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A 43-year-old Japanese woman with rheumatoid arthritis treated by infliximab and methotrexate for 11 years was admitted for proteinuria and purpura. A kidney biopsy revealed endothelial damage-dominant nephritis with IgA deposition. Infliximab and methotrexate were discontinued, and tocilizumab was started; however, proteinuria persisted. Therefore, tocilizumab was discontinued, and oral prednisolone and methylprednisolone pulse therapy were administered. After 6 months, urinary protein was less than 0.1 g/day, and purpura subsided. To our knowledge, this is the first case of endothelial damage-dominant nephritis related to IgA vasculitis involving the skin and kidney after long-term use of infliximab and methotrexate.

Background: Multiple treatment protocols have been described in literature for the treatment of terrible triad injury (TTI) of the elbow. We believe that repair of the medial collateral ligament (MCL) should be performed in preference to repair of a small coronoid fracture if the elbow is unstable after fixation/replacement of the radial head and repair of the lateral collateral ligament (LCL). The aim of this study is to report the outcomes of surgical treatment of patients with TTI associated with a small coronoid fracture in whom the coronoid fracture was not addressed. Methods: This study is a retrospective case series of 12 consecutive patients who underwent surgery for acute TTI with a small coronoid fracture (9 Regan–Morrey type I and 3 Regan–Morrey type II). Ten patients had complete MCL injuries. All patients underwent repair of the torn LCL and MCL and treatment of the radial head. The coronoid fracture was not surgically treated. At the final follow-up, the range of motion, degree of flexion contracture, Mayo elbow performance score (MEPS) and Disabilities of the Arm, Shoulder and Hand (DASH) were measured. Results: The mean follow-up period was 13.5 months. At the final follow-up, the mean arc of elbow flexion was 132° and the mean flexion contracture was 10°. The mean arc of forearm rotation was 148°. None of the patients demonstrated elbow instability. The mean MEPS was 92.5 points with seven having excellent results and five having good results. The average DASH score was 11.2 points. Conclusions: Our results showed that good elbow stability, arc of motion and clinical outcomes could be achieved without repair of small coronoid fractures in the treatment of TTI. The repair of MCL injuries should be given priority over the fixation of small coronoid fractures to regain elbow stability. Level of Evidence: Level IV (Therapeutic)

Glucose-dependent insulinotropic polypeptide (GIP) (also known as gastric inhibitory polypeptide) is a hormone produced in the upper gut and secreted to the circulation in response to the ingestion of foods, especially fatty foods. Growing evidence supports the physiological and pharmacological relevance of GIP in obesity. In an obesity setting, inhibition of endogenous GIP or its receptor leads to decreased energy intake, increased energy expenditure, or both, eventually causing weight loss. Further, supraphysiological dosing of exogenous long-lasting GIP agonists alters energy balance and has a marked antiobesity effect. This remarkable yet paradoxical antiobesity effect is suggested to occur primarily via the brain. The brain is capable of regulating both energy intake and expenditure and plays a critical role in human obesity. In addition, the GIP receptor is widely distributed throughout the brain, including areas responsible for energy homeostasis. Recent studies have uncovered previously underappreciated roles of the GIP receptor in the brain in the context of obesity. This article highlights how the GIP receptor expressed by the brain impacts obesity-related pathogenesis.

A 60-year-old Japanese woman with polymyositis (PM) developed hemolytic anemia (hemoglobin of 7.3 g/dL), thrombocytopenia (platelet of 9.1×104/µL), and acute kidney injury (Cre of 4.7 mg/dL) at 14 days after starting steroid therapy. Renal biopsy revealed glomerular endothelial swelling with fibrin thrombi and fragmented erythrocytes in the capillary lumens. Hemolytic uremic syndrome (HUS) with thrombotic microangiopathy (TMA) was diagnosed. Hemodialysis and plasma exchange/plasma transfusion were initiated, but HUS did not subside. After 45 days, the patient died of hemorrhagic respiratory failure. Autopsy showed fibrin thrombi filling the glomerular vascular pole and the small arteries in most glomeruli, resulting in glomerular collapse and glomerular basement membrane (GBM) duplication. Although renal involvement by PM is rare, HUS/TMA should be remembered as one of the serious renal complications of PM.

Case 1: A 59-year-old Japanese woman with rheumatoid arthritis (RA) for 36 years was admitted for evaluation of deteriorating renal function. Her serum creatine was 4.2 mg/dL, and proteinuria was 6.5 g daily. Renal and duodenal biopsy revealed AA amyloidosis. After treatment with tocilizumab (a humanized anti-interleukin-6 receptor antibody), proteinuria decreased to 1.1 g daily. The patient's renal function subsequently remained stable for 8 years. Case 2: A 71-year-old Japanese man with RA for 30 years was admitted due to deterioration of renal function. Serum creatine was 2.9 mg/dL, and urinary protein excretion was 0.06 g daily. Renal and duodenal biopsy identified AA amyloidosis. Tocilizumab was initiated, and his renal function remained stable for 6 years. The 2nd duodenal biopsy showed a marked decrease of AA amyloid deposits. Conclusion: These two cases suggest that tocilizumab may preserve renal function in the setting of end-stage kidney disease and shift the point of no return for RA patients with AA amyloidosis and renal dysfunction.

Treatment of a Monteggia fracture-dislocation primarily includes anatomical reduction and fixation of the ulna. However, in rare cases, reduction of the radial head remains impossible even after performing this standard procedure. We have encountered patients with Monteggia fracture-dislocation whose radial head could be reduced by 'overcorrecting' the ulna. In this retrospective study, we aimed to propose an unreported subtype of Monteggia fracture-dislocation. Data of three patients (age 6, 14, and 16 years) with Monteggia fracture-dislocations whose radial head could not be reduced by anatomical fixation of the ulna were retrospectively reviewed. In all three patients, the radial head could not be reduced by anatomical reduction and internal fixation of the ulna even after confirmation of the absence of interposed tissue such as annular ligament in the radiocapitellar joint. However, the radial head could be reduced by fixation of the ulna in a posterior convex shape at the fracture site. At the final follow-up, stable reduction of the radial head was maintained in all patients. We hypothesized that these patients had simultaneous existence of a fracture and acute plastic deformity of the ulna. To the best of our knowledge, this pathological state has not been reported previously but it may not be extremely rare and may only be unrecognized. We believe that a new subtype, that is, type A + C, should be established based on Letts' classification.

We herein report the case of myeloperoxidase (MPO) anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis with anti-glomerular basement membrane (anti-GBM) antibody positivity that successfully treated with mizoribine (MZR) as an immunosuppressive drug for remission maintenance therapy after the initiation of dialysis in addition to plasma exchange (PE) and glucocorticoid treatment to control the disease condition. A 79-year-old woman developed serious renal dysfunction and pulmonary alveolar hemorrhaging due to MPO–ANCA and anti-GBM antibody double-positive vasculitis. She was started on hemodialysis and was treated with methylprednisolone (m-PSL) pulse therapy with PE, followed by oral prednisolone (PSL). The pulmonary alveolar hemorrhaging disappeared, and both antibody titers immediately decreased but then rose again. Thus, m-PSL pulse therapy performed again in combination with combined with MZR treatment. Her poor renal function was irreversible; however, this therapy decreased both antibody titers, and they did not increase again. The patient developed pancytopenia and hyperuricemia. It was considered likely that these conditions developed in association with MZR treatment. We, therefore, measured the patient’s blood concentration of MZR, and the maintenance dose was finally set at 50 mg after each dialysis session. The patient’s pancytopenia and hyperuricemia improved and PSL could be smoothly tapered. This is the first case report of the use of MZR for remission maintenance therapy in a patient on hemodialysis who was positive for both ANCA and anti-GBM antibodies. The findings suggest that MZR can be used safely and effectively in such cases.

Nutrient excess, a major driver of obesity, diminishes hypothalamic responses to exogenously administered leptin, a critical hormone of energy balance. Here, we aimed to identify a physiological signal that arises from excess caloric intake and negatively controls hypothalamic leptin action. We found that deficiency of the gastric inhibitory polypeptide receptor (Gipr) for the gut-derived incretin hormone GIP protected against diet-induced neural leptin resistance. Furthermore, a centrally administered antibody that neutralizes GIPR had remarkable antiobesity effects in diet-induced obese mice, including reduced body weight and adiposity, and a decreased hypothalamic level of SOCS3, an inhibitor of leptin actions. In contrast, centrally administered GIP diminished hypothalamic sensitivity to leptin and increased hypothalamic levels of Socs3. Finally, we show that GIP increased the active form of the small GTPase Rap1 in the brain and that its activation was required for the central actions of GIP. Altogether, our results identify GIPR/Rap1 signaling in the brain as a molecular pathway linking overnutrition to the control of neural leptin actions.

We previously described the success and usefulness of two operative techniques for creating a radial artery-first or second dorsal metacarpal vein arteriovenous fistula (AVF) in the first interdigital space of the dorsal hand using the most distal site and autologous veins in the upper limb. These techniques utilize the dorsal metacarpal veins on the radial side of the dorsal hand. Developing these ideas, we devised a novel operative technique for creating a transposed radial artery-third metacarpal vein AVF in the first interdigital space of the dorsal hand using the most distal vein on the ulnar side of the upper limb and most distal site in the upper limb. The distinctive advantage of this technique is that it can be applied to patients whose cephalic vein in the forearm and the dorsal metacarpal veins on the radial side of the dorsal hand are of a poor quality. We herein report the steps of this technique and describe its successful performance in a patient who has been on hemodialysis for 14 months without any additional vascular access interventions or postoperative complications. We consider this technique to be a valuable option in select patients who meet the applicable conditions. The creation of the first AVF as distally as possible is ideal, and it offers a further viable option of distal native vascular access that may be overlooked.

SUMMARY The neuroendocrine system coordinates metabolic and behavioral adaptations to fasting, including reducing energy expenditure, promoting counterregulation, and suppressing satiation and anxiety to engage refeeding. Here, we show that steroid receptor coactivator-2 (SRC-2) in pro-opiomelanocortin (POMC) neurons is a key regulator of all these responses to fasting. POMC-specific deletion of SRC-2 enhances the basal excitability of POMC neurons; mutant mice fail to efficiently suppress energy expenditure during food deprivation. SRC-2 deficiency blunts electric responses of POMC neurons to glucose fluctuations, causing impaired counterregulation. When food becomes available, these mutant mice show insufficient refeeding associated with enhanced satiation and discoordination of anxiety and food-seeking behavior. SRC-2 coactivates Forkhead box protein O1 (FoxO1) to suppress POMC gene expression. POMC-specific deletion of SRC-2 protects mice from weight gain induced by an obesogenic diet feeding and/or FoxO1 overexpression. Collectively, we identify SRC-2 as a key molecule that coordinates multifaceted adaptive responses to food shortage., In brief Yang et al. demonstrate that SRC-2 in POMC neurons coordinates multifaceted adaptive responses to food shortage, including reducing energy expenditure, promoting counterregulation and suppressing satiation and anxiety to engage refeeding. These effects are mediated by SRC-2 functions to regulate POMC gene expression and modulate POMC neuron activities., Graphical Abstract

A brachio-brachial arteriovenous fistula with superficialization of the brachial vein and superficialization of the brachial artery are useful vascular access techniques for hemodialysis patients. However, both typically require a long skin incision from the antecubital fossa toward the axillary fossa. In addition, the brachio-brachial arteriovenous fistula in particular, which is created with not a one-stage but a two-stage procedure, requires a relatively long time of 2–3 months before it can be used for hemodialysis. Furthermore, superficialization of the brachial artery usually requires nonarterialized superficial veins for blood return. In cases where patients have no adequate superficial veins for creating an arteriovenous fistula, we have adopted a one-stage operative technique to create a brachio-brachial arteriovenous fistula with superficialization of not only the brachial vein but also the brachial artery using a short skin incision. This technique of a brachio-brachial arteriovenous fistula with superficialization of the brachial artery has several advantages over traditional approaches, including a minimally invasive procedure and early use for vascular access. To our knowledge, the presently described technique and the related data have not been previously reported in the English literature. We herein report the steps of this technique and the midterm follow-up outcomes.

Background Concerns about sodium overload when using sodium polystyrene sulfonate (Na-resin) as an ion-exchange resin for the treatment of hyperkalemia led our institution to gradually shift to the use of calcium polystyrene sulfonate (Ca-resin). However, as serum potassium levels were insufficiently controlled and patients experienced constipation, we returned to using Na-resin and observed better results than previously. Objective As few papers have examined the potassium adsorption ability of Ca-resin compared with Na-resin, we investigated this issue within our institution. Methods We studied potassium adsorption in patients who switched from Ca-resin to an equivalent amount of Na-resin (change group). We also investigated the incidence of sodium loading with Na-resin, including in patients newly commencing Na-resin treatment (new start group). Results Mean (± standard deviation) serum potassium levels decreased significantly, from 5.5 ± 0.6 to 4.9 ± 0.6 mEq/l in the change group and from 5.9 ± 0.4 to 4.7 ± 0.6 mEq/l in the new start group. No changes were observed in blood pressure, weight gain or serum sodium levels in the change group, but serum sodium levels in the new start group increased significantly, from 137.4 ± 2.3 to 139.0 ± 2.5 mEq/l, although they remained within the normal range. Conclusions Our results indicate that Na-resin exhibited an advantage in treating hyperkalemia when used in small amounts. However, when prescribing an ion-exchange resin at a higher dose, physicians should select the type and amount of resin according to the sodium and/or calcium load in each case.

Volar locking plate (VLP) fixation for distal radius fractures (DRF) is a technically demanding procedure, where accurate placement of the distal screws for subchondral articular support is essential. The purpose of this retrospective, case-control study was to compare a computed tomography (CT) navigation system for VLP fixation of intra-articular DRF with conventional freehand fluoroscopy guided surgery. Twelve consecutive patients with DRF, AO type C3.1, underwent VLP fixation using intraoperative CT navigation (navigated group) and 16 consecutive patients had conventional freehand fluoroscopy guided surgery (non-navigated group). Follow-up was done mean 12 (range, 4-18) months after surgery. Radiological outcomes included evaluation of placement for the distal fixation screws and radiological parameters such as; radial inclination, palmar tilt, ulnar variance, fracture-gap, and step-off. Clinical outcomes included grip strength, wrist range of motion, Mayo wrist score, and the Disabilities of the arm, shoulder and hand (DASH) questionnaire. Dorsal cortical and articular screw penetrations were significantly more common in the non-navigated group compared with the navigated group. At the final follow-up, a significantly larger intra-articular fracture gap was observed in the non-navigated group compared to the navigated group. There were no significant differences in clinical outcomes between the two treatment groups. Our results suggest that CT navigation guided surgery for VLP fixation of type C3 DRF, compared with conventional freehand fluoroscopy guided surgery, provides a more accurate placement of the distal screws which minimize the risk for intra-articular and dorsal cortical screw penetration.

The objective of the present study is to evaluate the effect of filtration coefficient and internal filtration on dialysis fluid flow and mass transfer coefficient in dialyzers using dimensionless mass transfer correlation equations. Aqueous solution of vitamin B12 clearances were obtained for REXEED-15L as a low flux dialyzer, and APS-15EA and APS-15UA as high flux dialyzers. All the other design specifications were identical for these dialyzers except for filtration coefficient. The overall mass transfer coefficient was calculated, moreover, the exponents of Reynolds number (Re) and film mass transfer coefficient of the dialysis-side fluid (k D) for each flow rate were derived from the Wilson plot and dimensionless correlation equation. The exponents of Re were 0.4 for the low flux dialyzer whereas 0.5 for the high flux dialyzers. Dialysis fluid of the low flux dialyzer was close to laminar flow because of its low filtration coefficient. On the other hand, dialysis fluid of the high flux dialyzers was assumed to be orthogonal flow. Higher filtration coefficient was associated with higher k D influenced by mass transfer rate through diffusion and internal filtration. Higher filtration coefficient of dialyzers and internal filtration affect orthogonal flow of dialysis fluid.

Background: Leukocyte removal therapy (LRT) is an effective treatment for active ulcerative colitis (UC). The present study was performed to evaluate the relapse-free period after LRT and identify risk factors for relapse. Methods: In total, 94 patients who underwent first-time LRT for remission of moderate to severe UC from April 2004 to March 2016 were enrolled in the present study. The patients were randomly assigned to one of 2 treatments: leukocytapheresis (LCAP; n = 43) or granulocyte and monocyte/macrophage adsorptive apheresis (GMA; n = 51). The 5-year cumulative relapse-free rate and risk factors for relapse were evaluated. Results: The therapeutic response rate was 82% for GMA and 70% for LCAP without a statistically significant difference. The 5-year relapse-free rate was 34.7% in the LRT group. The 5-year relapse-free rate in patients aged > 40 years was 49.9%, which was significantly higher than that in patients aged ≤40 years (22.9%, p < 0.01). The relapse-free period was longer in the older than younger patients. Conclusions: The relapse-free period after LRT was examined in patients with UC, and 34.7% of patients achieved clinical remission within a 5-year period. The risk factor for early relapse after LRT was younger age.

Background The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab is a low-density lipoprotein (LDL)-lowering drug with a new mechanism, which is currently available in Japan. Here, for the first time, we report the successful use of the PCSK9 inhibitor in a patient with refractory nephrotic syndrome. Case presentation A 61-year-old woman was diagnosed with minimal change-type nephrotic syndrome in October 2012. She received prednisolone (PSL) and cyclosporin A (CyA), but she experienced several cycles of relapse and remission and was hospitalized in May 2016 due to relapse. However, in spite of steroid pulse therapy and adrenocorticotropic hormone (ACTH) administration, her urinary protein level did not improve. We started her on evolocumab with the expectation of equivalent LDL-lowering effects as seen with LDL apheresis. After that, the LDL cholesterol level and UP/UC were concomitantly decreased, and the serum albumin was increased. This was maintained even when we reduced the PSL dose. This suggests that evolocumab clinically improves the nephrotic condition. Conclusion No other report has described the use of evolocumab for nephrotic syndrome (NS) or its effect on similar nephrotic conditions. We believe that the findings presented here are unique and may be beneficial when treating similar cases.

The effect of tonsillectomy on IgA nephropathy remains controversial. The aim of this study was to compare the effect of tonsillectomy on the outcome, end stage kidney disease (ESKD) and all-cause death in IgA nephropathy patients who did and did not undergo tonsillectomy.All basic data were retrospectively gathered from patients who had undergone renal biopsies at two Japanese clinical centres. Two hundred and twenty-seven patients were eligible for the study, with a median age of 34 (Interquartile range (IQR): 25-43) years and median follow-up of 92 (IQR: 40-178) months. The primary endpoint was the composite outcome of the onset of ESKD and all-cause death before ESKD. We performed a Cox proportional hazard regression analysis after adjusting for patient characteristics using the inverse probability therapy weighting (IPTW) method and a Cox analysis using the Matching method. Similarly, we analyzed these outcomes in a mild cohort.We were unable to find any significant advantages of tonsillectomy in either analysis (IPTW and matching, HR: 0.40 (0.12-1.36) P = 0.072 and 0.78 (0.13-4.64) P = 0.786). However, in the mild cohort analysis, our data showed that the Tonsillectomy group tended to be less likely to reach the composite outcomes than the Not Tonsillectomy group with statistical significance (hazard ratio (HR),0.001 [CI0.001 to0.001, P = 0.039]).In this study, our findings led us to conclude that performing tonsillectomy in an early and timely manner may have predisposition of less poor prognosis.

We examined the thyroid function of non-dialysis-dependent chronic kidney disease (CKD) patients in Japan.Serum-free thyroxine, free triiodothyronine, thyroid-stimulating hormone (TSH), and thyroglobulin (Tg) levels were evaluated in 37 CKD patients. CKD was defined as sustained kidney damage for more than 3 months and was classified as CKD 1+2 (n = 11), 3+4 (n = 10), or 5 (n = 16), which were defined by glomerular filtration rates of ≥ 60, 15 - 59, or 15 mL/min/1.73mThe prevalence of primary hypothyroidism (TSH ≥ 4.83 mU/L) in CKD 1+2, CKD 3+4, and CKD 5 was 9%, 20%, and 56%, respectively (p 0.05). Unexpectedly, elevated serum Tg levels ( 30 ng/mL), a marker of the reversible recovery of the thyroid function, were found in 67% of the CKD 5 patients (p0.05). The serum TSH and Tg levels became lower, without replacement therapy, after the initiation of hemodialysis and iodine restriction, and there was a significant correlation between the serum TSH and Tg levels in the CKD 5 patients (p0.05).The high prevalence of reversible hypothyroidism and the TSH-dependent elevation of the serum Tg levels was suggested in Japanese patients with advanced CKD. The excess ingestion and the impaired urinary excretion of iodine may be responsible for this reversible thyroid dysfunction. .

Background Goodpasture’s syndrome is a rare disease that is characterized by rapidly progressive glomerulonephritis and diffuse alveolar hemorrhage. Case presentation A 71-year-old Japanese man who had chronic interstitial pneumonia was diagnosed as having Goodpasture’s syndrome. Both anti-glomerular basement membrane antibody and myeloperoxidase anti-neutrophil cytoplasmic antibody were increased. Despite intensive treatments, including mechanical ventilation, he died from respiratory failure. Pathological findings at autopsy showed rapidly progressive glomerulonephritis in his kidneys, diffuse alveolar hemorrhage, hyaline membranes, and fibroblastic foci in his lungs. The cause of death was diagnosed as respiratory failure as a result of diffuse alveolar damage induced by a combination of diffuse alveolar hemorrhage and exacerbation of interstitial pneumonia. Conclusions We report a case of Goodpasture’s syndrome complicated with pre-existing chronic interstitial pneumonia and positive myeloperoxidase anti-neutrophil cytoplasmic antibody. We reviewed six similar cases reported in the literature and concluded that Goodpasture’s syndrome with pre-existing interstitial pneumonia and myeloperoxidase anti-neutrophil cytoplasmic antibody is related to a poor prognosis.

A chronic traumatic hyperextension of the proximal interphalangeal (PIP) joint can result from traumatic volar plate (VP) disruption. For the treatment of this disorder, reconstruction procedures have been traditionally recommended, because the condition of the VP was not considered susceptible to repair due to retraction or attenuation. The purpose of this paper is to present the operative technique and report the clinical results of late VP repair. Late VP repair was performed for chronic, post-traumatic hyperextension deformity of the PIP joint of the little finger resulting from VP disruption in seven consecutive patients. The range of motion and the lateral stability of the PIP joint were evaluated. The radiographic images were also used to evaluate the alignment and degenerative changes of the PIP joint. Clinical results were classified according to Catalano's criteria. Intraoperative findings showed that the VP could be mobilised and repaired in all cases. The hyperextension was well corrected, and none showed recurrence of the initial deformity. Average flexion of the PIP joint was 92° (range = 75-98°), and flexion contracture was 9° (range = 0-20°). On clinical evaluation, there were two excellent, three good, and two fair results. The postoperative radiographs revealed no degenerative change in the PIP joint in six patients. Late VP repair is a successful and reliable alternative and more physiologic than other reconstruction methods. One should first consider late VP repair, despite a long interval between injury and repair.

Latent membrane protein 2A (LMP2A) of Epstein-Barr virus (EBV) is widely expressed in EBV-associated malignancies. We demonstrate that LMP2A has a transformation ability. This study shows that LMP2A-induced transformation in several human nonhematopoietic cell lines was blocked in those cells expressing an immunoreceptor tyrosine-based activation motif (ITAM) LMP2A mutant. The Syk inhibitor or Syk-specific small interfering RNA (siRNA) inhibited LMP2A-induced transformation. These results indicate that the interaction of the LMP2A ITAM with Syk is a key step for LMP2A-mediated transformation.

Background: The medial epicondyle nonunion becomes symptomatic valgus instability with medial elbow pain and joint instability due to dysfunction of the medial collateral ligament (MCL), thus requiring surgical treatment. The purpose of the present study is to report the clinical result of the fragment excision and ligament reconstruction by free tendon graft in the treatment of symptomatic medial epicondyle nonunion. Methods: A retrospective study of five consecutive patients was performed. All five patients had signs and symptoms of valgus instability of the elbow. The mean period of nonunion was 25 years, and their injuries progressed asymptomatically until symptoms developed in adulthood after a second injury. Results: All patients were treated by fragment excision and MCL reconstruction. At the final follow-up, no patients exhibited pain or instability. The mean joint range of motion was 0o of extension and 138o of flexion, with an MEPS of 100 points in all patients. Conclusions: By ligament reconstruction for MCL insufficiency and removing the bone fragments avoided irritation by the bone fragments, pain and instability disappeared, good range of motion was restored, and excellent outcomes were achieved in all patients. We believe that fragment excision and MCL reconstruction should be considered as the treatment option for symptomatic medial epicondyle nonunion of the humerus.

The present study examined how muscle cross-sectional area (CSA) indices determined at rest and during maximal voluntary contraction (MVC) are related to muscle strength in middle-aged and elderly individuals (22 men and 36 women, 51-77 years). The muscle thickness (MT) of elbow flexors and circumference (C) at the level 60% distal to the upper arm was measured by ultrasonography and a measuring tape, respectively, both at rest and during isometric MVC of elbow flexion. The muscle strength (F) of elbow flexors was calculated by dividing the torque developed during MVC by the forearm length of each subject. The product of MT and C (MTxC) and the square of MT (MT) were defined as the muscle CSA indices. The F was significantly correlated with MTxC during MVC (r = 0.905, p < or = 0.001) and at rest (r = 0.778, p < or = 0.001), with the former relationship significantly stronger than the latter (p < or = 0.001). Similarly, F was significantly correlated with MT both during MVC (r = 0.896, p < or = 0.001) and at rest (r = 0.780, p < or = 0.001), and there was also a significant difference between the correlation coefficients (p < or = 0.01). These findings show that, in middle-aged and elderly individuals, muscle strength is more closely related to muscle CSA indices during MVC than at rest. It is concluded that the present muscle CSA indices taken during MVC enable easy and practical evaluation of the muscle strength per size of elbow flexors in middle-aged and elderly individuals.

The objective of the present study was to evaluate the characteristics of protein adsorption on the inner surface of various dialysis membranes, to develop protein adsorption-resistant biocompatible dialysis membranes. The adsorption force of human serum albumin (HSA) on the inner surface of a dialysis membrane and the smoothness of the membrane were evaluated from a nanoscale perspective by atomic force microscopy. The content ratio of the hydrophilic polymer, polyvinylpyrrolidone (PVP), was determined by attenuated total reflection Fourier transform infrared spectroscopy. Nine synthetic-polymer dialysis membranes on the market made of polysulfone (PSF), polyethersulfone (PES), polyester polymer-alloy (PEPA), and ethylene vinylalcohol (EVAL) were used in the present study. The HSA adsorption force on the surface of the hydrophobic polymer PEPA membrane was higher than that on the hydrophilic polymer EVAL membrane surface. It has been considered beneficial, for decreasing the HSA adsorption force, to cover a hydrophobic polymer membrane surface with PVP. However, there were some areas on PVP-containing membrane surfaces at which much higher HSA adsorption forces were observed. The HSA adsorption force gave a nearly linear correlation with the surface roughness on the PSF membrane surface. However, the HSA adsorption force was uncorrelated with the PVP content ratio for any of the PSF membrane surfaces tested. In conclusion, protein adsorption can be minimized by the use of dialysis membranes made of hydrophobic polymers containing PVP with a smooth surface.

Epstein-Barr virus (EBV) latent membrane protein 2A (LMP2A) is widely expressed in EBV-infected cells within the infected human host and EBV-associated malignancies, suggesting that LMP2A is important for EBV latency, persistence, and EBV-associated tumorigenesis. Previously, we demonstrated that LMP2A provides an antiapoptotic signal through the activation of phosphatidylinositol 3-kinase (PI3-K)/Akt pathway in vitro. However, the exact function of LMP2A in tumor progression is not well understood. In this study, we found that LMP2A did not induce anchorage-independent cell growth in a human keratinocyte cell line, HaCaT, but did in a human gastric carcinoma cell line, HSC-39. In addition, LMP2A activated the PI3-K/Akt pathway in both HaCaT and HSC-39 cells; however, LMP2A did not activate Ras in HaCaT cells but did in HSC-39 cells. Furthermore, the Ras inhibitors manumycin A and a dominant-negative form of Ras (RasN17) and the PI3-K inhibitor LY294002 blocked LMP2A-mediated Akt phosphorylation and anchorage-independent cell growth in HSC-39 cells. These results suggest that constitutive activation of the Ras/PI3-K/Akt pathway by LMP2A is a key factor for LMP2A-mediated transformation.

Transforming growth factor (TGF)-β1 induces not only cell growth inhibition or apoptosis but also Epstein–Barr virus (EBV) reactivation in some Burkitt's lymphoma (BL) cell lines. The purpose of this study was to define the role of TGF-β signaling molecules in response to TGF-β1-mediated cell growth inhibition, apoptosis, and EBV reactivation in BL cell lines. First, we confirmed the effect of TGF-β1 on the cell growth and EBV reactivation in six BL cell lines. TGF-β1 induced cell growth inhibition and EBV reactivation in these cell lines but did not in Akata cells. To elucidate the mechanism of TGF-β1 unresponsiveness in Akata cells, we studied the expression of TGF-β receptors and the intracellular signaling molecules Smads. All cell lines expressed TGF-β type I receptor, Smad2, Smad3, and Smad4. TGF-β type II receptor (R-II) was expressed in all cell lines except Akata cells. Introduction of the TGF-β R-II into Akata cells results in sensitivity to TGF-β1-mediated growth inhibition, apoptosis, and EBV reactivation. In addition, to test a possibility to the transcriptional repression of the TGF-β R-II gene in Akata cells, the effect of histone deacetylation (HDAC) inhibitor, trichostatin A (TSA) was examined. The expression of TGF-β R-II in Akata cells was induced by TSA treatment. These results suggest that the lack of functional TGF-β R-II impedes the progression of signals through TGF-β1 and becomes a determinant of unresponsiveness to TGF-β1-mediated growth inhibition and EBV reactivation. J. Med. Virol. 78:1456–1464, 2006. © 2006 Wiley-Liss, Inc.

Epstein-Barr virus (EBV) is a human herpesvirus that establishes a lifelong latent infection of B cells. Within the immune system, apoptosis is a central mechanism in normal lymphocyte homeostasis both during early lymphocyte development and in response to antigenic stimuli. In this study, we found that latent membrane protein 2A (LMP2A) inhibited B-cell receptor (BCR)-induced apoptosis in Burkitt's lymphoma cell lines. Genistein, a specific inhibitor of tyrosine-specific protein kinases, blocked BCR-induced apoptosis and EBV reactivation in the cells. These findings indicate that LMP2A blocks BCR-induced cell apoptosis and EBV reactivation through the inhibition of activation of tyrosine kinases by BCR cross-linking.

In order to study the mechanism of Epstein-Barr virus (EBV) infection in gastric carcinoma cells, we characterized the EBV infection in signet ring cell line HSC-39, derived from a human gastric carcinoma. HSC-39 cells were highly susceptible to cell-free EBV infection by Akata and P3HR-1 EBV strains. EBV nuclear antigen (EBNA) and EBV-encoded small RNA (EBER) were detected in the infected cells. Akata and P3HR-1 EBV-infected cell clones were isolated by a limiting dilution technique. The Akata and P3HR-1 EBV-infected clones differed from each other in morphology and growth patterns. Akata EBV-infected clones had lower growth rates than did P3HR-1 EBV-infected clones in both liquid and soft agar mediums. Both the infected HSC-39 cells and the clones expressed EBNA1 and EBER, but did not express EBNA2, latent membrane protein (LMP) 1 and LMP2A. The Q promoter (p), but not the Cp/Wp for EBNA transcription, was active in the infected HSC-39 cells and all clones. No lytic infection was observed in either infected parental cells or any clones. Uninfected HSC-39 cells did not express a principal EBV receptor CD21; however, Akata but not P3HR-1 EBV-infected clones expressed low levels of CD21 mRNA. These results demonstrate that the cellular phenotypes of HSC-39 cells are altered by EBV infection in strain-specific manner. We propose the HSC-39 cell line as a model target for the study of the mechanism and significance of EBV infection in gastric carcinoma.

Eliminating Epstein-Barr virus (EBV) genomes from infected cells is an intriguing theoretical strategy in therapy for EBV-associated malignant diseases. Respective patterns were characterized for hydroxyurea (HU)-promoted loss of EBV genomes from EBV-infected epithelioid cell lines derived from the noncancerous portion of gastric carcinoma tissues and Burkitt's lymphoma (BL) cell lines. Epithelioid cell lines GT38 and PN were less sensitivity to HU than BL cell lines Akata, Raji, and Daudi in terms of cell growth inhibition and cell cycle arrest. On passage in medium with 50 microM HU, the fraction of EBV nuclear antigen (EBNA)-positive cells was reduced substantially in the BL cell lines, but only slightly in the epithelioid cell lines. EBV DNA was reduced in Akata, Raji, and Daudi cells upon passage in 50 microM HU by 95%, 70%, and 50%, respectively, but by only 10% in GT38 cells, in which EBV DNA reduction was enhanced at increased concentrations of HU. This indicates that EBV genome is more easily lost from BL cell lines than from epithelioid cell lines upon culturing in HU. These findings support the view that the elimination of EBV could be therapeutically effective in EBV-associated BL by HU.

The usefulness of primary chemotherapy has been widely recognized and applied to routine clinical practice to improve prognosis by downstaging. Nevertheless, none of many trials has been able to show a positive effect of primary chemotherapy in terms of prognosis, and predictive factors of outcome have not been defined and are still under investigation. Primary chemotherapy was given to 50 patients with advanced breast cancer. Predictive factors involved in clinical or pathological response to primary chemotherapy (3 cycles of CE(F) therapy) were investigated. The response rate in all patients was 56.0% (CR: 3 patients PR: 25 patients) and 64.1% in patients without distant metastases. MIB-1 was related to the clinical response and EIC (extensive intraductal component) was related to the pathological response; the response was high in patients with EIC negative tumors. Responders had tumors with higher proliferative activity, which decreased significantly after chemotherapy. Patients with a decrease of more than 30% in proliferative activity after chemotherapy had significantly higher disease-free survival rates. The proliferative activity and EIC status were useful predictors of clinical or pathological response to primary chemotherapy. A decrease in proliferative activity by chemotherapy significantly correlated with clinical response and reflected a favorable prognosis. The number of patients benefiting from primary chemotherapy might steadily increase by detecting these predictive factors.

Smad family proteins play a pivotal role in transmitting the transforming growth factor-beta (TGF-beta) superfamily signals from the cell surface to the nucleus. In response to ligand stimulation, Smad4 forms a complex with respective receptor-specific Smads, and the complex translocates into the nucleus and regulates gene expression. Thus, the nuclear entry of the Smad complex is one of the key steps in signal transduction. However, little is known about regulatory mechanisms for nucleocytoplasmic transport of Smads. Here we report identification of a functional, leucine-rich nuclear export signal (NES) in Smad4, which regulates subcellular distribution of Smad4. We then show evidence suggesting that the NES-dependent cytoplasmic localization of Smad4 is important for ensuring optimal TGF-beta responsivenesses in transcriptional activation. Moreover, we show that the NES of Smad4 is specifically inactivated by the stimulus-dependent hetero-oligomerization with receptor-specific Smads during the TGF-beta-induced nuclear translocation of Smad4. Taken together, these results suggest an important regulatory role of the NES of Smad4 in TGF-beta signaling.

The CD40 molecule plays important roles in B cell activation, proliferation, and immunoglobulin (Ig) class switching. In Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCL), CD40 mediates growth inhibition and EBV reactivation via the CD40 signaling pathways. CD40 cross-linking with a monoclonal antibody arrests cell growth in G1 and induces expression of p27kip1 cyclin-dependent kinase inhibitor. CD40 cross-linking also induces EBV reactivation, as detected by the induction of EBV-specific early antigen, immediate early BZLF1 RNA, and its protein product ZEBRA. These results support hypotheses that the proliferation of EBV-infected B cells in vivo can be inhibited by interactions with the CD40 ligand on activated helper T cells, and latent EBV is reactivated via the signaling pathways controlled by CD40 interactions.

Treatment of advanced or recurrent breast cancer with medroxyprogesterone acetate (MPA) shows high response rates and the accessory effects of appetite stimulation, improvement in performance status (PS) and bone marrow protection. In recent years, interleukin-6 (IL-6) has been reported to cause cachexia. In this study, to clarify the significance of IL-6 in advanced or recurrent breast cancer, the relationship between the IL-6 level and clinical findings or effect of MPA was investigated. Sixty-five patients with recurrent or advanced breast cancer participated in a prospective study. The age of patients ranged from 28 to 79 years with an average age of 51.3 years. IL-6 level was investigated in these patients dosed with 800 mg/day of MPA and in 17 postoperative nonrecurrent patients. Serum MPA level was measured by high-performance liquid chromatography and IL-6 level was measured prior to MPA administration, 4 weeks (in 59 cases) and 12 weeks (in 32 patients) after MPA administration by ELISA. Serum IL-6 level was significantly higher in recurrent cases, especially in those with visceral metastasis. Further, in patients for whom MPA therapy was effective, the IL-6 level prior to the treatment was clearly low. The IL-6 level was significantly increased after 4 weeks. However, response to MPA was significantly higher and PS was improved in those cases demonstrating less increased IL-6 levels after 4 weeks. In addition, the effect of MPA was significantly related to a higher serum concentration of MPA-positive ER, and longer disease-free interval, although there was no significant predictive factor for the clinical effect of MPA therapy in multivariate analysis. In conclusion, MPA therapy was effective in cases demonstrating a low IL-6 level and less increased IL-6 levels after 4 weeks. PS was improved in those cases in which the degree of IL-6 increase was suppressed by MPA, and many such cases showed low IL-6 levels prior to MPA therapy. Furthermore, PS was improved even in nonresponders to MPA. Therefore, it is suggested that MPA therapy might be useful in treating recurrent breast cancer, and its benefits might be mediated by IL-6.

BACKGROUND Bone metastases from breast carcinoma are frequently observed as postoperative pathologic conditions; however, in many cases, diagnosis and treatment are difficult. Although most diagnoses of bone metastases are made by plain radiography (X-P) or bone scintigraphy, the use of magnetic resonance imaging (MRI) has enabled detailed imaging of foci, and many more lesions have become detectable. In the current study, the authors evaluated the relation between the diagnosis of bone metastases of breast carcinoma and clinicopathologic factors, especially those of proliferative activity and effects of treatment. METHODS The subjects consisted of 51 breast carcinoma patients (mean age, 51.2 years) with vertebral metastases diagnosed by plain radiography, bone scintigraphy, or MRI. Twenty-eight of the 51 patients were premenopausal and 27 of the 51 had bone metastases only. The patients were classified into the following groups: Group A, 24 patients who showed similar findings in plain radiography, bone scintigraphy, and MRI; Group C, 14 who showed no abnormalities on radiography or bone scintigraphy but whose lesions were diagnosed by MRI only; and Group B, 13 patients with findings intermediate between Groups A and C. The proliferative activity of tumors was evaluated by determining the level of DNA polymerase α. RESULTS Regarding the relation to clinicopathologic factors, a significant number of patients with estrogen receptor (ER) negative tumors who had a high level of DNA polymerase α, short disease free intervals (DFI), and metastases to other organs were included in Group C. Prognoses of patients in Group C were poor. CONCLUSIONS For the diagnosis of breast carcinoma with bone metastasis, different correlations were noted among the various biologic characteristics, such as ER status and proliferative activity. That is, bone scintigraphy sufficiently reflected foci in patients with ER positive tumors or tumors with low proliferation, whereas bone scintigraphy was false-negative in patients with ER negative or highly proliferative tumors, showing that MRI was useful in diagnosing such patients. Therefore, consideration of malignant features, such as proliferative activity and ER status, is believed necessary during the postoperative follow-up of breast carcinoma patients. Cancer 1999;85:1782–8. © 1999 American Cancer Society.

M-phase-promoting factor (MPF), a complex of cdc2 and a B-type cyclin, is a key regulator of the G2/M cell cycle transition. Cyclin B1 accumulates in the cytoplasm through S and G2 phases and translocates to the nucleus during prophase. We show here that cytoplasmic localization of cyclin B1 during interphase is directed by its nuclear export signal (NES)-dependent transport mechanism. Treatment of HeLa cells with leptomycin B (LMB), a specific inhibitor of the NES-dependent transport, resulted in nuclear accumulation of cyclin B1 in G2 phase. Disruption of an NES which has been identified in cyclin B1 here abolished the nuclear export of this protein, and consequently the NES-disrupted cyclin B1 when expressed in cells accumulated in the nucleus. Moreover, we show that expression of the NES-disrupted cyclin B1 or LMB treatment of the cells is able to override the DNA damage-induced G2 checkpoint when combined with caffeine treatment. These results suggest a role of nuclear exclusion of cyclin B1 in the DNA damage-induced G2 checkpoint.

Background: Double free muscle transfer for the treatment of traumatic total brachial plexus injury provides useful prehensile function. We studied the outcome of this muscle transfer procedure, including the changes in disability and quality-of-life scores. Methods: Thirty-six patients with traumatic total brachial plexus injury who underwent double free muscle transfer for reconstruction from 2002 to 2008 and had a minimum follow-up of twenty-four months after the second free muscle transfer were studied. All were evaluated preoperatively and postoperatively with use of the Disabilities of the Arm, Shoulder and Hand (DASH) and Short Form-36 (SF-36) questionnaires. A separate questionnaire was used to determine job status, pain, use of the reconstructed hand, and satisfaction with the procedure. Results: The mean patient age was twenty-nine years (range, sixteen to forty-nine years), and the mean duration of follow-up was thirty-six months (range, twenty-four to seventy-nine months). The mean active range of motion was 23° (range, 0° to 80°) for shoulder flexion, 31° (range, 0° to 90°) for shoulder abduction, −18° (range, −80° to 40°) for shoulder external rotation, 62° (range, 0° to 130°) for the shoulder rotation arc, 119° (range, 90° to 150°) for elbow flexion, and −33° (range, −60° to −20°) for elbow extension. The power of elbow flexion was M4 in twenty-five patients and M3 in eleven. Twenty-three patients had triceps nerve reconstruction; extension was M0 in two of these patients, M1 in seven, M2 in ten, and M3 in four. Total active motion of the fingers was 46° (range, 0° to 98°), with a mean hook grip strength of 4 kg (range, 0 to 12 kg). Wilcoxon tests revealed significant improvements in the DASH score and the SF-36 physical functioning, role physical, and physical component summary scores. The majority of patients worked but had changed their type of work, used the reconstructed hand in activities of daily living that required both hands, and were satisfied with the procedure. Conclusions: Double free muscle transfer yielded satisfactory function and allowed use of the reconstructed hand in activities that required both hands. The improvement in the DASH score was greater than that in the SF-36 score. Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Studies have suggested that manipulations of the central melanocortin circuitry by pharmacological agents produce robust effects on the regulation of body weight and glucose homeostasis. In this review, we discuss recent findings from genetic mouse models that have further established the physiological relevance of this circuitry in the context of glucose and energy balance. In addition, we will discuss distinct neuronal populations that respond to central melanocortins to regulate food intake, energy expenditure, insulin sensitivity, and insulin secretion, respectively. Finally, multiple hormonal and neural cues (e.g., leptin, estrogen, and serotonin) that use the melanocortin systems to regulate energy and glucose homeostasis will be reviewed. These findings suggest that targeting the specific branches of melanocortin circuits may be potential avenues to combat the current obesity and diabetes epidemics.

Several neurodegenerative diseases involve the selective damage of neuron cells resulting from the accumulation of amyloid fibril formation. Considering that the formation of amyloid fibrils as well as their precursor oligomers is cytotoxic, the agents that prevent the formation of oligomers and/or fibrils might allow the development of a novel therapeutic approach to neurodegenerative diseases. Here, we show pyrroloquinoline quinone (PQQ) inhibits the amyloid fibril formation of the amyloid proteins, amyloid beta (1-42) and mouse prion protein. The fibril formation of mouse prion protein in the presence of PQQ was dramatically prevented. Similarly, the fibril formation of amyloid beta (1-42) also decreased. With further advanced pharmacological approaches, PQQ may become a leading anti-neurodegenerative compound in the treatment of neurodegenerative diseases.

Latent membrane protein 2A (LMP2A) blocks B-cell receptor signal transduction in vitro by binding the Syk and Lyn protein tyrosine kinases. As well as blocking B-cell signal transduction, LMP2A has been shown to activate the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway, which acts as a survival signal in both B cells and epithelial cells. Transforming growth factor β1 (TGF-β1) is a multifunctional cytokine that plays important roles in regulating cell growth and differentiation in many biological systems. The loss of the growth-inhibitory response to the TGF-β1 signal is found in many cancers and is widely thought to promote tumor development. In this study, we found that LMP2A induced the phosphorylation of Akt (serine 473) in Burkitt's lymphoma cell line Ramos and in gastric carcinoma cell line HSC-39 and partially enhanced cell viability following TGF-β1 treatment. In addition, LMP2A partially inhibited TGF-β1-induced DNA fragmentation and cleavage of poly(ADP-ribose) polymerase (PARP). In the presence of LY294002, an inhibitor of PI3-K, the LMP2A-mediated inhibitory effects on TGF-β1-induced DNA fragmentation and cleavage of PARP were alleviated. Furthermore, LMP2A did not alter the levels of expression of type I and type II TGF-β1 receptors. Taken together, these results suggest that LMP2A may inhibit TGF-β1-mediated apoptosis through activation of the PI3-K/Akt pathway.

Accumulated low molecular weight proteins in hemodialysis patients require a high-flux dialyzer. There have been several methods proposed for enhancing internal filtration, including narrowing the inside diameter of the hollow fibers, lengthening the fibers, and increasing the fiber density ratio. We tried to enhance the internal filtration by increasing the pressure drop in the dialysate compartment through increasing the fiber density ratio. If the fiber density ratio is too high, however, an irregular dialysate path may result, thus decreasing dialysis performance. Therefore, we took note of the shape of the inner housing and added a short taper structure, which improved the dialysate path dramatically. Consequently, we developed an internal filtration-enhanced dialyzer (APS-Prototype) to improve dialysis performance. The internal filtration rate in water (measured by Doppler ultrasound) was 13.2 l/session for the APS-Prototype and 5.3 l/session for the APS-15E. The amount of alpha1-microglobulin (alpha1-MG) in bovine plasma was 0.34 g for the APS-Prototype and 0.11 g for the APS-15E. In addition, the amount of alpha1-MG in vivo was 29.0% +/- 5.8% for the APS-Prototype, significantly higher than that for the APS-15E (13.6% +/- 1.9%). The desirable loss of albumin is 2-4 g in hemodiafiltration, and it was 3.92 +/- 1.03 g for the APS-Prototype. The prototype showed excellent solute removal performance with no clinical or engineering problems.

Vascular endothelial growth factor (VEGF) is an important factor involved in angiogenesis. Many studies have reported that the expression of VEGF in breast cancer is an unfavorable prognostic factor. However, there are few studies that have analyzed blood VEGF levels because most used serum VEGF, generally thought to originate from platelets. We measured plasma VEGF levels, which evaluate the level of tumor-derived VEGF, in various breast diseases. We analyzed 15 patients with benign breast disease, 187 patients with primary breast cancer, 32 patients with no postoperative recurrence, and 56 patients with recurrence. Plasma VEGF levels were measured by ELISA. Plasma VEGF levels were higher in malignant than in benign breast disease, and were also high in patients with recurrence or distant metastasis. In primary cases, higher VEGF levels were clearly correlated with menopause and overexpression of p53, and postmenopausal patients with high levels had a significantly lower disease-free survival rate. These results suggest that plasma VEGF levels in breast cancer have a clinical significance in that they are associated with the extent or metastasis of malignant lesions and are involved in angiogenesis in postmenopausal patients.

Epstein-Barr virus (EBV)-infected, gastric epithelial cell line GT38 is resistant to TGF-beta 1-mediated growth inhibition and apoptosis, although TGF-beta 1 partially induces EBV reactivation in the cells. These findings indicate that abnormalities exist in these cells in the TGF-beta 1-mediated signaling pathway, influencing growth inhibition and apoptosis. In order to characterize the steps with abnormalities, we analyzed the TGF-beta 1/MAPK/p21 pathway in the cells. TGF-beta 1 activated MAPK (ERK 1/2) and p21 in the TGF-beta 1-susceptible cell line HSC-39 but not in GT38 cells. GT38 cells had higher constitutive levels of ERK 1/2 phosphorylation and p21 expression than did HSC-39 cells. U0126, a specific inhibitor of MEK, suppressed TGF-beta 1-mediated ERK 1/2 phosphorylation and p21 induction in HSC-39 cells and constitutive ERK 1/2 phosphorylation in GT38 cells. EBV latent membrane protein 1 (LMP1) induced constitutive ERK 1/2 phosphorylation and NF-kappa B activation in LMP1-transfected HSC-39 cells, which then became resistant to TGF-beta 1-mediated growth inhibition, TGF-beta 1-mediated ERK 1/2 phosphorylation, and p21 induction, and proliferated in low-serum medium. These results are consistent with the conclusion that the TGF-beta 1/MAPK/p21 pathway is required for TGF-beta 1-mediated growth inhibition, and that the resistance to TGF in GT38 cells is derived from constitutive MAPK phosphorylation induced by LMP1.

In order to understand mechanistic relationships between signaling pathways regulating mitogen-activated protein kinase (MAPK) phosphorylation and Epstein-Barr virus (EBV) reactivation, we compared MAPK phosphorylation, and EBV reactivation and latency in Burkitt's lymphoma cell lines (BLCLs) versus B lymphoblastoid cell lines (LCLs). EBV was reactivated in the BLCLs Akata and Raji, and in a LCL OB-R33 cells after cross-linking surface immunoglobulin (sIg) with anti-Ig. After stimulation with anti-Ig, MAPK phosphorylation was strongly induced in all BLCLs and in a few LCLs, but not in other LCLs. MAPK was constitutively phosphorylated in most LCLs but not in BLCLs. Expression of EBNA2 and LMP1, and LMP2A was analyzed with both immunoblotting and RT-PCR. EBNA2 and LMP1 were expressed in most LCLs and in some BLCLs. LMP2A was expressed in all BLCLs and LCLs except Namalwa cells. To test the hypothesis that LMPI induces constitutive MAPK phosphorylation, the LMP1 expression vector was transfected into Akata cells. MAPK phosphorylation was not induced in such transfected cells. Our results indicate that BLCLs and LCLs respectively have distinct MAPK phosphorylation patterns, and that induction of MAPK phosphorylation correlates with EBV reactivation in a few cell lines but not in most of the tested cell lines.

The classical mitogen-activated protein kinase (MAPK, also known as ERK) pathway is widely involved in eukaryotic signal transductions. In response to extracellular stimuli, MAPK becomes activated and translocates from the cytoplasm to the nucleus. At least two pathways for the nuclear import of MAPK are shown to exist; passive diffusion of a monomer and Ran-dependent active transport of a dimer, the detailed molecular mechanism of which is unknown. In this study, we have reconstituted nuclear import of MAPK in vitro by using digitonin-permeabilized cells with GFP-fused MAPK protein (GFP-MAPK), which is too large to pass through the nuclear pore by passive diffusion. GFP-MAPK was able to accumulate in the nucleus irrespective of its phosphorylation state. This import of GFP-MAPK occurred even in the absence of any soluble cytosolic factors or ATP but was inhibited by wheat germ agglutinin or an excess amount of importin-beta or at low temperatures. Moreover, MAPK directly bound to an FG repeat region of nucleoporin CAN/Nup214 in vitro. Taken together, these results suggest the third pathway for nuclear import of MAPK, in which MAPK passes through the nuclear pore by directly interacting with the nuclear pore complex.

A great deal of research has been conducted focusing on membrane materials with reference to their blood compatibility, but blood compatibility is influenced both by the material used in membranes and their structure, and by the flow conditions at the membrane surface. Accordingly, the relationship between membrane surface roughness and hemocompatibility has been evaluated using five types of membranes of differing surface roughness by evaluating the inner surfaces of the hollow fibers by atomic force microscopy (AFM) and by measuring platelet adhesion ratios using bovine blood. The yield stress, which equates to flow characteristics, was also evaluated using a glycerol suspension of polymethylmethacrylate (PMMA), a Bingham fluid. It was found that membranes having rough surfaces had high platelet adhesion ratios and poor hemocompatibility, whereas those with smoother surfaces had lower platelet adhesion ratios and better hemocompatibility. Measurement of the yield stresses for these membranes revealed higher values for those with rough surfaces, and lower values for those with smoother polyethylene glycol (PEG) grafted surfaces. This suggests that flow conditions at the membrane surface differ according to its surface roughness, and that this difference in flow conditions also influences hemocompatibility.

Background and Objectives Apoptosis is essential to maintain homeostasis in living organisms and occurs in a variety of tissues in response to both physiological and pathological stimuli. In breast cancer, most cytotoxic drugs and hormonal treatments induce apoptosis. We studied the relationships between apoptosis and clinicopathological variables or prognosis in 143 patients with operable breast cancer. Methods Apoptosis was numerically graded in 5 consecutive 40× high-power fields (HPF) of hematoxylin-eosin (H&E) stained sections, since we showed that there was a significant correlation of H&E staining with terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining. Results The average number of apoptotic cells was 19.9 (0∼168)/5 HPF, and cases were classified into 3 groups based on the number of apoptotic cells/5HPF: 0 to 10, 11 to 30, and 31+. The level of apoptosis increased with increasing size of the tumor, and apoptosis was rarely seen in tumors with positive ER or lower proliferative activity, as assessed by DNA polymerase α. As shown by DNA content analysis, apoptotic cells were observed more frequently in tumors with low G1 and high S-phase fractions. In addition, apoptosis was correlated with overexpression of p53 and poor prognosis. Although apoptosis did not correlate with EIC (extensive intraductal component) status, tumors with comedo component had higher values of apoptosis than those without comedo component. Conclusions In breast cancer, apoptosis might reflect biological behavior, namely a higher degree of biological aggressiveness and unfavorable prognosis. J. Surg. Oncol. 1999;71:226–234. © 1999 Wiley-Liss, Inc.