Viscosupplementation with High Molecular Weight Hyaluronic Acid for Hip Osteoarthritis: a Systematic Review and Meta-Analysis of Randomised Control Trials of the Efficacy on Pain, Functional Disability, and the Occurrence of Adverse Events.

PURPOSE OF THE STUDY: Hip osteoarthritis (OA) has a prevalence of around 6.4% and is the second most commonly affected joint. This review aims to assess the clinical outcomes of intra-articular high molecular weight hyaluronic acid (HMWHA) in the management of hip osteoarthritis. MATERIAL AND METHODS: We conducted a comprehensive search across PubMed, Google Scholar, and the Cochrane Library for randomised trials investigating the effectiveness of high molecular weight hyaluronic acid (HMWHA) in the treatment of hip osteoarthritis. Quality and risk of bias assessments were performed using the Cochrane RoB2 tool. To synthesise the data, we utilised the Standardised Mean Difference (SMD) for assessing pain relief through the Visual Analogue Scale (VAS) and the Lequesne index (LI) for evaluating functional outcomes. Risk Ratio (RR) was calculated to assess the occurrence of complications. RESULTS: A total of four studies involving HMWHA and control groups were included. The standardised mean difference (SMD) for the Visual Analogue Scale (VAS) (SMD -0.056; 95% CI; -0.351, 0.239; p = 0.709) and the Lequesne index (SMD -0.114; 95% CI; -0.524, 0.296; p = 0.585) were not statistically significant. Analysis for complications demonstrated an overall relative risk ratio (RR) of 0.879 (95% CI; 0.527, 1.466; p = 0.622), and was not statistically significant. DISCUSSION AND CONCLUSIONS: Intra-articular HMWHA in hip OA can significantly reduce pain and improve functional recovery when compared with the condition before treatment. However, there is no significant difference between HMWHA, or saline, or other therapeutic treatments. Currently, available evidence indicates that intra-articular HMWHA in hip OA would not increase the risk of adverse events. KEY WORDS: hip osteoarthritis, hyaluronic acid, intra-articular, molecular weight, viscosupplementation.

First Results from CUORE: A Search for Lepton Number Violation via 0νßß Decay of

The CUORE experiment, a ton-scale cryogenic bolometer array, recently began operation at the Laboratori Nazionali del Gran Sasso in Italy. The array represents a significant advancement in this technology, and in this work we apply it for the first time to a high-sensitivity search for a lepton-number-violating process: ^{130}Te neutrinoless double-beta decay. Examining a total TeO_{2} exposure of 86.3 kg yr, characterized by an effective energy resolution of (7.7±0.5) keV FWHM and a background in the region of interest of (0.014±0.002) counts/(keV kg yr), we find no evidence for neutrinoless double-beta decay. Including systematic uncertainties, we place a lower limit on the decay half-life of T_{1/2}^{0ν}(^{130}Te)>1.3×10^{25} yr (90% C.L.); the median statistical sensitivity of this search is 7.0×10^{24} yr. Combining this result with those of two earlier experiments, Cuoricino and CUORE-0, we find T_{1/2}^{0ν}(^{130}Te)>1.5×10^{25} yr (90% C.L.), which is the most stringent limit to date on this decay. Interpreting this result as a limit on the effective Majorana neutrino mass, we find m_{ßß}<(110-520) meV, where the range reflects the nuclear matrix element estimates employed.

Publisher's Note: Search for Majorana Neutrinos Near the Inverted Mass Hierarchy Region with KamLAND-Zen [Phys. Rev. Lett. 117, 082503 (2016)].

This corrects the article DOI: 10.1103/PhysRevLett.117.082503.

Search for Majorana Neutrinos Near the Inverted Mass Hierarchy Region with KamLAND-Zen.

We present an improved search for neutrinoless double-beta (0νßß) decay of ^{136}Xe in the KamLAND-Zen experiment. Owing to purification of the xenon-loaded liquid scintillator, we achieved a significant reduction of the ^{110m}Ag contaminant identified in previous searches. Combining the results from the first and second phase, we obtain a lower limit for the 0νßß decay half-life of T_{1/2}^{0ν}>1.07×10^{26} yr at 90% C.L., an almost sixfold improvement over previous limits. Using commonly adopted nuclear matrix element calculations, the corresponding upper limits on the effective Majorana neutrino mass are in the range 61-165 meV. For the most optimistic nuclear matrix elements, this limit reaches the bottom of the quasidegenerate neutrino mass region.

Search for Neutrinoless Double-Beta Decay of (130)Te with CUORE-0.

We report the results of a search for neutrinoless double-beta decay in a 9.8 kg yr exposure of (130)Te using a bolometric detector array, CUORE-0. The characteristic detector energy resolution and background level in the region of interest are 5.1±0.3 keV FWHM and 0.058±0.004(stat)±0.002(syst)counts/(keV kg yr), respectively. The median 90% C.L. lower-limit half-life sensitivity of the experiment is 2.9×10(24) yr and surpasses the sensitivity of previous searches. We find no evidence for neutrinoless double-beta decay of (130)Te and place a Bayesian lower bound on the decay half-life, T(1/2)(0ν)>2.7×10(24) yr at 90% C.L. Combining CUORE-0 data with the 19.75 kg yr exposure of (130)Te from the Cuoricino experiment we obtain T(1/2)(0ν)>4.0×10(24) yr at 90% C.L. (Bayesian), the most stringent limit to date on this half-life. Using a range of nuclear matrix element estimates we interpret this as a limit on the effective Majorana neutrino mass, m(ßß)<270-760 meV.

Comparison of ASL and DCE MRI for the non-invasive measurement of renal blood flow: quantification and reproducibility.

OBJECTIVES: To investigate the reproducibility of arterial spin labelling (ASL) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and quantitatively compare these techniques for the measurement of renal blood flow (RBF). METHODS: Sixteen healthy volunteers were examined on two different occasions. ASL was performed using a multi-TI FAIR labelling scheme with a segmented 3D-GRASE imaging module. DCE MRI was performed using a 3D-FLASH pulse sequence. A Bland-Altman analysis was used to assess repeatability of each technique, and determine the degree of correspondence between the two methods. RESULTS: The overall mean cortical renal blood flow (RBF) of the ASL group was 263 ± 41 ml min(-1) [100 ml tissue](-1), and using DCE MRI was 287 ± 70 ml min(-1) [100 ml tissue](-1). The group coefficient of variation (CVg) was 18 % for ASL and 28 % for DCE-MRI. Repeatability studies showed that ASL was more reproducible than DCE with CVgs of 16 % and 25 % for ASL and DCE respectively. Bland-Altman analysis comparing the two techniques showed a good agreement. CONCLUSIONS: The repeated measures analysis shows that the ASL technique has better reproducibility than DCE-MRI. Difference analysis shows no significant difference between the RBF values of the two techniques. KEY POINTS: Reliable non-invasive monitoring of renal blood flow is currently clinically unavailable. Renal arterial spin labelling MRI is robust and repeatable. Renal dynamic contrast-enhanced MRI is robust and repeatable. ASL blood flow values are similar to those obtained using DCE-MRI.

Measurement of muon capture on the proton to 1% precision and determination of the pseudoscalar coupling gP.

The MuCap experiment at the Paul Scherrer Institute has measured the rate Λ(S) of muon capture from the singlet state of the muonic hydrogen atom to a precision of 1%. A muon beam was stopped in a time projection chamber filled with 10-bar, ultrapure hydrogen gas. Cylindrical wire chambers and a segmented scintillator barrel detected electrons from muon decay. Λ(S) is determined from the difference between the µ(-) disappearance rate in hydrogen and the free muon decay rate. The result is based on the analysis of 1.2 × 10(10) µ(-) decays, from which we extract the capture rate Λ(S) = (714.9 ± 5.4(stat) ± 5.1(syst)) s(-1) and derive the proton's pseudoscalar coupling g(P)(q(0)(2) = -0.88 m(µ)(2)) = 8.06 ± 0.55.

Limit on neutrinoless ßß decay of 136Xe from the first phase of KamLAND-Zen and comparison with the positive claim in 76Ge.

We present results from the first phase of the KamLAND-Zen double-beta decay experiment, corresponding to an exposure of 89.5 kg yr of (136)Xe. We obtain a lower limit for the neutrinoless double-beta decay half-life of T(1/2)(0ν)>1.9×10(25) yr at 90% C.L. The combined results from KamLAND-Zen and EXO-200 give T(1/2)(0ν)>3.4×10(25) yr at 90% C.L., which corresponds to a Majorana neutrino mass limit of <(120-250) meV based on a representative range of available matrix element calculations. Using those calculations, this result excludes the Majorana neutrino mass range expected from the neutrinoless double-beta decay detection claim in (76)Ge, reported by a part of the Heidelberg-Moscow Collaboration, at more than 97.5% C.L.

A comprehensive review of current treatments for granulomatous cheilitis.

Granulomatous cheilitis (GC) is a poorly understood disease process belonging to the larger group of orofacial granulomatosis. The treatment of GC has proven exceedingly difficult. While various treatments have been applied to GC, there has been no uniform or predictably successful model demonstrated in the literature. Poor understanding of the aetiological mechanisms underpinning GC has significantly hampered the development of an effective approach to treatment. Those therapies that have shown promise principally consist of agents with anti-inflammatory activity such as corticosteroids and immunomodulatory medications. On a careful review of the literature, we have found no systematic review and assessment of current treatments. We seek to address this absence in the available literature by providing a consolidated overview of current treatment for GC.

Diversity in junctional sequences associated with the common human V gamma 9 and V delta 2 gene segments in normal blood and lung compared with the limited diversity in a granulomatous disease.

The T cell receptor (TCR) junctional regions (N regions) of the common human V gamma 9 and V delta 2 gene segments were sequenced from the blood and lung of normal individuals (195 transcripts) and a group of individuals with sarcoidosis (220 transcripts), a granulomatous disease in which increased numbers of V gamma 9+ gamma/delta + T cells are often observed. In normal individuals, the vast majority (86%) of blood V gamma 9 transcripts used the J gamma P gene segment. In contrast to this restriction of J region usage, there was a large diversity of the junctional region, with less than 20% of blood V gamma 9 junctional regions showing identical sequences for any one normal individual. For the blood V delta 2 transcripts in normal individuals, there was restriction of J region usage, with 93% using J delta 1. The junctional regions were even more diverse than for V gamma 9, with a unique sequence observed in each transcript examined. Compared with blood, sequences from the normal lung showed a small increase in identical junctional regions, particularly in one individual where 46% of V gamma 9 transcripts examined were identical, suggesting a response of some gamma/delta T cells to antigens found in the lung in the normal state. In marked contrast to normals, some individuals with sarcoidosis had large numbers of V gamma 9 transcripts, as well as V delta 2 transcripts, sharing identical sequences. For V gamma 9 blood transcripts, two individuals showed 84 and 56% of junctional region sequences to be identical, respectively. Similarly, blood V delta 2 transcripts showed 43, 33, and 25% identical junctional region sequences in three individuals. In the sarcoid patient with the most striking over-representation of blood V gamma 9 junctional sequences, lung V gamma 9 transcripts showed increased (67%) use of the same junctional region sequence as in blood. This limited diversity of TCR junctional regions among some individuals with sarcoidosis suggests a response from specific stimuli, possibly antigenic, and that gamma/delta T cells may play a specific role in granuloma formation in sarcoidosis, as has been suggested in other granulomatous diseases.

Crucial role of tumor necrosis factor receptor 1 expression on nonhematopoietic cells for B cell localization within the splenic white pulp.

During immune responses the initial activation of B cells takes place in T cell zones of periarteriolar lymphoid sheaths (PALS) of the splenic white pulp. After initial activation, B cells migrate into the primary follicles and, in association with follicular dendritic cells (FDCs), undergo clonal expansion and differentiation giving rise to germinal centers (GCs). Peanut agglutinin binding (PNA+) cells of the GC differentiate further into memory or plasma cells. Here we report that in tumor necrosis factor receptor 1-deficient mice (TNFR1(-/-)), the location of B cells was altered and that plasma cells were abnormally distributed in the splenic PALS. In contrast to lymphotoxin alpha-deficient mice (LTalpha-/-), bone marrow or fetal liver transplantation did not correct the abnormal organization of the spleen, location of B cells, the lack of an FDC network, nor the antibody response in TNFR1(-/-) mice. These results argue for a crucial role of TNFR1 expression on nonhematopoietic cells for the maintenance of the splenic architecture and proper B cell location. In addition, the lack in development of an FDC network after adoptive transfer suggests that either FDCs are not of bone marrow origin or that they depend on signals from nonhematopoietic cells for maturation.

Refining the Genomic Region Containing a Major Locus Controlling Fruit Maturity in Peach.

Maturity date (MD), defined as the duration between the first calendar day of the year and maturity, and fruit development period (FDP), defined as the duration between full bloom and maturity, are highly variable in peach [Prunus persica (L.) Batsch]. There is a need to discover molecular markers associated with these traits in order to enhance the efficiency and reliability of breeding for extending the harvest season in peach. An association mapping population consisting of 132 peach accessions was phenotypically evaluated for MD and FDP, and genotypically characterized using the genotyping-by-sequencing (GBS) approach. The phenotypic and genotypic data collected were used to conduct a genome-wide association study (GWAS). The GWAS identified three SNPs on chromosome 4 that are significantly associated with both FDP and MD. These three SNPs covered a region of 43,067 bp; we referred to this region as the MD/FDP locus. Seven genes were identified in the MD/FDP locus. One or more of these genes is believed to regulate some aspect of maturity in peach. The data reported here is expected to aid in marker-assisted seedling selection (MASS) targeted towards widening peach germplasm for maturity, particularly early maturity.

Skeletal Muscle Metastasis to Vastus Lateralis from a Urothelial Carcinoma: A Case Report and Review of Its Diagnosis and Management.

Bladder cancer is a common genitourinary tract malignancy. Urothelial carcinoma is the most frequent type of bladder cancer and it commonly metastasises to lymph nodes, bone, lung and liver by a haematogenous route. Skeletal metastases are very rare and are usually present in patients with advanced metastatic disease. We present an unusual case of a 71-year-old male with a urothelial carcinoma metastasis to the vastus lateralis muscle 3 months following a cystoprostatectomy for muscle invasive bladder cancer.

Unmasking immune reconstitution inflammatory syndrome: a report of tuberculous epididymo-orchitis mimicking a testicular tumour in a Caucasian AIDS patient.

Worldwide, it is estimated that 14.8% of all new tuberculosis cases in adults are attributable to HIV infection. Genitourinary tuberculosis is a known complication and is considered to be a severe form of extrapulmonary tuberculosis. Isolated tuberculous epididymo-orchitis is rare. We report a Caucasian HIV-positive heterosexual male with a clinical diagnosis of testicular tumour for which he underwent a right orchidectomy. Tuberculous epididymo-orchitis was confirmed by histology. In this case, all Immune Reconstitution Inflammatory Syndrome (IRIS) criteria were met. We want to convey the message that in HIV-positive patients presenting with testicular swelling, an infective aetiology should be considered. This will increase the possibility of early diagnosis and proper management.

Gene targeting of the immune system: the surprises continue.

To date, an impressive number of mutant mice strains have been generated by targeted mutagenesis of the immune system. During the past year, such knockout mice have been particularly valuable in revealing the biological functions of certain cytokines and their receptors, and also in identifying cell surface molecules critical for T-cell activation. Advances in targeting technologies also figure prominently in the accomplishments of the past year, with cell type specific gene targeting representing a major refinement of current methodologies.

Effects of electric fields on human mesenchymal stem cell behaviour and morphology using a novel multichannel device.

The intrinsic piezoelectric nature of collagenous-rich tissues, such as bone and cartilage, can result in the production of small, endogenous electric fields (EFs) during applied mechanical stresses. In vivo, these EFs may influence cell migration, a vital component of wound healing. As a result, the application of small external EFs to bone fractures and cutaneous wounds is actively practiced clinically. Due to the significant regenerative potential of stem cells in bone and cartilage healing, and their potential role in the observed improved healing in vivo post applied EFs, using a novel medium throughput device, we investigated the impacts of physiological and aphysiological EFs on human bone marrow-derived mesenchymal stem cells (hBM-MSCs) for up to 15 hours. The applied EFs had significant impacts on hBM-MSC morphology and migration; cells displayed varying degrees of conversion to a highly elongated phenotype dependent on the EF strength, consistent perpendicular alignment to the EF vector, and definitive cathodal migration in response to EF strengths ≥0.5 V cm(-1), with the fastest migration speeds observed at between 1.7 and 3 V cm(-1). We observed variability in hBM-MSC donor-to-donor responses and overall tolerances to applied EFs. This study thus confirms hBM-MSCs are responsive to applied EFs, and their rate of migration towards the cathode is controllable depending on the EF strength, providing new insight into the physiology of hBM-MSCs and possibly a significant opportunity for the utilisation of EFs in directed scaffold colonisation in vitro for tissue engineering applications or in vivo post implantation.

Increasing expression of the normal human CFTR cDNA in cystic fibrosis epithelial cells results in a progressive increase in the level of CFTR protein expression, but a limit on the level of cAMP-stimulated chloride secretion.

Cystic fibrosis (CF) results from mutations of the CF transmembrane conductance regulator (CFTR) gene and the consequent defective regulation of cAMP-stimulated Cl- permeability across epithelial cell apical membranes. Given that in vitro transfer of normal CFTR cDNA corrects this defect and that recombinant adenovirus (Ad) vectors can transfer the normal human CFTR cDNA in vivo, Ad vectors have significant potential in the development of effective strategies for CF gene therapy. One concern is whether CFTR overexpression achievable with Ad vectors may have untoward effects on cAMP-stimulated Cl- efflux. To address this, the CF pancreatic epithelial cell line CFPAC-1 was infected with increasing doses of AdCFTR, a recombinant Ad containing the normal CFTR cDNA, and analyzed for CFTR mRNA and protein levels and CFTR function. As the AdCFTR dose increased [multiplicity of infection (moi) 0-1,000], CFTR mRNA and protein levels increased. However, while CFTR function measured by cAMP-stimulated 36Cl- efflux was observed with low doses of the vector (moi 20), there was no further increase in CFTR function with increasing doses of AdCFTR (moi from 20 to 1,000). These data suggest that after AdCFTR-mediated gene transfer, epithelial cells limit the level of cAMP-stimulated Cl- secretion despite increasing levels of CFTR protein.

Gene transfer to freshly isolated human respiratory epithelial cells in vitro using a replication-deficient adenovirus containing the human cystic fibrosis transmembrane conductance regulator cDNA.

Cystic fibrosis (CF) results from mutations of the CF transmembrane conductance regulator (CFTR) gene and subsequent defective regulation of cAMP-stimulated chloride (Cl-) permeability across the apical membrane of epithelial cells. In vitro transfer of normal CFTR cDNA corrects this defect, and studies in experimental animals have shown successful gene transfer to airway epithelium in vivo using a recombinant adenoviral vector containing the human CFTR cDNA (AdCFTR), supporting the feasibility of in vivo AdCFTR-mediated gene therapy for the respiratory manifestations of CF. One step in applying this therapy to CF patients is to evaluate the safety and efficacy of AdCFTR-mediated gene transfer in the actual target for human gene therapy, human airway epithelium. The present study demonstrates that AdCFTR restores cAMP-stimulated Cl- permeability in human CF bronchial epithelial cells. In addition, the study utilizes freshly isolated human airway epithelial cells from the nose and/or bronchi of normal individuals and/or individuals with CF to demonstrate that after in vitro AdCFTR-mediated gene transfer: (i) AdCFTR DNA does not replicate as a function of dose and time; (ii) CF epithelial cells express AdCFTR-mediated normal human CFTR mRNA; and (iii) CF epithelial cells, including terminally differentiated ciliated cells (the most common airway epithelial cell type), express the normal human CFTR protein. Together, these data support the use of AdCFTR in human gene therapy trials and suggest that biologic efficacy should be achievable in vivo.

Production, purification, and crystallization of human interleukin-1 beta converting enzyme derived from an Escherichia coli expression system.

Interleukin-1 beta converting enzyme (ICE) is a cysteine protease that catalyzes the conversion of the inactive precursor form of IL-1 beta to an active mature form. The mature form of IL-1 beta is involved in mediating inflammatory responses and in the progression of autoimmune diseases. We recently reported on the production of active human ICE in insect cells using the baculovirus expression system (Wang XM et al., 1994, Gene 145:273-277). Because the levels of expression achieved with this system were limiting for the purpose of performing detailed biochemical and biophysical studies, we examined the production of ICE in Escherichia coli. By using a tac promoter-based expression system and fusion to thioredoxin we were able to recover high levels of active ICE protein. The expressed protein, which was distributed between the soluble and insoluble fractions, was purified to homogeneity from both fractions using a combination of classical and affinity chromatography. Comparisons of ICE derived from both fractions indicated that they were comparable in their specific activities, subunit composition, and sensitivities to specific ICE inhibitors. The combined yields of ICE obtained from the soluble and insoluble fractions was close to 1 mg/L of induced culture. Recombinant human ICE was crystallized in the presence of a specific ICE inhibitor in a form suitable for X-ray crystallographic analysis. This readily available source of ICE will facilitate the further characterization of this novel and important protease.

Gene expression, purification and characterization of recombinant human neutrophil collagenase.

Human neutrophil collagenase (HNC) is a member of a family of matrix metalloproteinases (MMP). HNC is capable of cleaving all three alpha-chains of types I, II and III collagens. In rheumatoid and osteo-arthritis, MMP members have been implicated in the pathology associated with these diseases due to the accelerated breakdown of the extracellular matrix of articular cartilage. A cDNA coding for the HNC catalytic domain (lacking both the propeptide and C-terminal fragments) was sub-cloned into the pETlla prokaryotic expression vector. The cloned fragment encodes a protein that extends from amino acids (aa) Met100 through Gly262 of the full-length proenzyme, which as a result, would not require proteolytic or chemical activation. The HNC construct was expressed in Escherichia coli and recombinant mature, truncated neutrophil collagenase (re-mNC-t) was produced at high levels (approx. 30% of total bacterial protein). The re-mNC-t protein was extracted from inclusion bodies by solubilization in 6 M urea, followed by ion-exchange chromatography. The protein was refolded to an active conformation in the presence of Ca2+ and Zn2+. A final purification step on size-exclusion chromatography yielded 30 mg per liter of active re-mNC-t with minor autodegradative products. Alternatively, hydroxamate affinity chromatography was used to obtain pure, non-degraded re-mNC-t (20-25 mg per liter). The catalytic activity of re-mNC-t was abolished by known MMP inhibitors and the Ki measurement against actinonin was similar to that of HNC prepared from human blood.