the importance of aberrant B cell regulation in autoimmunity has driven the clinical development of novel B cell-directed biologic therapies with the potential to treat a range of autoimmune disorders. The first of these drugs—rituximab, a chimeric monoclonal antibody against the B cell-specific surface marker CD20—was recently approved for treating rheumatoid arthritis in patients with an inadequate response to other biologic therapies. The aim of this review is to discuss the potential use of rituximab in the management of other autoimmune disorders. Results from early phase clinical trials indicate that rituximab may provide clinical benefit in systemic lupus erythematosus, Sjögren’s syndrome, vasculitis, and thrombocytopenic purpura. Numerous case reports and several small pilot studies have also been published reporting the use of rituximab in conditions such as myositis, antiphospholipid syndrome, Still’s disease, and multiple sclerosis. In general, the results from these preliminary studies encourage further testing of rituximab therapy in formalized clinical trials. Based on results published to date, it is concluded that rituximab, together with other B cell-directed therapies currently under clinical development, is likely to provide an important new treatment option for a number of these difficult-to-treat autoimmune disorders

Advances in rheumatology: new targeted therapeutics

Treatment of inflammatory arthritides - including rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis - has seen much progress in recent years, partially due to increased understanding of the pathogenesis of these diseases at the cellular and molecular levels. These conditions share some common mechanisms. Biologic therapies have provided a clear advance in the treatment of rheumatological conditions. Currently available TNF-targeting biologic agents that are licensed for at east one of the above-named diseases are etanercept, infliximab, adalimumab, golimumab, and certolizumab. Biologic agents with a different mechanism of action have also been approved in rheumatoid arthritis (rituximab, abatacept, and tocilizumab). Although these biologic agents are highly effective, there is a need for improved management strategies. There is also a need for education of family physicians and other healthcare professionals in the identification of early symptoms of inflammatory arthritides and the importance of early referral to rheumatologists for diagnosis and treatment. Also, researchers are developing molecules - for example, the Janus kinase inhibitor CP-690550 (tofacitinib) and the spleen tyrosine kinase inhibitor R788 (fostamatinib) - to target other aspects of the inflammatory cascade. Initial trial results with new agents are promising, and, in time, head-to-head trials will establish the best treatment options for patients. The key challenge is identifying how best to integrate these new, advanced therapies into daily practice

Myocardial tagging by Cardiovascular Magnetic Resonance: evolution of techniques--pulse sequences, analysis algorithms, and applications

Cardiovascular magnetic resonance (CMR) tagging has been established as an essential technique for measuring regional myocardial function. It allows quantification of local intramyocardial motion measures, e.g. strain and strain rate. The invention of CMR tagging came in the late eighties, where the technique allowed for the first time for visualizing transmural myocardial movement without having to implant physical markers. This new idea opened the door for a series of developments and improvements that continue up to the present time. Different tagging techniques are currently available that are more extensive, improved, and sophisticated than they were twenty years ago. Each of these techniques has different versions for improved resolution, signal-to-noise ratio (SNR), scan time, anatomical coverage, three-dimensional capability, and image quality. The tagging techniques covered in this article can be broadly divided into two main categories: 1) Basic techniques, which include magnetization saturation, spatial modulation of magnetization (SPAMM), delay alternating with nutations for tailored excitation (DANTE), and complementary SPAMM (CSPAMM); and 2) Advanced techniques, which include harmonic phase (HARP), displacement encoding with stimulated echoes (DENSE), and strain encoding (SENC). Although most of these techniques were developed by separate groups and evolved from different backgrounds, they are in fact closely related to each other, and they can be interpreted from more than one perspective. Some of these techniques even followed parallel paths of developments, as illustrated in the article. As each technique has its own advantages, some efforts have been made to combine different techniques together for improved image quality or composite information acquisition. In this review, different developments in pulse sequences and related image processing techniques are described along with the necessities that led to their invention, which makes this article easy to read and the covered techniques easy to follow. Major studies that applied CMR tagging for studying myocardial mechanics are also summarized. Finally, the current article includes a plethora of ideas and techniques with over 300 references that motivate the reader to think about the future of CMR tagging

Pregnancy-related pelvic girdle pain: an update

A large number of scientists from a wide range of medical and surgical disciplines have reported on the existence and characteristics of the clinical syndrome of pelvic girdle pain during or after pregnancy. This syndrome refers to a musculoskeletal type of persistent pain localised at the anterior and/or posterior aspect of the pelvic ring. The pain may radiate across the hip joint and the thigh bones. The symptoms may begin either during the first trimester of pregnancy, at labour or even during the postpartum period. The physiological processes characterising this clinical entity remain obscure. In this review, the definition and epidemiology, as well as a proposed diagnostic algorithm and treatment options, are presented. Ongoing research is desirable to establish clear management strategies that are based on the pathophysiologic mechanisms responsible for the escalation of the syndrome's symptoms to a fraction of the population of pregnant women