Management of Rheumatoid Arthritis: Possibilities and Challenges of Mesenchymal Stromal/Stem Cell-Based Therapies.

Rheumatoid arthritis (RA) is a highly prevalent, chronic, and progressive autoimmune disorder primarily affecting joints and muscles. The associated inflammation, pain, and motor restriction negatively impact patient quality of life (QOL) and can even contribute to premature mortality. Further, conventional treatments such as antiinflammatory drugs are only symptomatic. Substantial progress has been made on elucidating the etiopathology of overt RA, in particular the contributions of innate and adaptive immune system dysfunction to chronic inflammation. Although the precise mechanisms underlying onset and progression remain elusive, the discovery of new drug targets, early diagnosis, and new targeted treatments have greatly improved the prognosis and QOL of patients with RA. However, a sizable proportion of patients develop severe adverse effects, exhibit poor responses, or cannot tolerate long-term use of these drugs, necessitating more effective and safer therapeutic alternatives. Mounting preclinical and clinical evidence suggests that the transplantation of multipotent adult stem cells such as mesenchymal stromal/stem cells is a safe and effective treatment strategy for controlling chronic inflammation and promoting tissue regeneration in patients with intractable diseases, including RA. This review describes the current status of MSC-based therapies for RA as well as the opportunities and challenges to broader clinical application.

Relationship between the morphology of osteophytes and cartilage lesions in anterior ankle impingement in athletes: a cross-sectional study.

BACKGROUND: The present study aimed to describe the frequency and severity of tram-track lesions in anterior ankle impingement in athletes and to evaluate the association between osteophyte morphology and severity of tram-track lesions, the distinctive cartilage lesions associated with tibial osteophytes in anterior ankle impingement syndrome. METHODS: We evaluated 34 athletes who underwent arthroscopic osteophyte resection for anterior ankle impingement between January 2017 and March 2021. RESULTS: We found tram-track lesions in 26 athletes (76.5%). Arthroscopic findings revealed the distribution of the International Cartilage Repair Society grades of tram-track lesions (grade 0, eight; grade 1, seven; grade 2, ten; grade 3, nine; grade 4, zero). These findings indicate that athletes with anterior ankle impingement syndrome may have more severe cartilage lesions than non-athletes. There was a positive correlation between the International Cartilage Repair Society grade and osteophyte size (r = 0.393, p = 0.021). We divided athletes into two groups according to the presence or absence of osteophyte protrusion into the joint space. Osteophyte protrusion was present in 14 athletes (41.2%). All athletes in the protrusion-type group had tram-track lesions; seven (50%) had International Cartilage Repair Society grade 3. The protrusion-type group's International Cartilage Repair Society grade was significantly higher than that of the non-protrusion-type group (p = 0.008). The osteophyte sizes in the two groups were not significantly different (p = 0.341). CONCLUSIONS: Based on these findings, osteophyte protrusion should be assessed when an indication of arthroscopic treatment for anterior ankle impingement syndrome is considered, particularly in athletes.

Glenoid wear after humeral head replacement with using a single implant in patients with cuff tear arthropathy more than five years.

BACKGROUND: The aim of this study was to investigate glenoid wear in patients with humeral head replacement with a smaller humeral head, who were observed for >5 years, and to examine the relationship between radiographic changes and clinical outcome. METHODS: In this study, 41 shoulders of 41 patients (13 men, 28 women) were followed up for >5 years. The mean patient age at the time of surgery was 70.5 years. The average follow-up period at short-term was 26.0 months, and intermediate-term was 66.5 months. We classified glenoid wear into four grades (i.e., Grade 0 to Grade 3). Age, sex, clinical scores, and range of motion were investigated in relation to the grade of glenoid wear. Radiographs of glenoid wear evaluated in the short-term were subsequently compared to radiographs obtained in the intermediate-term period. RESULTS: At the final follow-up, 16 (39%) patients had Grade 0 wear, 11 (27%) patients had Grade 1 wear, 10 (24%) patients had Grade 2 wear, and 4 (10%) patients had Grade 3 wear. The University of California-Los Angeles score, Japanese Orthopaedic Association score, and active forward flexion were significantly lower in the Grade 3 patients; however, Grade 3 patients did not have significant pain. No significant difference in age, sex, Constant score, active external rotation, and active internal rotation in relation to the grade of glenoid wear was observed. In total, 25 (61%) patients showed a progression of glenoid wear. Cases in which glenoid wear progressed after 4 years after surgery were rare. Two patients of Grade 3 underwent total shoulder arthroplasty revision at 16 months and 38 months, respectively. CONCLUSIONS: Glenoid wear occurred in 61% of patients at 5 years follow-up. Pain of Grade 3 patients was mild, therefore, if pain is not severe, revision surgery may not be necessary.

An analysis of the demographic history of the risk allele R4810K in RNF213 of moyamoya disease.

BACKGROUND: Ring finger protein 213 (RNF213) is a susceptibility gene of moyamoya disease (MMD). A previous case-control study and a family analysis demonstrated a strong association of the East Asian-specific variant, R4810K (rs112735431), with MMD. Our aim is to uncover evolutionary history of R4810K in East Asian populations. METHODS: The RNF213 locus of 24 MMD patients in Japan were sequenced using targeted-capture sequencing. Based on the sequence data, we conducted population genetic analysis and estimated the age of R4810K using coalescent simulation. RESULTS: The diversity of the RNF213 gene was higher in Africans than non-Africans, which can be explained by bottleneck effect of the out-of-Africa migration. Coalescent simulation showed that the risk variant was born in East Asia 14,500-5100 years ago and came to the Japanese archipelago afterward, probably in the period when the known migration based on archaeological evidences occurred. CONCLUSIONS: Although clinical data show that the symptoms varies, all sequences harboring the risk allele are almost identical with a small number of exceptions, suggesting the MMD phenotypes are unaffected by the variants of this gene and rather would be more affected by environmental factors.

Neutrino Masses from Planck-Scale Lepton Number Breaking.

We consider an extension of the standard model by right-handed neutrinos and we argue that, under plausible assumptions, a neutrino mass of O(0.1) eV is naturally generated by the breaking of the lepton number at the Planck scale, possibly by gravitational effects, without the necessity of introducing new mass scales in the model. Some implications of this framework are also briefly discussed.

Humeral head histopathological changes in cuff tear arthropathy.

PURPOSE: The aim of this study was to investigate the histopathological changes in the humeral head in cuff tear arthropathy (CTA) compared with those in glenohumeral osteoarthritis (OA) and humeral neck fracture, which served as non-cuff tear controls. METHODS: Twenty-three humeral heads extracted at the time of shoulder prosthesis arthroplasty between June 2014 and July 2015 were evaluated in the present study. The diagnoses included four-part humeral neck fracture ( n = 4; average age, 85.0 years), glenohumeral OA ( n = 4; average age, 71.0 years), and CTA ( n = 15; average age, 73.0 years). The humeral heads were evaluated pathologically by hematoxylin and eosin and Safranin-O staining, and the thickness of the articular cartilage was measured. RESULTS: Fibrillation, thinning, and tearing of the cartilage were observed in the superior area of the humeral heads in CTA and glenohumeral OA. In CTA cases, clusters of chondrocytes in the cartilage were observed. Moreover, the thickness of the cartilage layer in the middle of the humeral head was 1.54 ± 0.07, 0.32 ± 0.46, and 2.19 ± 0.50 mm in humeral neck fracture, glenohumeral OA, and CTA, respectively. The cartilage layer in CTA was thicker than that in glenohumeral OA (CTA vs. OA: p < 0.05). CONCLUSION: OA changes in the superior area of the humeral heads and thickening of the cartilage layer from the middle to the inferior of the humeral heads were confirmed histopathologically, suggesting that simultaneous mechanical and nutritional factors might be contributing to CTA pathogenesis. The current study provided the better understanding of cartilage damage and thickening in CTA. This will help guide treatment options in the setting of CTA.

Cancellation Mechanism for Dark-Matter-Nucleon Interaction.

We consider a simple Higgs portal dark-matter model, where the standard model is supplemented with a complex scalar whose imaginary part plays the role of weakly interacting massive particle dark matter (DM). We show that the direct DM detection cross section vanishes at the tree level and zero momentum transfer due to a cancellation by virtue of a softly broken symmetry. This cancellation is operative for any mediator masses. As a result, our electroweak-scale dark matter satisfies all of the phenomenological constraints quite naturally.

The allele frequency of ALDH2*Glu504Lys and ADH1B*Arg47His for the Ryukyu islanders and their history of expansion among East Asians.

OBJECTIVES: A cline of frequencies of the derived allele of the ALDH2 gene, which causes a deficiency of an enzyme and "facial flushing" in humans who drink alcohol, has been known among the people of the Japanese archipelago. This cline is conventionally explained by admixture with immigrants from the Asian continent occurring during the Yayoi period. Previous studies lack sufficient data from the peripheral regions of the indigenous Jomon people, and those data the ADH1B gene that is involved in the Class I ADH gene cluster and contains another variant leading to a functional change. METHODS: We focused on the southwestern-most people from the Ryukyu Islands (n = 218) and those from northern Kyushu (n = 21) where the Yayoi immigrants likely arrived. We investigated both the Class I ADH and ALDH2 loci, as well as neutral genetic markers. RESULTS: In the Ryukyu Islands, the frequencies of the ancestral alleles in both loci were always higher than those in mainland Japan, while the frequencies of ADH1B were less than those of the derived allele. A haplotype block was not observed in ALDH2 but was in Class I ADH. DISCUSSION: Our data suggest that the derived allele of ALDH2 came with the Yayoi immigrants from the Asian continent to the Japanese archipelago. However, the derived allele of ADH1B is unlikely to be related to the Yayoi migration. Therefore, we postulate that the expansion of the derived allele of ADHIB in East Asia could be traced back to the last glacial period.

X-ray lines and self-interacting dark matter.

We study the correlation between a monochromatic signal from annihilating dark matter and its self-interacting cross section. We apply our argument to a complex scalar dark sector, where the pseudo-scalar plays the role of a warm dark matter candidate while the scalar mediates its interaction with the Standard Model. We combine the recent observation of the cluster Abell 3827 for self-interacting dark matter and the constraints on the annihilation cross section for monochromatic X-ray lines. We also confront our model to a set of recent experimental analyses and find that such an extension can naturally produce a monochromatic keV signal corresponding to recent observations of Perseus or Andromeda, while in the meantime it predicts a self-interacting cross section of the order of [Formula: see text], as recently claimed in the observation of the cluster Abell 3827. We also propose a way to distinguish such models by future direct detection techniques.

Internal bremsstrahlung signature of real scalar dark matter and consistency with thermal relic density.

A gamma-ray excess from the Galactic center consistent with line emission around 130 GeV was recently found in the Fermi-LAT data. Although the Fermi-LAT Collaboration has not confirmed its significance, such a signal would be a clear signature of dark matter annihilation. Until now, there have been many attempts to explain the excess by dark matter. However, these efforts tend to give too-small cross sections into photons if consistency with the correct thermal relic density of dark matter is required. In this Letter, we consider a simple Yukawa interaction that can be compatible with both aspects and show which parameters are favored.

A genetic analysis of the Sakishima islanders reveals no relationship with Taiwan aborigines but shared ancestry with Ainu and main-island Japanese.

The Sakishima islands are members of the Ryukyu island chain, stretching from the southwestern tip of the Japanese archipelago to Taiwan in the East China Sea. Archaeological data indicate cultural similarities between inhabitants of prehistoric Sakishima and Neolithic Taiwan. Recent studies based on tooth crown traits show remarkably high inter-island diversity among Ryukyu islanders, suggesting that the Sakishima islanders might have genetic backgrounds distinct from main-island Okinawa people. To investigate the genetic diversity of the Ryukyu islanders, we analyzed mtDNA, Y chromosome, and autosomal short tandem repeat loci in a sample of main-island Okinawa people and Sakishima (Miyako and Ishigaki) islanders whose participated in a previous study of tooth crown morphology. Our phylogenetic analysis of maternal (mtDNA) and paternal (Y chromosome) lineages shows that the Sakishima islanders are more closely related to people from the Japanese archipelago than to Taiwan aborigines. Miyako islanders and the Hokkaido Ainu have the first and second highest frequencies (respectively) of the Y-chromosomal Alu-insertion polymorphism, which is a presumable Jomon marker. Genetic diversity statistics show no evidence of demographic reduction or of extreme isolation in each island's population. Thus, we conclude that 1) Neolithic expansion from Taiwan did not contribute to the gene pool of modern Sakishima islanders, 2) male-lineage of the Ryukyu islanders likely shares a common ancestor with the Hokkaido Ainu who are presumably direct descendants of the Jomon people, and 3) frequent reciprocal gene flow among islands has masked the trace of common ancestry in the Ryukyu island chain.

A common variation in EDAR is a genetic determinant of shovel-shaped incisors.

Shovel shape of upper incisors is a common characteristic in Asian and Native American populations but is rare or absent in African and European populations. Like other common dental traits, genetic polymorphisms involved in the tooth shoveling have not yet been clarified. In ectodysplasin A receptor (EDAR), where dysfunctional mutations cause hypohidrotic ectodermal dysplasia, there is a nonsynonymous-derived variant, 1540C (rs3827760), that has a geographic distribution similar to that of the tooth shoveling. This allele has been recently reported to be associated with Asian-specific hair thickness. We aimed to clarify whether EDAR 1540C is also associated with dental morphology. For this purpose, we measured crown diameters and tooth-shoveling grades and analyzed the correlations between the dental traits and EDAR genotypes in two Japanese populations, inhabitants around Tokyo and in Sakishima Islands. The number of EDAR 1540C alleles in an individual was strongly correlated with the tooth-shoveling grade (p = 7.7 x 10(-10)). The effect of the allele was additive and explained 18.9% of the total variance in the shoveling grade, which corresponds to about one-fourth of the heritability of the trait reported previously. For data reduction of individual-level metric data, we applied a principal-component analysis, which yielded PC1-4, corresponding to four patterns of tooth size; this result implies that multiple factors are involved in dental morphology. The 1540C allele also significantly affected PC1 (p = 4.9 x 10(-3)), which denotes overall tooth size, and PC2 (p = 2.6 x 10(-3)), which denotes the ratio of mesiodistal diameter to buccolingual diameter.

Persistence of human papillomavirus infection as a predictor for recurrence in carcinoma of the cervix after radiotherapy.

OBJECTIVE: This study was undertaken to examine a possible correlation between clearance or persistence of human papillomavirus (HPV) infection and radiation response in carcinoma of the cervix. STUDY DESIGN: We reviewed 97 patients with HPV-positive cervical squamous cell carcinoma (International Federation of Gynecology and Obstetrics [FIGO] stage IB-IVA) treated with radiotherapy. Examination of HPV DNA was performed by the polymerase chain reaction-based assay. RESULTS: Cervical HPV DNA cleared in 42 patients (43.3%) and persisted in 55 patients (56.7%) at the end of irradiation. All of 42 HPV-cleared patients (100.0%) and 50 of 55 HPV-persistent patients (90.9%) had complete response. Of 92 patients with complete response, 20 (21.7%) had local recurrence develop. The recurrence rate was significantly higher in HPV-persisted patients (34.0%) than in HPV-cleared patients (7.1%) ( P = .0016). Univariate analysis demonstrated the significant differences for both 5-year local disease-free survival (LDFS) and overall survival (OAS) between HPV-cleared and HPV-persisted groups. Multivariate analysis showed that persistence of HPV DNA was the most powerful independent predictor for LDFS and OAS compared with other prognostic factors, such as FIGO stage or node swelling. CONCLUSION: In HPV-positive cervical carcinoma, persistence of HPV DNA in the cervix at the end of irradiation was highly predictive of LDFS and OAS.