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To investigate the role of endogenous TSG-6 in human osteoarthritis (OA) and assess the disease-modifying potential of a TSG-6-based biological treatment in cell, explant and animal models of OA. Knee articular cartilages from OA patients were analyzed for TSG-6 protein and mRNA expression using immunohistochemistry and RNAscope, respectively. The inhibitory activities of TSG-6 and its isolated Link module (Link_TSG6) on cytokine-induced degradation of OA cartilage explants were compared. Human mesenchymal stem/stromal cell-derived chondrocyte pellet cultures were used to determine the effects of Link_TSG6 and full-length TSG-6 on IL-1α-, IL-1β-, or TNF-stimulated ADAMTS4 , ADAMTS5 , and MMP13 mRNA expression. Link_TSG6 was administered i.a. to the rat ACLTpMMx model; cartilage damage and tactile allodynia were assessed. TSG-6 is predominantly associated with chondrocytes in regions of cartilage damage where high TSG-6 expression aligns with low MMP13, the major collagenase implicated in OA progression. Link_TSG6 is more potent than full-length TSG-6 at inhibiting cytokine-mediated matrix breakdown in human OA cartilage explants;>50% of donor cartilages, from 59 tested, were responsive to Link_TSG6 treatment. Link_TSG6 also displayed more potent effects in 3D pellet cultures, suppressing ADAMTS4 , ADAMTS5 , and MMP13 gene expression, which was consistent with reduced aggrecanase and collagenase activities in explant cultures. Link_TSG6 treatment reduced touch-evoked pain behavior and dose-dependently inhibited cartilage damage in a rodent model of surgically-induced OA. Link_TSG6 has enhanced chondroprotective activity compared to the full-length TSG-6 protein and shows potential as a disease modifying OA drug via its inhibition of aggrecanase and collagenase activity. [ABSTRACT FROM AUTHOR]

Background: Following debridement of infected prostheses that require reconstruction with an endoprosthetic replacement (EPR), instability related to segmental residual bone defects present a challenge in management with 2-stage reimplantation.Methods: We retrospectively reviewed all patients treated for revision total joint or endoprosthetic infection at the knee from 1998 to 2018. At our institution, patients with skeletal defects >6 cm following explant of prosthesis and debridement (stage 1) were managed with intramedullary nail-stabilized antibiotic spacers. Following stage 1, antimicrobial therapy included 6 weeks of intravenous antibiotics and a minimum of 6 weeks of oral antibiotics. Following resolution of inflammatory markers and negative tissue cultures, reimplantation (stage 2) of an EPR was performed.Results: Twenty-one patients at a mean age of 54 ± 21 years were treated for prosthetic joint infection at the knee. Polymicrobial growth was detected in 38% of cases, followed by coagulase-negative staphylococci (24%) and Staphylococcus aureus (19%). Mean residual skeletal defect after stage 1 treatment was 20 cm. Prosthetic joint infection eradication was achieved in 18 (86%) patients, with a mean Musculoskeletal Tumor Society score of 77% and mean knee range of motion of 100°. Patients with polymicrobial infections had a greater number of surgeries prior to infection (P = .024), and were more likely to require additional debridement prior to EPR (odds ratio 12.0, P = .048).Conclusion: Management of large segmental skeletal defects at the knee following explant using intramedullary stabilized antibiotic spacers maintain stability and result in high rates of limb salvage with conversion to an endoprosthesis. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic has redefined global health care. With almost 13 million confirmed cases worldwide, medical professionals have been forced to modify their practice to take care of an expanded, critically ill population. Institutions have been challenged to implement innovative ways to maximize the utility and the safety of residents and personnel. Guided by lessons learned from prior mass causalities, wars, and previous pandemics, adjustments have been made in order to provide optimal care for all patients while still protecting limited resources and the lives of health care workers. Specialists who are trained in the management of lethal aspects of this disease continue to have a high demand and obvious role. Orthopedic surgeons, with ill-defined roles, have been redeployed to manage complex medical problems. Still, the need to manage trauma, fractures, infections, tumors, and dislocations remains a necessity. Various innovative measures have been taken to maximize the utility and safety of residents in the inpatient and outpatient setting. Commonalities to most measures and distinct changes in practice philosophy can be identified and applied to both current and future pandemic responses. [ABSTRACT FROM AUTHOR]

Ganglion cysts are among the most common benign soft tissue masses. Although surgery has been shown to be effective, ∼12% to 42% of cases with long-term follow-up have been reported to recur. The purpose of this study was to determine the impact of the topical application of mitomycin C used as an adjuvant to surgery on recurrence rate of ganglion cysts. A retrospective analysis was done on all patients surgically treated by 1 surgeon for ganglion cysts. The primary end point was local recurrence after the procedure, determined clinically and by ultrasound. Secondary outcomes included wound complication rate, adverse effects, and overall patient satisfaction. A total of 98 consecutive patients were included in this study and assigned to a study group in a nonrandomized manner. The control group (n = 52) consisted of patients who underwent surgical resection only. The study group (n = 46) consisted of patients who underwent surgical resection with application of topical mitomycin C. No patients were lost to follow-up. Of the 52 patients in the control group, 13 (25.0%) had recurrence of the ganglion cyst. In contrast, in the experimental study group, 2 patients (4.3%) had a recurrence. There was no difference in superficial wound infections between the 2 groups. In this study, we found that the use of topical mitomycin C as an adjuvant to surgical resection significantly reduced the recurrence rate. Wound infection and overall nonrecurrence complication rates were similar to those of other studies. [ABSTRACT FROM AUTHOR]

Abstract: The current study investigates the pharmacotherapeutic use of morphine as a preventative treatment for stress-enhanced fear learning, an animal model that closely mimics symptoms of post-traumatic stress disorder (PTSD). PTSD is a chronic and debilitating anxiety disorder characterized by exaggerated fear and/or anxiety that may develop as a result of exposure to a traumatic event. In this model, rats are exposed to a severe stressor (15foot shocks) in one environment (Context A) and then subsequently exposed to a milder form of the same stressor (single foot shock) in a different environment (Context B). Animals that did not receive prior shock treatment exhibit fear responsiveness to Context B in line with the severity of the single shock given in this context. Animals that had received prior shock treatment in Context A exhibit an exaggerated learned fear response to Context B. Furthermore, animals receiving a single dose of morphine immediately following the severe stressor in Context A continue to show an enhanced fear response in Context B. However, animals receiving repeated morphine administration (three injections) after exposure to the severe stressor in Context A or a single dose of morphine at 48h after the severe stressor no longer exhibit an enhancement in fear learning to Context B. These results are consistent with clinical studies suggesting that morphine treatment following a severe stressor may be useful in preventing or reducing the severity of PTSD in at-risk populations. [Copyright &y& Elsevier]

Abstract: NHC-promoted O- to C-carboxyl transfer of 3-allyl indolyl phenyl carbonates generates 3-allyl-3-phenoxycarbonyl-oxindoles with good catalytic efficiency, which are readily converted into (±)-N-benzyl-coerulescine and (±)-horsfiline. [Copyright &y& Elsevier]

Abstract: Sounds, whether speech or non-speech, vary in how rapidly their peak amplitudes are reached. The time taken for sounds to reach their maximum amplitude is known as the rise time and this variable is an important perceptual cue for representation of the sound amplitude envelope. In the experiments described here healthy adult volunteers passively listened to tones varying in rise time. An oddball design was used and both N1 and MMN components were examined. Experiment 1 contrasted tone stimuli of 15 ms vs. 185 ms rise time. The shorter 15 ms rise time stimuli elicited an N1b over central frontal electrodes of significantly greater amplitude than the 185 ms rise time stimuli. MMN was also observable for both the 15 ms and 185 ms rise time tones when the same stimuli served as deviant vs. standard. Experiment 2 explored the possible confound of rise time and overall stimulus intensity change (tones with shorter rise times sound louder). New stimuli were created in which overall stimulus intensity between short and long rise times was perceptually matched. N1b amplitude differences to the contrastive rise times were still observed, suggesting that N1b may reflect an auditory cortex detector mechanism sensitive to changes in rise time, relatively independently of sound intensity changes. These findings are discussed with reference to their implications for speech perception processes. [Copyright &y& Elsevier]

Background: Mobilization of hemopoietic progenitor cells from the bone marrow (BM) is a feature of inflammatory asthmatic responses. Understanding the mechanisms regulating progenitor cell mobilization and trafficking to the peripheral circulation might be important for the development of effective asthma therapies. Objective: We investigated the role of adhesion molecules in the mobilization of hemopoietic progenitor cells from the BM during an allergen-induced asthmatic response. Methods: BM and peripheral blood samples were obtained from dual-responders with mild asthma before and at several time points after allergen challenge. Fluctuations in expression and adhesive properties of β1- and β2-integrins on CD34+CD45+ progenitor cells were assessed by using flow cytometry and adhesion to protein-coated wells, respectively. Results: On BM-derived CD34+CD45+ cells, expression of very late antigen (VLA) 4, but not VLA-5 or Mac-1, decreased significantly 24 hours after allergen challenge and had begun to recover by 48 hours after challenge. In peripheral blood allergen challenge induced a significant decrease in VLA-4 levels after 6 hours, which had not recovered by 96 hours after challenge. Similarly, VLA-5 expression decreased, most prominently at 72 to 96 hours after allergen challenge. In contrast, Mac-1 levels did not change. Chemokine-stimulated adhesion of BM-derived CD34+CD45+ cells to fibronectin was significantly attenuated 24 hours after challenge. Furthermore, adhesion to fibronectin and vascular cell adhesion molecule 1 was greatly reduced by anti-VLA-4 or anti-VLA-5 antibodies. Conclusions: Preferential downregulation of β1-integrin expression on progenitor cells can reduce the tethering forces to BM components, thus facilitating their egress to the peripheral circulation during an allergic inflammatory response. [Copyright &y& Elsevier]

Abstract: Potential links between the language and motor systems in the brain have long attracted the interest of developmental psychologists. In this paper, we investigate a link often observed (e.g., [Wolff, P.H., 2002. Timing precision and rhythm in developmental dyslexia. Reading and Writing, 15 (1), 179–206.] between motor tapping and written language skills. We measure rhythmic finger tapping (paced by a metronome beat versus unpaced) and motor dexterity, phonological and auditory processing in 10-year old children, some of whom had a diagnosis of developmental dyslexia. We report links between paced motor tapping, auditory rhythmic processing and written language development. Motor dexterity does not explain these relationships. In regression analyses, paced finger tapping explained unique variance in reading and spelling. An interpretation based on the importance of rhythmic timing for both motor skills and language development is proposed. [Copyright &y& Elsevier]

Initial confirmatory factor analyses showed that parental ratings of 209 children and youth with dyslexia in a family genetics study loaded onto factors for Inattention (Self-Regulation of Covert Attention based on two indicators—Focused and Goal-Directed Attention) and Hyperactivity (Overt Behavior based on two indicators—Motor Control and Inhibition); neither indicator is correlated with age. Structural equation modeling then evaluated a multi-level neural architecture with Covert Attention and Overt Behavior at one level, Word-Level Language Processes (Orthographic, Phonological, and Rapid Automatic Naming) at a second level, and Reading and Writing Achievement at a third level. Covert Attention, but not Overt Behavior, was significantly related to factors for orthographic coding of written words and rapid naming of orthographic stimuli, but not to the phonological coding factor for aural words. These orthographic, rapid naming, and phonological factors had significant paths to reading and writing outcomes, but the Covert Attention factor had links to reading and writing outcomes only through the mediating orthographic and rapid naming factors. Treatment and brain imaging studies provided converging evidence that attention may exert greater effects on orthographic word form than phonological word form. The neurolinguistic significance for a complex brain system, modeled at different levels of analysis, is that non-language processes such as attention may exert distal influences even though language exerts direct proximal influences on reading and writing outcomes; this claim is supported by recent physiological findings about the role of fast visual system as an attention gating mechanism in processing letter sequences. The educational significance is that instruction should direct dyslexic's attention to the orthographic units within written words to facilitate the translating of orthographic into phonological word forms. [ABSTRACT FROM AUTHOR]

Abstract: The present experiments demonstrate that children as young as five years old (M =5:2) generalize beyond their input on the basis of minimal exposure to a novel argument structure construction. The novel construction that was used involved a non-English phrasal pattern: VN1N2, paired with a novel abstract meaning: N2 approaches N1. At the same time, we find that children are keenly sensitive to the input: they show knowledge of the construction after a single day of exposure but this grows stronger after 3days; also, children generalize more readily to new verbs when the input contains more than one verb. [Copyright &y& Elsevier]

Abstract: Geminiviruses infect a wide range of economically important crop plants. This review covers genetic engineering approaches currently being evaluated for the development of crops resistant to geminiviruses. In the past, most of these have involved pathogen-derived resistance strategies such as the expression of mutant or truncated viral proteins that interfere with virus infection, or transcription of viral RNA sequences that silence the expression of virus genes. Recently, however, alternatives to pathogen-derived resistance have been investigated. These include the use of geminivirus-inducible toxic proteins to kill infected cells, and the expression of DNA binding proteins, peptide aptamers or GroEL homologues that either disrupt geminivirus infections or lessen their harmful effects. Despite moderate successes in the engineering of geminivirus resistance using many of these strategies, no comparative data are available either on the relative merits of different approaches, or on how well the various resistant transgenic plants that have been produced will fare in the field. We anticipate that high geminivirus mutation and recombination rates could seriously undermine the durability of most currently available resistance transgenes. It should, however, be possible to achieve robust transgenic geminivirus resistance either by using mixtures of genes targeting multiple virus processes via multiple mechanisms, or by using “tolerance” genes that alleviate symptoms but do not selectively favour resistance-breaking virus mutants. [Copyright &y& Elsevier]

Abundant evidence from the medical, veterinary, and animal science literature demonstrates that there is substantial room for improvement of the clarity, completeness, and accuracy of reporting of intervention studies. More rigorous reporting guidelines are needed to improve the quality of data available for use in comparisons of outcomes (or meta-analyses) of multiple studies. Because of the diversity of factors that affect reproduction and the complexity of interactions between these, a systematic approach is required to design, conduct, and analyze basic and applied studies of dairy cattle reproduction. Greater consistency, clarity, completeness, and correctness of design and reporting will improve the value of each report and allow for greater depth of evaluation in meta-analyses. Each of these benefits will improve understanding and application of current knowledge and better identify questions that require additional modeling or primary research. The proposed guidelines and checklist will aid in the design, conduct, analysis, and reporting of intervention studies. We propose an adaptation of the REFLECT (Reporting Guidelines for Randomized Controlled Trials for Livestock and Food Safety) statement to provide guidelines and a checklist specific to reporting intervention studies in dairy cattle reproduction. Furthermore, we provide recommendations that will assist investigators to produce studies with greater internal and external validity that can more often be included in systematic reviews and global meta-analyses. Such studies will also assist the development of models to describe the physiology of reproduction. [ABSTRACT FROM AUTHOR]

Clinical trials using vaccine measles virus (MV) as anticancer therapy are already underway. We compared the oncolytic potential of MV in two B-cell malignancies; adult acute lymphoblastic leukemia (ALL, an aggressive leukemia) and chronic lymphocytic leukemia (CLL, an indolent leukemia overexpressing Bcl-2) using patient-derived material. In vitro, distinct cytopathological effects were observed between MV-infected primary ALL and CLL cells, with large multinucleated syncytia forming in ALL cultures compared to minimal cell-to-cell fusion in infected CLL cells. Cell viability and immunoblotting studies confirmed rapid cell death in MV-infected ALL cultures and slower MV oncolysis of CLL cells. In cell lines, overexpression of Bcl-2 diminished MV-induced cell death providing a possible mechanism for the slower kinetic of MV oncolysis in CLL. In vivo, intratumoral MV treatment of established subcutaneous ALL xenografts had striking antitumor activity leading to complete resolution of all tumors. The antitumor activity of MV was also evident in disseminated ALL xenograft models. In summary, both ALL and CLL are targets for MV-mediated lysis albeit with different kinetics. The marked sensitivity of both primary ALL cells and ALL xenografts to MV oncolysis highlights the tremendous potential of MV as a novel replicating-virus therapy for adult ALL. [ABSTRACT FROM AUTHOR]

Abstract: It has been hypothesised that auditory processing may be enhanced in autism spectrum disorders (ASD). We tested auditory discrimination ability in 72 adolescents with ASD (39 childhood autism; 33 other ASD) and 57 IQ and age-matched controls, assessing their capacity for successful discrimination of the frequency, intensity and duration differences in pairs of sounds. At the group level, auditory discrimination ability did not differ between the adolescents with and without ASD. However, we found a subgroup of 20% of individuals in the ASD group who showed ‘exceptional’ frequency discrimination skills (defined as 1.65 SDs above the control mean) and who were characterised by average intellectual ability and delayed language onset. Auditory sensory behaviours (i.e. behaviours in response to auditory sensory input) are common in ASD and we hypothesised that these would relate to auditory discrimination ability. For the ASD group, poor performers on the intensity discrimination task reported more auditory sensory behaviours associated with coping with loudness levels. Conversely, those who performed well on the duration discrimination task reported more auditory sensory behaviours across the full range measured. Frequency discrimination ability did not associate with auditory sensory behaviours. We therefore conclude that (i) enhanced frequency discrimination is present in around 1 in 5 individuals with ASD and may represent a specific phenotype; and (ii) individual differences in auditory discrimination ability in ASD may influence the expression of auditory sensory behaviours by modulating the degree to which sounds are detected or missed in the environment. [Copyright &y& Elsevier]

Abstract: Leaf samples from 155 maize streak virus (MSV)-infected maize plants were collected from 155 farmers’ fields in 23 districts in Uganda in May/June 2005 by leaf-pressing infected samples onto FTA® Classic Cards. Viral DNA was successfully extracted from cards stored at room temperature for 9 months. The diversity of 127 MSV isolates was analysed by PCR-generated RFLPs. Six representative isolates having different RFLP patterns and causing either severe, moderate or mild disease symptoms, were chosen for amplification from FTA cards by bacteriophage ϕ29 DNA polymerase using the TempliPhi™ system. Full-length genomes were inserted into a cloning vector using a unique restriction enzyme site, and sequenced. The 1.3-kb PCR product amplified directly from FTA-eluted DNA and used for RFLP analysis was also cloned and sequenced. Comparison of cloned whole genome sequences with those of the original PCR products indicated that the correct virus genome had been cloned and that no errors were introduced by the ϕ29 polymerase. This is the first successful large-scale application of FTA card technology to the field, and illustrates the ease with which large numbers of infected samples can be collected and stored for downstream molecular applications such as diversity analysis and cloning of potentially new virus genomes. [Copyright &y& Elsevier]