The use of PRP injections in the management of knee osteoarthritis.

Osteoarthritis (OA) is a degenerative disease involving joint damage, an inadequate healing response and progressive deterioration of the joint architecture that commonly affects the knee and/or hip joints. It is a major world public health problem and is predicted to increase rapidly with an ageing population and escalating rate of obesity. Autologous blood-derived products possess much promise in the repair and regeneration of tissue and have important roles in inflammation, angiogenesis, cell migration and metabolism in pathological conditions, including OA. Utilising platelet-rich plasma (PRP) to treat tendon, ligament and skeletal muscle has shown variable results across many studies with the current evidence base for the efficacy of PRP in treating sports injuries remaining inconclusive. More uniformly positive results have been observed by various studies for PRP in OA knee in comparison to hyaluronic acid, other intra-articular injections and placebo than in other musculoskeletal tissue. However, methodological concerns as well as satisfactory PRP product classification prevent the true characterisation of this treatment. Thus, further research is required to investigate how leukocyte inclusion, activation and platelet concentration affect therapeutic efficacy. Furthermore, the optimisation of timing, dosage, volume, frequency and rehabilitation strategies need to be ascertained. For knee OA management, these concerns must be addressed before this promising treatment can be widely implemented

Growing old, yet staying young: The role of telomeres in bats' exceptional longevity

Understanding aging is a grand challenge in biology. Exceptionally long-lived animals have mechanisms that underpin extreme longevity. Telomeres are protective nucleotide repeats on chromosome tips that shorten with cell division, potentially limiting life span. Bats are the longest-lived mammals for their size, but it is unknown whether their telomeres shorten. Using >60 years of cumulative mark-recapture field data, we show that telomeres shorten with age inRhinolophus ferrumequinumandMiniopterus schreibersii, but not in the bat genus with greatest longevity,Myotis. As in humans, telomerase is not expressed inMyotis myotisblood or fibroblasts. Selection tests on telomere maintenance genes show thatATMandSETX, which repair and prevent DNA damage, potentially mediate telomere dynamics inMyotisbats. Twenty-one telomere maintenance genes are differentially expressed inMyotis, of which 14 are enriched for DNA repair, and 5 for alternative telomere-lengthening mechanisms. We demonstrate how telomeres, telomerase, and DNA repair genes have contributed to the evolution of exceptional longevity inMyotisbats, advancing our understanding of healthy aging

Role of Factor VII in Correcting Dilutional Coagulopathy and Reducing Re-operations for Bleeding Following Non-traumatic Major Gastrointestinal and Abdominal Surgery

Objective The objective of this study is to evaluate the effectiveness of rfVIIa in reducing blood product requirements and re-operation for postoperative bleeding after major abdominal surgery. Background Hemorrhage is a significant complication after major gastrointestinal and abdominal surgery. Clinically significant bleeding can lead to shock, transfusion of blood products, and re-operation. Recent reports suggest that activated rfVIIa may be effective in correcting coagulopathy and decreasing the need for re-operation. Methods This study was a retrospective review over a 4-year period of 17 consecutive bleeding postoperative patients who received rfVIIa to control hemorrhage and avoid re-operation. Outcome measures were blood and clotting factor transfusions, deaths, thromboembolic complications, and number of re-operations for bleeding. Results Seventeen patients with postoperative hemorrhage following major abdominal gastrointestinal surgery (nine pancreas, four sarcoma, two gastric, one carcinoid, and one fistula) were treated with rfVIIa. In these 17 patients, rfVIIa was administered for 18 episodes of bleeding (dose 2,400-9,600 mcg, 29.8-100.8 mcg/kg). Transfusion requirement of pRBC and FFP were each significantly less than pre-rfVIIa. Out of the 18 episodes, bleeding was controlled in 17 (94%) without surgery, and only one patient returned to the operating room for hemorrhage. There were no deaths and two thrombotic complications. Coagulopathy was corrected by rfVIIa from 1.37 to 0.96 (p<0.0001). Conclusion Use of rfVIIa in resuscitation for hemorrhage after non-traumatic major abdominal and gastrointestinal surgery can correct dilutional coagulopathy, reducing blood product requirements and need for re-operation

Genome-wide linkage scan for colorectal cancer susceptibility genes supports linkage to chromosome 3q

Background: Colorectal cancer is one of the most common causes of cancer-related mortality. The disease is clinically and genetically heterogeneous though a strong hereditary component has been identified. However, only a small proportion of the inherited susceptibility can be ascribed to dominant syndromes, such as Hereditary Non-Polyposis Colorectal Cancer (HNPCC) or Familial Adenomatous Polyposis (FAP). In an attempt to identify novel colorectal cancer predisposing genes, we have performed a genome-wide linkage analysis in 30 Swedish non-FAP/non-HNPCC families with a strong family history of colorectal cancer.Methods: Statistical analysis was performed using multipoint parametric and nonparametric linkage.Results: Parametric analysis under the assumption of locus homogeneity excluded any common susceptibility regions harbouring a predisposing gene for colorectal cancer. However, several loci on chromosomes 2q, 3q, 6q, and 7q with suggestive linkage were detected in the parametric analysis under the assumption of locus heterogeneity as well as in the nonparametric analysis. Among these loci, the locus on chromosome 3q21.1- q26.2 was the most consistent finding providing positive results in both parametric and nonparametric analyses Heterogeneity LOD score (HLOD) = 1.90, alpha = 0.45, Non-Parametric LOD score (NPL) = 2.1).Conclusion: The strongest evidence of linkage was seen for the region on chromosome 3. Interestingly, the same region has recently been reported as the most significant finding in a genome-wide analysis performed with SNP arrays; thus our results independently support the finding on chromosome 3q

A Cluster Randomised Trial Introducing Rapid Diagnostic Tests into Registered Drug Shops in Uganda: Impact on Appropriate Treatment of Malaria

Background: Inappropriate treatment of malaria is widely reported particularly in areas where there is poor access to health facilities and self-treatment of fevers with anti-malarial drugs bought in shops is the most common form of care-seeking. The main objective of the study was to examine the impact of introducing rapid diagnostic tests for malaria (mRDTs) in registered drug shops in Uganda, with the aim to increase appropriate treatment of malaria with artemisinin-based combination therapy (ACT) in patients seeking treatment for fever in drug shops. Methods: A cluster-randomized trial of introducing mRDTs in registered drug shops was implemented in 20 geographical clusters of drug shops in Mukono district, central Uganda. Ten clusters were randomly allocated to the intervention (diagnostic confirmation of malaria by mRDT followed by ACT) and ten clusters to the control arm (presumptive treatment of fevers with ACT). Treatment decisions by providers were validated by microscopy on a reference blood slide collected at the time of consultation. The primary outcome was the proportion of febrile patients receiving appropriate treatment with ACT defined as: malaria patients with microscopically-confirmed presence of parasites in a peripheral blood smear receiving ACT or rectal artesunate, and patients with no malaria parasites not given ACT. Findings: A total of 15,517 eligible patients (8672 intervention and 6845 control) received treatment for fever between January-December 2011. The proportion of febrile patients who received appropriate ACT treatment was 72·9% versus 33·7% in the control arm; a difference of 36·1% (95% CI: 21·3 – 50·9), p<0·001. The majority of patients with fever in the intervention arm accepted to purchase an mRDT (97·8%), of whom 58·5% tested mRDT-positive. Drug shop vendors adhered to the mRDT results, reducing over-treatment of malaria by 72·6% (95% CI: 46·7– 98·4), p<0·001) compared to drug shop vendors using presumptive diagnosis (control arm). Conclusion: Diagnostic testing with mRDTs compared to presumptive treatment of fevers implemented in registered drug shops substantially improved appropriate treatment of malaria with ACT

5-Hydroxytryptamine Modulates Migration, Cytokine and Chemokine Release and T-Cell Priming Capacity of Dendritic Cells In Vitro and In Vivo

Beside its well described role in the central and peripheral nervous system 5-hydroxytryptamine (5-HT), commonly known as serotonin, is also a potent immuno-modulator. Serotoninergic receptors (5-HTR) are expressed by a broad range of inflammatory cell types, including dendritic cells (DCs). In this study, we aimed to further characterize the immuno-biological properties of serotoninergic receptors on human monocyte-derived DCs. 5-HT was able to induce oriented migration in immature but not in LPS-matured DCs via activation of 5-HTR1 and 5-HTR2 receptor subtypes. Accordingly, 5-HT also increased migration of pulmonary DCs to draining lymph nodes in vivo. By binding to 5-HTR3, 5-HTR4 and 5-HTR7 receptors, 5-HT up-regulated production of the pro-inflammatory cytokine IL-6. Additionally, 5-HT influenced chemokine release by human monocyte-derived DCs: production of the potent Th1 chemoattractant IP-10/CXCL10 was inhibited in mature DCs, whereas CCL22/MDC secretion was up-regulated in both immature and mature DCs. Furthermore, DCs matured in the presence of 5-HT switched to a high IL-10 and low IL-12p70 secreting phenotype. Consistently, 5-HT favoured the outcome of a Th2 immune response both in vitro and in vivo. In summary, our study shows that 5-HT is a potent regulator of human dendritic cell function, and that targeting serotoninergic receptors might be a promising approach for the treatment of inflammatory disorders

The Max b-HLH-LZ Can Transduce into Cells and Inhibit c-Myc Transcriptional Activities

The inhibition of the functions of c-Myc (endogenous and oncogenic) was recently shown to provide a spectacular therapeutic index in cancer mouse models, with complete tumor regression and minimal side-effects in normal tissues. This was achieved by the systemic and conditional expression of omomyc, the cDNA of a designed mutant of the b-HLH-LZ of c-Myc named Omomyc. The overall mode of action of Omomyc consists in the sequestration of Max and the concomitant competition of the Omomyc/Max complex with the endogenous c-Myc/Max heterodimer. This leads to the inhibition of the transactivation of Myc target genes involved in proliferation and metabolism. While this body of work has provided extraordinary insights to guide the future development of new cancer therapies that target c-Myc, Omomyc itself is not a therapeutic agent. In this context, we sought to exploit the use of a b-HLH-LZ to inhibit c-Myc in a cancer cell line in a more direct fashion. We demonstrate that the b-HLH-LZ domain of Max (Max*) behaves as a bona fide protein transduction domain (PTD) that can efficiently transduce across cellular membrane via through endocytosis and translocate to the nucleus. In addition, we show that the treatment of HeLa cells with Max* leads to a reduction of metabolism and proliferation rate. Accordingly, we observe a decrease of the population of HeLa cells in S phase, an accumulation in G1/G0 and the induction of apoptosis. In agreement with these phenotypic changes, we show by q-RT-PCR that the treatment of HeLa cells with Max* leads to the activation of the transcription c-Myc repressed genes as well as the repression of the expression of c-Myc activated genes. In addition to the novel discovery that the Max b-HLH-LZ is a PTD, our findings open up new avenues and strategies for the direct inhibition of c-Myc with b-HLH-LZ analogs

Tissue-Specific Target Analysis of Disease-Associated MicroRNAs in Human Signaling Pathways

MicroRNAs are a large class of post-transcriptional regulators that bind to the 3′ untranslated region of messenger RNAs. They play a critical role in many cellular processes and have been linked to the control of signal transduction pathways. Recent studies indicate that microRNAs can function as tumor suppressors or even as oncogenes when aberrantly expressed. For more general insights of disease-associated microRNAs, we analyzed their impact on human signaling pathways from two perspectives. On a global scale, we found a core set of signaling pathways with enriched tissue-specific microRNA targets across diseases. The function of these pathways reflects the affinity of microRNAs to regulate cellular processes associated with apoptosis, proliferation or development. Comparing cancer and non-cancer related microRNAs, we found no significant differences between both groups. To unveil the interaction and regulation of microRNAs on signaling pathways locally, we analyzed the cellular location and process type of disease-associated microRNA targets and proteins. While disease-associated proteins are highly enriched in extracellular components of the pathway, microRNA targets are preferentially located in the nucleus. Moreover, targets of disease-associated microRNAs preferentially exhibit an inhibitory effect within the pathways in contrast to disease proteins. Our analysis provides systematic insights into the interaction of disease-associated microRNAs and signaling pathways and uncovers differences in cellular locations and process types of microRNA targets and disease-associated proteins

Genetic linkage analysis in the age of whole-genome sequencing

For many years, linkage analysis was the primary tool used for the genetic mapping of Mendelian and complex traits with familial aggregation. Linkage analysis was largely supplanted by the wide adoption of genome-wide association studies (GWASs). However, with the recent increased use of whole-genome sequencing (WGS), linkage analysis is again emerging as an important and powerful analysis method for the identification of genes involved in disease aetiology, often in conjunction with WGS filtering approaches. Here, we review the principles of linkage analysis and provide practical guidelines for carrying out linkage studies using WGS data

A Framework for Exploring Functional Variability in Olfactory Receptor Genes

BACKGROUND: Olfactory receptors (ORs) are the largest gene family in mammalian genomes. Since nearly all OR genes are orphan receptors, inference of functional similarity or differences between odorant receptors typically relies on sequence comparisons. Based on the alignment of entire coding region sequence, OR genes are classified into families and subfamilies, a classification that is believed to be a proxy for OR gene functional variability. However, the assumption that overall protein sequence diversity is a good proxy for functional properties is untested. METHODOLOGY: Here, we propose an alternative sequence-based approach to infer the similarities and differences in OR binding capacity. Our approach is based on similarities and differences in the predicted binding pockets of OR genes, rather than on the entire OR coding region. CONCLUSIONS: Interestingly, our approach yields markedly different results compared to the analysis based on the entire OR coding-regions. While neither approach can be tested at this time, the discrepancy between the two calls into question the assumption that the current classification reliably reflects OR gene functional variability