Inhibitory effect of baricitinib on microglia and STAT3 in a region with a weak blood-brain barrier in a mouse model of rheumatoid arthritis.

OBJECTIVES: In patients with RA, baricitinib not only improves arthritis symptom severity, but also patients' neuropsychological symptoms, such as depression and fatigue. However, the cellular mechanisms through which baricitinib can affect neural activity is unexplored. While the blood-brain barrier (BBB) permeability of this drug remains unclear, Janus kinase inhibitors (JAKi) might reach the area postrema, which is a unique brain region with a weak BBB function. Our recent study demonstrated microglial activation during experimental arthritis in the area postrema. Therefore, we sought to assess the effect of baricitinib on microglia in the area postrema using the CIA mouse model. METHODS: Microglia number and morphology in the area postrema were assessed by immunostaining for ionized calcium-binding adaptor molecule-1 (Iba-1). Data were collected on post-immunization day 35 (early phase) and 84 (late phase), and compared between baricitinib- and vehicle-treated mice. The effect on signal transducers and activators of transcription (STAT3) in the area postrema was also immunohistochemically examined. Behavioural outcomes were assessed by examining feeding behaviours and sucrose preference tests. RESULTS: In the early phase, activated microglial levels in the area postrema were decreased by baricitinib, accompanied by the inhibition of phosphorylated-STAT3 and recovery of food intake and sucrose preference. On the other hand, baricitinib did not affect microglial morphology in the late phase. CONCLUSION: Our results demonstrate that baricitinib can affect brain cells, specifically microglia, in the brain region with a weak BBB and mitigate aberrant behaviours during autoimmune arthritis, pointing to the potential therapeutic effect of JAKi on brain pathologies underpinning RA.

Olfactory Bulbs in Arthritis Model Mouse Persistently Express Interleukin-6 before the Onset of Arthritis: Relationship to Food Intake.

INTRODUCTION: Rheumatoid arthritis (RA) can be comorbid with psychiatric symptoms. Brain abnormalities in RA patients and in arthritis models have been reported. However, it remains unclear when these abnormalities occur and where they are distributed. In this study, we analyzed spatiotemporal changes in gene expression in the brains of mice with collagen-induced arthritis (CIA). METHODS: Mice were divided into three groups: (i) CIA (all mice developed arthritis on day 35): complete Freund's adjuvant (CFA) and type II collagen at initial immunization, and incomplete Freund's adjuvant (IFA) and type II collagen at booster immunization; (ii) C(+/-) (50% mice developed arthritis on day 35): only IFA at booster immunization; and (iii) C(-/-) (no arthritis): only CFA at initial immunization and only IFA at booster immunization. Whole brains were collected at ten stages of arthritis and divided into six sections. Real-time polymerase chain reaction was performed using RNA extracted from the brain, and the expression of proinflammatory cytokines and glial markers was semi-quantified. Arthritis score, body weight, and food and water intakes were recorded and analyzed for correlations with brain gene expression. We also investigated the effect of interleukin-6 (IL-6) injection in the olfactory bulbs (OBs) on the food intake. RESULTS: After booster immunization, a transient increase in Integrin subunit α-M and IL-1ß was observed in multiple areas in CIA. IL-6 is persistently expressed in the OB before the onset of arthritis, which is correlated with body weight loss and decreased food intake. This change in the OB was observed in the C(+/-) but not in the C(-/-) groups. In the C(+/-) group, non-arthritic mice showed the same changes in the OB as the arthritic mice. This elevation in IL-6 levels persisted throughout the chronic phase until day 84. In addition, IL-6 injection into the OB reduced food intake. CONCLUSION: Persistent elevation of IL-6 in the OB from the early stage of arthritis may be an important finding that might explain the neuropsychiatric pathophysiology of RA, including appetite loss, which is present in the early stages of the disease and manifests as a variety of symptoms over time.

Inflammation and Bone Metabolism in Rheumatoid Arthritis: Molecular Mechanisms of Joint Destruction and Pharmacological Treatments.

Rheumatoid arthritis (RA) is an inflammatory disease characterized by a variety of symptoms and pathologies often presenting with polyarthritis. The primary symptom in the initial stage is joint swelling due to synovitis. With disease progression, cartilage and bone are affected to cause joint deformities. Advanced osteoarticular destruction and deformation can cause irreversible physical disabilities. Physical disabilities not only deteriorate patients' quality of life but also have substantial medical economic effects on society. Therefore, prevention of the progression of osteoarticular destruction and deformation is an important task. Recent studies have progressively improved our understanding of the molecular mechanism by which synovitis caused by immune disorders results in activation of osteoclasts; activated osteoclasts in turn cause bone destruction and para-articular osteoporosis. In this paper, we review the mechanisms of bone metabolism under physiological and RA conditions, and we describe the effects of therapeutic intervention against RA on bone.

Mortality related to drug-resistant organisms in surgical sepsis-3: an 8-year time trend study using sequential organ failure assessment scores.

The difference in sequential organ failure assessment (SOFA) scores from the baseline to sepsis is a known predictor of sepsis-3 outcome, but the prognostic value of drug-resistant organisms for mortality is unexplained. We employed sepsis stewardship and herein report an observational study. Study subjects were patients admitted to the Departments of Surgery/Chest Surgery from 2011 through 2018 with a diagnosis of sepsis and a SOFA score of 2 or more. Our sepsis stewardship methods included antimicrobial and diagnostic stewardship and infection control. We determined the primary endpoint as in-hospital death and the secondary endpoint as the annual trend of the risk-adjusted mortality ratio (RAMR). For mortality, we performed logistic regression analysis based on SOFA score, age, sex, comorbid disease, and the presence of methicillin-resistant Staphylococcus aureus (MRSA) and extended-spectrum beta-lactamase inhibitor-producing bacteria. In a total of 457 patients, two factors were significant predictors for fatality, i.e., SOFA score of 9 or more with an odds ratio (OR) 4.921 and 95% confidence interval [95% CI] 1.968-12.302 (P = 0.001) and presence of MRSA with an OR 1.83 and 95% CI 1.003-3.338 (P = 0.049). RAMR showed a decrease during the study years (P < 0.05). Early detection of MRSA may help patients survive surgical sepsis-3. Thus, MRSA-oriented diagnosis may play a role in expediting treatment with anti-MRSA antimicrobials.

How do neuropathic pain-like symptoms affect health-related quality of life among patients with rheumatoid arthritis?: A comparison of multiple pain-related parameters.

Objectives: Rheumatoid arthritis (RA) pain is thought to be nociceptive. However, recent studies indicate that RA also involves the neuropathic pain (NP) mechanism. We examined pain features and the effect of NP-like symptoms on health-related quality of life (HRQOL) among patients with RA.Methods: The painDETECT questionnaire (PDQ) was used to evaluate NP-like symptoms among 145 outpatients with RA. Disease activity, pain quality, and HRQOL were evaluated. We compared clinical parameters between patients with and without NP-like symptoms and analyzed pain features and the effect of NP-like symptoms on HRQOL, along with multiple other pain-related parameters.Results: Thirty (20.7%) patients had NP-like symptoms (PDQ ≥13). Patient global assessment and evaluator global assessment diverged for patients with RA who had NP-like symptoms. Of the examined pain-related parameters, PDQ score (p = .038, ß = -.173) was associated with the Short-Form 36-Item Health Survey role-social component summary score, but not with the physical or mental component summary scores.Conclusion: NP-like symptoms affected HRQOL among patients with RA. There was discordance between global assessments by patients and by evaluators for patients with RA who had NP-like symptoms. Therefore, NP-like symptoms should be given somewhat more attention when treating patients with RA.

Prokineticin 2 antagonist, PKRA7 suppresses arthritis in mice with collagen-induced arthritis.

BACKGROUND: Prokineticin 2 (PK2) expression is upregulated in mice with collagen-induced arthritis (CIA), an animal model of rheumatoid arthritis. The purpose of our study was to investigate the effects of PK2 inhibition on CIA. METHODS: PK2, prokineticin receptor (PKR) 1, and PKR2 mRNA transcripts in the joints of CIA mice were measured by real-time PCR on Days 21, 28, and 35 (n = 15/day). Localization of PKR1 and PKR2 proteins was examined immunohistochemically. PKRA7, a PK2 antagonist, was administered intraperitoneally for 2 weeks to CIA mice, and the severity of arthritis was compared between treated (n = 12) and untreated (n = 12) mice. The gene expression levels of inflammatory cytokines IL-1ß, IL-6, TNF-α, and VEGF were also measured by real-time PCR and compared between treated (n = 6) and untreated (n = 6) CIA mice. The data was statistically analyzed, and P values of less than 0.05 were considered significant. RESULTS: In the thickened synovial membrane, PKR1 protein was expressed in infiltrating neutrophils, while PKR2 expression was found in macrophage-like mononuclear cells. PK2 gene expression was significantly more pronounced on Days 28 and 35 than on Day 21 (2.15 and 2.03 versus 1.00, P = 0.0311 and 0.0247; Dunn's multiple comparison). PKR2 gene expression levels were significantly higher on Days 28 and 35 compared to Day 21 (25.4 and 39.3 versus 1.0, P = 0.002 and < 0.0001; Dunn's multiple comparison). Administration of PKRA7 suppressed the severity of arthritis (P < 0.001; two-way analysis of variance). A gene expression analysis of inflammatory cytokines revealed significantly reduced IL-1ß and lL-6 expression in the joints of PKRA7-treated mice compared to untreated mice (0.1 versus 1.0, P = 0.0043 and 0.04 versus 1.0, P = 0.0022, respectively; Mann-Whitney test). CONCLUSIONS: PK2 inhibition suppressed arthritis in mice with CIA.

Constitutive plasmacytoid dendritic cell migration to the splenic white pulp is cooperatively regulated by CCR7- and CXCR4-mediated signaling.

Although the spleen plays an important role in host defense against infection, the mechanism underlying the migration of the innate immune cells, plasmacytoid dendritic cells (pDCs), into the spleen remains ill defined. In this article, we report that pDCs constitutively migrate into the splenic white pulp (WP) in a manner dependent on the chemokine receptors CCR7 and CXCR4. In CCR7-deficient mice and CCR7 ligand-deficient mice, compared with wild-type (WT) mice, substantially fewer pDCs were found in the periarteriolar lymphoid sheath of the splenic WP under steady-state conditions. In addition, the migration of adoptively transferred CCR7-deficient pDCs into the WP was significantly worse than that of WT pDCs, supporting the idea that pDC trafficking to the splenic WP requires CCR7 signaling. WT pDCs responded to a CCR7 ligand with modest chemotaxis and ICAM-1 binding in vitro, and priming with the CCR7 ligand enabled the pDCs to migrate efficiently toward low concentrations of CXCL12 in a CXCR4-dependent manner, raising the possibility that CCR7 signaling enhances CXCR4-mediated pDC migration. In agreement with this hypothesis, CCL21 and CXCL12 were colocalized on fibroblastic reticular cells in the T cell zone and in the marginal zone bridging channels, through which pDCs appeared to enter the WP. Furthermore, functional blockage of CCR7 and CXCR4 abrogated pDC trafficking into the WP. Collectively, these results strongly suggest that pDCs employ both CCR7 and CXCR4 as critical chemokine receptors to migrate into the WP under steady-state conditions.

Prospective randomized clinical trial of a change in gastric emptying and nutritional status after a pylorus-preserving pancreaticoduodenectomy: comparison between an antecolic and a vertical retrocolic duodenojejunostomy.

BACKGROUND: Although an antecolic duodenojejunostomy was reported to reduce post-operative delayed gastric emptying (DGE) compared with a retrocolic duodenojejunostomy after a pylorus-preserving pancreaticoduodenectomy (PPPD), the long-term effects of these procedures have rarely been studied. The aim of this prospective, randomized, clinical trial was to investigate the influence of the reconstruction route on post-operative gastric emptying and nutrition. METHODS: Reconstruction was performed in 116 patients with an antecolic duodenojejunostomy (A group, n = 58) or a vertical retrocolic duodenojejunostomy (VR group, n = 58). Post-operative complications, including DGE, gastric emptying variables assessed by (13) C-acetate breath test and nutrition, were compared between the two groups for 1 year post-operatively. RESULTS: The incidence of DGE was not significantly different between the procedures (A group: 12.1%; VR group: 20.7%, P = 0.316). At post-operative month 1, gastric emptying was prolonged in the VR versus the A group but not significantly so. At post-operative month 6, gastric emptying was accelerated significantly in the A versus the VR group. Post-operative weight recovery was significantly better in the VR versus the A group at post-operative month 12 (percentage of pre-operative weight, A group: 93.8 ± 1.2%; VR group: 98.5 ± 1.3%, P = 0.015). CONCLUSIONS: A vertical retrocolic duodenojejunostomy was an acceptable procedure for the lower incidence of DGE and may contribute to better weight gain affected by moderate gastric emptying.

[A case of long-term survival after low-dose FP systemic chemotherapy for a tumor thrombus in the inferior caval vein and multiple lung metastases from recurrent hepatocellular carcinoma].

We report a case of long-term survival of a patient who received low-dose 5-fluorouracil and cisplatin (FP) systemic chemotherapy and underwent partial resection of the lung for a tumor thrombus in the inferior caval vein (IVC) and multiple lung metastases from recurrent hepatocellular carcinoma (HCC). The patient was a 66-year-old man who was admitted to our hospital for the treatment of a 13-cm liver tumor. He underwent an extended posterior sectionectomy of the liver. Pathological diagnosis revealed moderately differentiated hepatocellular carcinoma (vp1, vv1, sm[-, 1.5mm], ch, T3N0M0, stage III). At 3 months postoperatively, computed tomography (CT) revealed a tumor thrombus in the IVC and multiple (>20) lung tumors that were considered HCC recurrences. Low-dose FP systemic chemotherapy was initiated, and the tumors reduced in size. However, a new lesion in the left lung was detected at 13 months postoperatively. Thoracoscopyassisted resection of the tumor that was histologically diagnosed as an HCC metastasis was performed at 26 months postoperatively. The patient is cancer free at 46 months postoperatively. Therefore, low-dose FP systemic chemotherapy is one of the therapeutic options for the treatment of HCC recurrences of IVC tumor thrombi and multiple lung metastases. However, the occurrence of new lesions should be carefully monitored.

Nepmucin, a novel HEV sialomucin, mediates L-selectin-dependent lymphocyte rolling and promotes lymphocyte adhesion under flow.

Lymphocyte trafficking to lymph nodes (LNs) is initiated by the interaction between lymphocyte L-selectin and certain sialomucins, collectively termed peripheral node addressin (PNAd), carrying specific carbohydrates expressed by LN high endothelial venules (HEVs). Here, we identified a novel HEV-associated sialomucin, nepmucin (mucin not expressed in Peyer's patches [PPs]), that is expressed in LN HEVs but not detectable in PP HEVs at the protein level. Unlike conventional sialomucins, nepmucin contains a single V-type immunoglobulin (Ig) domain and a mucin-like domain. Using materials affinity-purified from LN lysates with soluble L-selectin, we found that two higher molecular weight species of nepmucin (75 and 95 kD) were decorated with oligosaccharides that bind L-selectin as well as an HEV-specific MECA-79 monoclonal antibody. Electron microscopic analysis showed that nepmucin accumulates in the extended luminal microvillus processes of LN HEVs. Upon appropriate glycosylation, nepmucin supported lymphocyte rolling via its mucin-like domain under physiological flow conditions. Furthermore, unlike most other sialomucins, nepmucin bound lymphocytes via its Ig domain, apparently independently of lymphocyte function-associated antigen 1 and very late antigen 4, and promoted shear-resistant lymphocyte binding in combination with intercellular adhesion molecule 1. Collectively, these results suggest that nepmucin may serve as a dual-functioning PNAd in LN HEVs, mediating both lymphocyte rolling and binding via different functional domains.

Characteristics and surgical outcome of HCC patients with low platelet count.

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) patients often have low platelet count (LPC). The aim of this study was to determine unique features of HCC patients with LPC. METHODOLOGY: HCC patients who underwent surgery were divided into two groups: LPC group (platelet count ≤100,000/mm³, n=84) and control group (platelet count >100,000/mm³, n=240). Surgical outcomes, risk factors for postoperative complications and prognostic factors were retrospectively compared. RESULTS: HCC patients with LPC had poorer liver function, smaller tumors, less anatomical resection and more frequent postoperative liver failure than control group patients. Postoperative survival was not different between the two groups. Tumor invasion to the main branch or trunk of portal vein (Vp3, 4) was the only risk factor for postoperative substantial complications in the LPC group. Postoperative survival was worse in patients with tumor diameter ≥4 cm or multiple tumors and in those who underwent preoperative transcatheter arterial chemoembolization (TACE) in the LPC group by multivariate analysis. Among them, preoperative TACE were not prognostic factors in the control group. CONCLUSIONS: In HCC patients with LPC, Vp3, 4 patients should be carefully monitored after surgery and preoperative TACE is not recommended for long-term postoperative survival.

Role of hilar resection in the treatment of hilar cholangiocarcinoma.

BACKGROUND/AIMS: The aim of this study was to clarify the role of bile duct resection without hepatectomy (hilar resection) in hilar cholangiocarcinoma. METHODOLOGY: We retrospectively compared surgical results for hilar cholangiocarcinoma between 8 patients treated with hilar resection and 21 patients treated with hepatectomy. RESULTS: All hilar resections were performed for Bismuth type I or II tumors with T2 or less lesions, whereas hepatectomy was done for type III or IV tumors excluding one type II tumor. R0 resection was equally achieved in both groups (62.5% in hilar resection group and 76.2% in hepatectomy group, p=0.469) and overall 5-year survival rates were comparable (21.9% vs. 23.6%, p=0.874). With respect to gross tumor appearance, R0 resection was achieved in all patients with papillary tumor in both groups with the excellent 5-year survivals (100% vs. 100%). In patients with nodular and flat tumors, R0 resection was achieved less frequently in the hilar resection vs. hepatectomy group (50% vs. 77.8%) mainly due to failure to clear the proximal ductal margin, resulting in poorer 5-year survival (0% vs. 18.7%). CONCLUSIONS: Hilar resection may be indicated for papillary T1 or 2 tumors in Bismuth type I or II cholangiocarcinoma.

Casirivimab-imdevimab neutralizing SARS-CoV-2: post-infusion clinical events and their risk factors.

BACKGROUND: Casirivimab-imdevimab has been developed to neutralize SARS-CoV-2. The global clinical trials in outpatients documented several adverse effects (AE), which mandate caution in Japan where part of patients return home. To investigate post-infusion clinical events and their risk factors, we attempted a retrospective study. MAIN BODY: Subjects were a consecutive series of inpatients with COVID-19 undergoing an infusion of casirivimab-imdevimab in our institute. The criteria for administration were in accordance with previous clinical trials, e.g., exclusion of patients necessitating oxygen supply. In Japan, however, SARS-CoV-2 vaccinees were eligible. Methods were review of background factors of status, imaging, and laboratory findings for the outcome of post-infusion events such as temperature increase (Temp+), pulse oximetry below 94%, and other events. Also, we documented the drug efficacy. Of a total of 96 patients with a median follow-up of 54 days, one (1.0%) died who alone was an exception demanding oxygen supply. Other 95 patients (99.0%) recovered from fever and hypoxia by Day 4 and later had no worsening of COVID-19. Median increase of body temperature was 1.0 degrees Celsius, which was used for computation of Temp+. Multivariate analysis showed that for Temp+ (n = 47), white blood cell counts more than 4.3 × 103/microliter (Odds Ratio [OR] 2.593, 95% Confidence Interval [CI] 1.060-6.338, P = 0.037) was at risk, whereas 2-time vaccination for SARS-CoV-2 (OR 0.128, 95% CI 0.026-0.636, P = 0.012) was a preventing factor. Likewise for lowered oximetry (n = 21), CT showing bilateral ground glass attenuation (OR 5.544, CI 1.599-19.228, P = 0.007) was a significant risk factor. Two patients (2.1%) showed bradycardia (asymptomatic, intervention not indicated) on Day 3 and recovery on Day 5. Limitations for this study included the difficulty distinguishing AE from worsening of COVID-19, thus we documented as clinical events. CONCLUSIONS: For 24 h after infusion of casirivimab-imdevimab, COVID-19 patients with increased white blood cell counts may be predisposed to temperature elevation more than 1.0 degrees centigrade, as may bilateral ground glass opacity to lowered oximetry. Thus, patients with leukocytosis and bilateral ground glass attenuation may need precaution for transient fever and hypoxia, respectively.

Delayed Rupture of All Digital Flexor Tendons Following Volar Locking Plate Fixation for Distal Radius Fracture: A Case Report.

A 68-year-old man with a right distal radius fracture treated with volar locking plate fixation previously was unable to flex his right thumb and four fingers without experiencing any adverse event. The flexor pollicis longus was reconstructed with a tendon graft using the lengthened flexor digitorum superficialis. The flexor digitorum profundus (FDP) of the ring finger was reconstructed with a tendon graft using the palmaris longus. The FDP of the index and little fingers was reconstructed using the interconnected tendon graft to the ring finger. Postoperatively, active flexion of all fingers and thumb was restored; however, he was unable to grasp thin objects because of the absence of full finger flexion. This is the first case wherein all nine flexor tendons being involved after volar locking plate fixation for a distal radius end fracture. We demonstrated a reconstructive procedure for long-standing multiple flexor tendon rupture after volar locking plate fixation.

Sustained microglial activation in the area postrema of collagen-induced arthritis mice.

BACKGROUND: Central nervous system (CNS)-mediated symptoms, such as fatigue, depression, and hyperalgesia, are common complications among patients with rheumatoid arthritis (RA). However, it remains unclear how the peripheral pathology of RA spreads to the brain. Accumulated evidence showing an association between serum cytokine levels and aberrant CNS function suggests that humoral factors participate in this mechanism. In contrast to the well-known early responses of microglia (CNS-resident immune cells) in the area postrema [AP; a brain region lacking a blood-brain barrier (BBB)] to experimental inflammation, microglial alterations in the AP during chronic inflammation like RA remain unclear. Therefore, to determine whether microglia in the AP can react to persistent autoimmune-arthritis conditions, we analyzed these cells in a mouse model of collagen-induced arthritis (CIA). METHODS: Microglial number and morphology were analyzed in the AP of CIA and control mice (administered Freund's adjuvant or saline). Immunostaining for ionized calcium-binding adaptor molecule-1 was performed at various disease phases: "pre-onset" [post-immunization day (PID) 21], "establishment" (PID 35), and "chronic" (PID 56 and 84). Quantitative analyses of microglial number and morphology were performed, with principal component analysis used to classify microglia. Interleukin-1ß (IL-1ß) mRNA expression was analyzed by multiple fluorescent in situ hybridization and real-time polymerase chain reaction. Behavioral changes were assessed by sucrose preference test. RESULTS: Microglia in the AP significantly increased in density and exhibited changes in morphology during the establishment and chronic phases, but not the pre-onset phase. Non-subjective clustering classification of cell morphology (CIA, 1,256 cells; saline, 852 cells) showed that the proportion of highly activated microglia increased in the CIA group during establishment and chronic phases. Moreover, the density of IL-1ß-positive microglia, a hallmark of functional activation, was increased in the AP. Sucrose preferences in CIA mice negatively correlated with IL-1ß expression in brain regions containing the AP. CONCLUSIONS: Our findings demonstrate that microglia in the AP can sustain their activated state during persistent autoimmune arthritis, which suggests that chronic inflammation, such as RA, may affect microglia in brain regions lacking a BBB and have various neural consequences.

Vascularized Bone Graft to the Lunate Combined with Shortening of the Capitate and Radius for Treatment of Advanced Kienböck Disease After a Follow-Up for More Than 10 Years.

Purpose: This study aimed to report the outcomes of patients with stage III Kienböck disease after treatment with a vascularized bone graft (VBG) to the lunate combined with capitate shortening osteotomy (CS) after a more than 10-year follow-up. Methods: A VBG to the lunate was combined with CS in 10 patients with stage III Kienböck disease (6 patients with stage IIIA and 4 with stage IIIB). We performed VBG, CS, and radial shortening osteotomy (RS) on 7 patients. Among them, 4 had undergone RS previously. The passive wrist extension angle and wrist flexion angle, grip strength (GS), carpal height ratio, Stahl index, visual analog scale of wrist pain, and Mayo modified wrist score were assessed before surgery and at the final follow-up. Results: The flexion angle decreased markedly after surgery, when GS increased in all 10 patients. Radiographic examinations revealed that the carpal height ratio decreased in 9 of 10 patients, whereas the Stahl index increased in 8 patients and remained unchanged in 2. The oldest 3 of 7 patients who underwent VBG, CS, and RS exhibited fusion of the proximal carpals except the pisiform. The mean visual analog scale decreased from 27.6 before surgery to 5.7 afterward. The Mayo modified wrist score improved in 9 patients after surgery and remained unchanged in one. Conclusions: In stage III Kienböck disease, VBG to the lunate combined with CS relieved wrist pain and increased GS and lunate height but was followed by severely restricted wrist motion. Fusion of the proximal carpals developed in 3 of 7 patients who received VBG with CS and RS. Type of study/level of evidence: Therapeutic Ⅳ.

Involvement of the lysophosphatidic acid-generating enzyme autotaxin in lymphocyte-endothelial cell interactions.

Autotaxin (ATX) is a secreted protein with lysophospholipase D activity that generates lysophosphatidic acid (LPA) from lysophosphatidylcholine. Here we report that functional ATX is selectively expressed in high endothelial venules (HEVs) of both lymph nodes and Peyer's patches. ATX expression was developmentally regulated and coincided with lymphocyte recruitment to the lymph nodes. In adults, ATX expression was independent of HEV-expressed chemokines such as CCL21 and CXCL13, innate immunity signals including those via TLR4 or MyD88, and of the extent of lymphocyte trafficking across the HEVs. ATX expression was induced in venules at sites of chronic inflammation. Receptors for the ATX enzyme product LPA were constitutively expressed in HEV endothelial cells (ECs). In vitro, LPA induced strong morphological changes in HEV ECs. Forced ATX expression caused cultured ECs to respond to lysophosphatidylcholine, up-regulating lymphocyte binding to the ECs in a LPA receptor-dependent manner under both static and flow conditions. Although in vivo depletion of circulating ATX did not affect lymphocyte trafficking into the lymph nodes, we surmise, based on the above data, that ATX expressed by HEVs acts on HEVs in situ to facilitate lymphocyte binding to ECs and that ATX in the general circulation does not play a major role in this process. Tissue-specific inactivation of ATX will verify this hypothesis in future studies of its mechanism of action.

CD4+CD25+ regulatory T cells in the small intestinal lamina propria show an effector/memory phenotype.

CD4(+)CD25(+) regulatory T cells (Tregs) have been implicated in the suppression of pathogenic responses to both self- and non-self-antigens in the intestine. However, their precise properties and functions in the gut, as well as the molecular basis of their recruitment to the gut, are poorly understood. Here, we found that most of the CD4(+)CD25(+) T cells in the small intestinal lamina propria (LP) express Foxp3 and exhibit an 'effector/memory' phenotype, CD44(hi)CD45RB(lo)CD62L(-), whereas only a minority of the Foxp3(+)CD4(+)CD25(+) T cells in the spleen and mesenteric lymph nodes showed this phenotype. The Tregs in the small intestinal LP (LP-Tregs) expressed higher levels of CCR4 and CCR9 and a substantially lower level of CCR7 than the Tregs in the spleen. In vitro, the LP-Tregs showed chemotaxis to CCL25/thymus-expressed chemokine. In addition, they showed efficient chemotaxis to the CCR4 ligands, CCL17/thymus and activation-regulated chemokine and CCL22/macrophage-derived chemokine, which are abundantly expressed by dendritic cells (DCs) in the small intestinal LP. In vivo, approximately 50% of the LP-Tregs were closely associated or in direct contact with LP-DCs. These findings demonstrate that LP-Tregs are phenotypically and functionally unique and raise the possibility that they are retained in the small intestinal LP through the action of CCL17 and CCL22, which are locally produced by LP-DCs.

Prospective randomized controlled study of gastric emptying assessed by (13)C-acetate breath test after pylorus-preserving pancreaticoduodenectomy: comparison between antecolic and vertical retrocolic duodenojejunostomy.

BACKGROUND/PURPOSE: To examine whether vertical retrocolic duodenojejunostomy is superior to antecolic duodenojejunostomy with respect to gastric emptying in a prospective, randomized, controlled study of patients undergoing pylorus-preserving pancreaticoduodenectomy (PpPD). METHODS: Thirty-five patients undergoing PpPD between March 2005 and July 2007 were enrolled in the study. All provided informed consent. During PpPD, the patients were randomly assigned to either the antecolic (antecolic group, n = 17) or vertical retrocolic route (vertical retrocolic group, n = 18) just before the reconstruction. Each patient ingested (13)C-acetate in a liquid meal before surgery and on postoperative day (POD) 30. Gastric emptying variables (Tmax, T1/2) were determined and compared between groups. RESULTS: Clinical delayed gastric emptying, defined as an inability of patients to take in an appropriate amount of solid food orally by POD 14, was found in 1 of 17 patients (6%) in the antecolic group and in 4 of 18 patients (22%) in the vertical retrocolic group, but the difference was not significant (P = 0.34). Tmax and T1/2 on POD 30 were prolonged in both groups in comparison to preoperative levels, but no significant difference was found between the two groups. Follow-up examinations revealed that gastric emptying had recovered to the preoperative level by POD 30 in approximately 80% of the patients, regardless of the reconstruction route. CONCLUSIONS: Vertical retrocolic duodenojejunostomy does not seem to offer an advantage with respect to gastric emptying.

Abatacept suppresses the telomerase activity of lymphocytes in patients with rheumatoid arthritis.

AIM: Telomere is a component of chromosomes that protects their ends from various stresses. The telomeres shorten during cell division, and their length is maintained by telomerase. The telomerase activity of lymphocytes was shown to be upregulated on lymphocyte activation, and abatacept was found to suppress the activation of T lymphocytes involved in pathogenesis of rheumatoid arthritis. Therefore, we investigated the effect of abatacept on lymphocyte telomerase activity in patients with rheumatoid arthritis. METHOD: This study included 11 patients diagnosed with rheumatoid arthritis based on American College of Rheumatology 2010 criteria, who received abatacept treatment from August 2012 to August 2013. We collected their clinical data and obtained peripheral blood samples before starting abatacept, and 1, 3, 6, and 12 months after treatment. Peripheral blood mononuclear cells were extracted using Ficoll density gradient centrifugation, and T and B lymphocytes were sorted by magnetic beads. The telomerase activity of lymphocytes was determined using the telomeric repeat amplification protocol. RESULTS: The telomerase activity of T lymphocytes declined from 0.357 to 0.161 (P < 0.01) at 12 months after abatacept treatment, and that of B lymphocytes declined from 0.554 to 0.202 (P < 0.01). The telomerase activity of B lymphocytes, but not that of T lymphocytes, was also significantly downregulated 1 month after treatment. CONCLUSION: Abatacept suppressed the telomerase activity of both T and B lymphocytes, although that of B lymphocytes was downregulated before T lymphocytes. These findings imply that the clinical efficacy of abatacept during the early phase depends on the suppression of B lymphocytes.