Intrathecal administration of conditioned serum from different species resolves Chemotherapy-Induced neuropathic pain in mice via secretory exosomes.

Chemotherapy-induced peripheral neuropathy (CIPN) is the most prevalent neurological complication of chemotherapy for cancer, and has limited effective treatment options. Autologous conditioned serum (ACS) is an effective biologic therapy used by intra-articular injection for patients with osteoarthritis. However, ACS has not been systematically tested in the treatment of peripheral neuropathies such as CIPN. It has been generally assumed that the analgesic effect of this biologic therapy results from augmented concentrations of anti-inflammatory cytokines and growth factors. Here we report that a single intrathecal injection of human conditioned serum (hCS) produced long-lasting inhibition of paclitaxel chemotherapy-induced neuropathic pain (mechanical allodynia) in mice, without causing motor impairment. Strikingly, the analgesic effect of hCS in our experiments was maintained even 8 weeks after the treatment, compared with non-conditioned human serum (hNCS). Furthermore, the hCS transfer-induced pain relief in mice was fully recapitulated by rat or mouse CS transfer to mice of both sexes, indicating cross-species and cross-sex effectiveness. Mechanistically, CS treatment blocked the chemotherapy-induced glial reaction in the spinal cord and improved nerve conduction. Compared to NCS, CS contained significantly higher concentrations of anti-inflammatory and pro-resolving mediators, including IL-1Ra, TIMP-1, TGF-ß1, and resolvins D1/D2. Intrathecal injection of anti-TGF-ß1 and anti-Il-1Ra antibody transiently reversed the analgesic action of CS. Nanoparticle tracking analysis revealed that rat conditioned serum contained a significantly greater number of exosomes than NCS. Importantly, the removal of exosomes by high-speed centrifugation largely diminished the CS-produced pain relief, suggesting a critical involvement of small vesicles (exosomes) in the beneficial effects of CS. Together, our findings demonstrate that intrathecal CS produces a remarkable resolution of neuropathic pain mediated through a combination of small vesicles/exosomes and neuroimmune/neuroglial modulation.

Effectiveness of intra-articular therapies in osteoarthritis: a literature review.

Osteoarthritis is a painful, chronic disease with widespread burden on patients, communities, health and social care systems. Conservative therapies, such as nonpharmacological interventions, systemic drug treatment and intra-articular therapies are used before resorting to surgery; nonetheless, disease control often remains inadequate. Recent advances in osteoarthritis management have aimed to provide greater variety of treatment options. Here, we summarize a targeted literature review evaluating efficacy and safety of intra-articular therapies for osteoarthritis. Injections of intra-articular therapies directly into the joint avoid conventional barriers to joint entry, increase bioavailability and lower systemic toxicity. Intra-articular corticosteroids and hyaluronic acid are established United States Food and Drug Administration (US FDA)/European Medicines Agency (EMA)-approved treatments; however, concerns exist regarding effect duration, safety, effectiveness across populations and heterogeneity. Newer therapies, such as autologous blood products and mesenchymal stem cells, are in development. Benefits of autologous blood products (e.g. platelet-rich plasma, autologous conditioned serum) include an expected improved safety profile and direct targeting of osteoarthritis-related pathophysiology. Autologous conditioned serum is cell-free and manufactured by a standardized process, whereas platelet-rich plasma composition and characteristics can vary. Currently, only limited efficacy comparisons between these biological treatments can be drawn; long-term clinical and safety studies are needed to increase the efficacy evidence base and earn consideration in treatment frameworks.

Autologous Conditioned Serum.

Autologous conditioned serum was developed in the mid 1990s as an expeditious, practical, and relatively inexpensive means of generating the interleukin-1 receptor antagonist, a naturally occurring inhibitor of the cytokine interleukin-1. The latter is thought to be an important mediator of inflammation, pain, and tissue destruction in musculoskeletal conditions. ACS has been widely and successfully used in the local treatment of human and equine osteoarthritis and radicular compression; it has also shown promise in treating tendinopathies, muscle injuries, and tunnel widening after reconstruction of the anterior cruciate ligament. Experience suggests that autologous conditioned serum is safe and effective.

How does surgery compare with advanced intra-articular therapies in knee osteoarthritis: current thoughts.

The objectives of osteoarthritis (OA) management are to reduce pain and inflammation, slow cartilage degradation, improve function and reduce disability. Current strategies for managing knee OA include nonpharmacological interventions, oral pharmacological treatments, localized intra-articular injections, and surgery. It has become evident that the inflammatory response is a key contributor to the development and progression of knee OA. Signaling pathways involving growth factors and cytokines are being investigated for the development of new therapies that target the underlying biological processes causing the disease. This concept of 'molecular orthopedics' enables more patient-centered diagnostic and treatment strategies. In contrast to other conservative therapies, which ultimately only address OA symptoms, intra-articular injections, in particular autologous conditioned serum (ACS), provide benefits that have the potential to outweigh those of established pharmacological treatments and surgery. Surgery has historically been considered the final solution for treatment of knee OA, both by treating physicians and by patients; however, there are increasing concerns regarding the lack of randomized clinical trials providing evidence to support this opinion. Intra-articular injection of ACS has demonstrated efficacy as a treatment for knee OA in a number of studies, with a very low rate of adverse events and side effects, compared with surgery. Treatment with ACS utilizes the release of anti-inflammatory cytokines and regenerative growth factors to support the natural healing processes in the knee, and has the potential to provide a valuable alternative to surgical intervention.

Characterization and mapping of LanrBo: a locus conferring anthracnose resistance in narrow-leafed lupin (Lupinus angustifolius L.).

KEY MESSAGE: A novel and highly effective source of anthracnose resistance in narrow-leafed lupin was identified. Resistance was shown to be governed by a single dominant locus. Molecular markers have been developed, which can be used for selecting resistant genotypes in lupin breeding. A screening for anthracnose resistance of a set of plant genetic resources of narrow-leafed lupin (Lupinus angustifolius L.) identified the breeding line Bo7212 as being highly resistant to anthracnose (Colletotrichum lupini). Segregation analysis indicated that the resistance of Bo7212 is inherited by a single dominant locus. The corresponding resistance gene was given the designation LanrBo. Previously published molecular anchor markers allowed us to locate LanrBo on linkage group NLL-11 of narrow-leafed lupin. Using information from RNAseq data obtained with inoculated resistant vs. susceptible lupin entries as well as EST-sequence information from the model genome Lotus japonicus, additional SNP and EST markers linked to LanrBo were derived. A bracket of two LanrBo-flanking markers allows for precise marker-assisted selection of the novel resistance gene in narrow-leafed lupin breeding programs.

From invited to uninvited participation (and back?): rethinking civil society engagement in technology assessment and development.

In recent years, citizens' and civil society engagement with science and technology has become almost synonymous with participation in institutionally organized formats of participatory technology assessment (pTA) such as consensus conferences or stakeholder dialogues. Contrary to this view, it is argued in the article that beyond these standardized models of "invited" participation, there exist various forms of "uninvited" and independent civil society engagement, which frequently not only have more significant impact but are profoundly democratically legitimate as well. Using the two examples of patient associations and environmental and consumer organizations in the field of nanotechnology, it is illustrated that interest-based civil society interventions do play an important role in the polycentric governance of science and technology. In conclusion, some implications for the activities of TA institutions and the design of novel TA procedures are outlined.

The "technoscientization" of medicine and its limits: technoscientific identities, biosocialities, and rare disease patient organizations.

The fact that the emergence of "technoscience," resulting from the coalescing of science and technology, may have serious social and cultural impact has been debated in recent years particularly with regard to the field of medicine. The present article is exploring the scope and limits of the "technoscientization" of medicine using the example of rare disease patient associations. It is investigated whether and to what extent these organizations adopt technoscientific illness identities and subscribe to the research priorities and objectives of biomedicine. In addition, it is analyzed whether Paul Rabinow's highly influential concept of biosociality entails a technoscientific model of identity or, quite to the contrary, offers a framework for contesting biomedical ascriptions of identities. As the article shows, patient associations do refer to technoscientific definitions of diseases yet constantly modify and transform them based on their everyday illness experiences. Likewise, the "biosociality" of rare disease patients emerges from the shared experience of having been neglected by mainstream medical research rather than from supposedly objective biomedical classifications.

Ryd4 (Hb): a novel resistance gene introgressed from Hordeum bulbosum into barley and conferring complete and dominant resistance to the barley yellow dwarf virus.

Barley yellow dwarf virus (BYDV) causes high yield losses in most of the major cereal crops worldwide. A source of very effective resistance was detected within the tetraploid wild species of Hordeum bulbosum. Interspecific crosses between a resistant H. bulbosum accession and H. vulgare cv. 'Igri' were performed to transfer this resistance into cultivated barley. Backcrosses to H. vulgare resulted in offspring which carried a single subterminal introgression of H. bulbosum chromatin on barley chromosome 3HL and proved to be fully resistant to BYDV-PAV, as inferred by ELISA values of zero or close to zero and lack of BYDV symptoms. Genetic analysis indicated a dominant inheritance of the BYDV-PAV resistance factor, which we propose to denote Ryd4 ( Hb ) . The identity and effect of Ryd4 ( Hb ) are discussed in relation to other known genes for BYDV resistance or tolerance, as well as the relevance of this gene for resistance breeding in barley.

Clinical responses to gene therapy in joints of two subjects with rheumatoid arthritis.

This paper provides the first evidence of a clinical response to gene therapy in human arthritis. Two subjects with rheumatoid arthritis received ex vivo, intraarticular delivery of human interleukin-1 receptor antagonist (IL-1Ra) cDNA. To achieve this, autologous synovial fibroblasts were transduced with a retrovirus, MFG-IRAP, carrying IL-1Ra as the transgene, or remained as untransduced controls. Symptomatic metacarpophalangeal (MCP) joints were injected with control or transduced cells. Joints were clinically evaluated on the basis of pain; the circumference of MCP joint 1 was also measured. After 4 weeks, joints underwent surgical synovectomy. There were no adverse events in either subject. The first subject responded dramatically to gene transfer, with a marked and rapid reduction in pain and swelling that lasted for the entire 4 weeks of the study. Remarkably, joints receiving IL-1Ra cDNA were protected from flares that occurred during the study period. Analysis of RNA recovered after synovectomy revealed enhanced expression of IL-1Ra and reduced expression of matrix metalloproteinase-3 and IL-1beta. The second subject also responded with reduced pain and swelling. Thus, gene transfer to human, rheumatoid joints can be accomplished safely to produce clinical benefit, at least in the short term. Using this ex vivo procedure, the transgene persisted within the joint for at least 1 month. Further clinical studies are warranted.

Autologous conditioned serum in the treatment of orthopedic diseases: the orthokine therapy.

The common strategies for the treatment of patients with orthopedic diseases do not address the underlying pathogenesis. Several biologically based, local therapies aiming to influence the cytokine imbalance are either in development or in the initial stages of clinical use. A method based on exposure of blood leukocytes to pyrogen-free surfaces (e.g. glass spheres) elicits an accumulation of anti-inflammatory cytokines, including interleukin-1 receptor antagonist, and several growth factors, including insulin-like growth factor-1, platelet-derived growth factor, and transforming growth factor-beta(1), in the liquid blood phase. Based on these observations, a new therapy using cell-free, autologous conditioned serum (ACS) from the incubation of whole blood with glass spheres was developed. The injection of ACS into affected tissue(s) has shown clinical effectiveness and safety in animal models and studies, as well as in human clinical studies, for the treatment of osteoarthritis, lumbar stenosis, disc prolapse, and muscle injuries.

GISH analysis of disomic Brassica napus-Crambe abyssinica chromosome addition lines produced by microspore culture from monosomic addition lines.

Two Brassica napus-Crambe abyssinica monosomic addition lines (2n=39, AACC plus a single chromosome from C. abyssinca) were obtained from the F(2) progeny of the asymmetric somatic hybrid. The alien chromosome from C. abyssinca in the addition line was clearly distinguished by genomic in situ hybridization (GISH). Twenty-seven microspore-derived plants from the addition lines were obtained. Fourteen seedlings were determined to be diploid plants (2n=38) arising from spontaneous chromosome doubling, while 13 seedlings were confirmed as haploid plants. Doubled haploid plants produced after treatment with colchicine and two disomic chromosome addition lines (2n=40, AACC plus a single pair of homologous chromosomes from C. abyssinca) could again be identified by GISH analysis. The lines are potentially useful for molecular genetic analysis of novel C. abyssinica genes or alleles contributing to traits relevant for oilseed rape (B. napus) breeding.