A positive direct Coombs' test in the absence of hemolytic anemia predicts high disease activity and poor renal response in systemic lupus erythematosus.

We determined the clinical utility of the direct Coombs' test in the absence of hemolytic anemia as an indicator of disease activity and therapeutic response in systemic lupus erythematosus (SLE). SLE patients without hemolytic anemia who visited our hospital from January 2016 to November 2016 were retrospectively evaluated with a direct Coombs' test. Clinical features, including SLE disease activity index (SLEDAI), treatment and laboratory findings were analyzed. For patients with lupus nephritis, we additionally evaluated the cumulative complete renal response rate over one year after induction therapy. Among 182 patients evaluated, 10 (5.8%) patients had a positive direct Coombs' test in the absence of hemolytic anemia. They had a higher SLEDAI ( p < 0.01), higher circulating immune complex levels ( p = 0.01), higher anti-DNA titers ( p < 0.01) and a lower complete renal response rate ( p = 0.03) compared with those who were negative. Multivariate analysis indicated that SLEDAI was an independent factor correlated with the direct Coombs' test without hemolytic anemia (odds ratio 2.4, 95% confidence interval 1.66-4.98, p < 0.01). A positive direct Coombs' test in the absence of hemolytic anemia may therefore represent a useful biomarker for assessing disease activity and therapeutic response.

Biomimetic flavin-catalysed reactions for organic synthesis.

Using simple riboflavin related compounds as biomimetic catalysts, catalytic oxidation of various substrates with hydrogen peroxide or molecular oxygen can be performed selectively under mild conditions. The principle of these reactions is fundamental and will provide a wide scope for environmentally benign future practical methods.

Continuing increased risk of oral/esophageal cancer after allogeneic hematopoietic stem cell transplantation in adults in association with chronic graft-versus-host disease.

BACKGROUND: The number of long-term survivors after hematopoietic stem cell transplantation (HSCT) showed steady increase in the past two decades. Second malignancies after HSCT are a devastating late complication. We analyzed the incidence of, risk compared with that in the general population, and risk factors for secondary solid cancers. PATIENTS AND METHODS: Patients were 17 545 adult recipients of a first allogeneic stem cell transplantation between 1990 and 2007 in Japan. Risks of developing secondary solid tumors were compared with general population by using standard incidence ratios (SIRs). RESULTS: Two-hundred sixty-nine secondary solid cancers were identified. The cumulative incidence was 0.7% [95% confidence interval (CI), 0.6%-0.9%] at 5 years and 1.7% (95% CI, 1.4%-1.9%) at 10 years after transplant. The risk was significantly higher than that in the general population (SIR=1.8, 95% CI, 1.5-2.0). Risk was higher for oral cancer (SIR=15.7, 95% CI, 12.1-20.1), esophageal cancer (SIR=8.5, 95% CI, 6.1-11.5), colon cancer (SIR=1.9, 95% CI, 1.2-2.7), skin cancer (SIR=7.2, 95% CI, 3.9-12.4), and brain/nervous system cancer (SIR=4.1, 95% CI, 1.6-8.4). The risk of developing oral, esophageal, or skin cancer was higher at all times after 1-year post-transplant. Extensive-type chronic graft-versus-host disease (GVHD) was a significant risk factor for the development of all solid tumors (RR=1.8, P<0.001), as well as for oral (RR=2.9, P<0.001) and esophageal (RR=5.3, P<0.001) cancers. Limited-type chronic GVHD was an independent risk factor for skin cancers (RR=5.8, P=0.016). CONCLUSION: Recipients of allogeneic HSCT had a significantly higher ∼2-fold risk of developing secondary solid cancers than the general population. Lifelong screening for high-risk organ sites, especially oral or esophageal cancers, is important for recipients with active, or a history of, chronic GVHD.

Effects of low-intensity, elastic band resistance exercise combined with blood flow restriction on muscle activation.

We examined the effects of blood flow-restricted, low-intensity resistance exercise (termed kaatsu) using an elastic band for resistance on muscle activation. Nine men performed triceps extension and biceps flexion exercises (four sets respectively) using an elastic band for resistance with blood flow restriction (BFR) or CON (unrestricted blood flow). During a BFR session, subjects wore pressure cuffs inflated to 170-260 mmHg on the proximal region of both arms. Surface electromyography (EMG) was recorded from the triceps brachii and biceps brachii muscles, and mean integrated EMG (iEMG) was analyzed. Blood lactate concentration was obtained before (Pre) and immediately after two exercises (Post). During triceps extension and biceps flexion exercises, muscle activation increased progressively (P < 0.05) under BFR (46% and 69%, respectively) but not under CON (12% and 23%, respectively). Blood lactate concentration at Post was higher (P < 0.05) under BFR than under CON (3.6 and 2.1 mmol/L, respectively). Blood lactate concentration at Post was significantly correlated with increased iEMG in both triceps extension (r = 0.65, P < 0.01) and biceps flexion exercises (r = 0.52, P < 0.05). We conclude that kaatsu training using elastic bands for resistance enhances muscle activation and may be an effective method to promote muscle hypertrophy in older adults or patients with a low level of activity.

Muscle size and arterial stiffness after blood flow-restricted low-intensity resistance training in older adults.

Previous studies have shown that blood flow-restricted low-intensity resistance training (BFR-RT) causes muscle hypertrophy while maintaining arterial function in young adults. We examined the effects of BFR-RT on muscle size and arterial stiffness in older adults. Healthy subjects (ages 61-84 years) were divided into BFR-RT (n = 9) or non-training control (CON; n = 10) groups. The BFR-RT group performed 20% and 30%, respectively, of one-repetition maximal (1-RM) knee extension and leg press exercises, 2 days/wk for 12 weeks. The BFR-RT group wore elastic cuffs (120-270 mmHg) on both legs during training. Magnetic resonance imaging-measured muscle cross-sectional area (CSA), 1-RM strength, chair stand (CS) test, and cardio-ankle vascular index testing (CAVI), an index of arterial stiffness, were measured before and 3-5 days after the final training session. Muscle CSA of the quadriceps (8.0%), adductors (6.5%), and gluteus maximus (4.4%), leg extension and leg press 1-RM strength (26.1% and 33.4%), and CS performance (18.3%) improved (P < 0.05) in the BFR-RT group, but not in the CON group. In CAVI testing, there were no changes in both two groups. In conclusion, BFR-RT improves muscle CSA as well as maximal muscle strength, but does not negatively affect arterial stiffness or humeral coagulation factors in older adults.

Impact of a donor source on adult Philadelphia chromosome-negative acute lymphoblastic leukemia: a retrospective analysis from the Adult Acute Lymphoblastic Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation.

BACKGROUND: We aimed to clarify the impact of the donor source of allogeneic stem cell transplantation (allo-SCT) on Philadelphia chromosome-negative acute lymphoblastic leukemia [Ph(-) ALL] with focus on cord blood (CB). PATIENTS AND METHODS: We retrospectively analyzed data of 1726 patients who underwent myeloablative allo-SCT for adult Ph(-) ALL. The sources of the allo-SCT were related donors (RD; N = 684), unrelated donors (URD; N = 809), and CB (N = 233). RESULTS: Overall survival (OS) in patients after CB allo-SCT in first complete remission (CR1) was comparable with that after RD or URD allo-SCT (RD: 65%, URD: 64% and CB: 57% at 4 years, P = 0.11). CB was not a significant risk factor for relapse or non-relapse mortality as well as for OS in multivariate analyses. Similarly, the donor source was not a significant risk factor for OS in subsequent CR or non-CR (RD: 47%, URD: 39% and CB: 48% in subsequent CR, P = 0.33; RD: 15%, URD: 21% and CB: 18% in non-CR, P = 0.20 at 4 years). CONCLUSION: Allo-SCT using CB led to OS similar to those of RD or URD in any disease status. To avoid missing the appropriate timing, CB is a favorable alternative source for adult Ph(-) ALL patients without a suitable RD or URD.

Clinical associations and risk factors for bleeding from colonic angiectasia: a case-controlled study.

AIM: A case-controlled study was performed to investigate the association of colonic angiectasia with other conditions and to identify risk factors for bleeding. METHOD: Information was collected from all patients who underwent colonoscopy at our hospital between January 2008 and December 2010. Data on 90 individuals with angiectasia [58 men; median age 69 (26-92) years] were compared with those of 180 individuals without angiectasia, matched for gender and age. RESULTS: Multivariate analysis showed that occult gastrointestinal bleeding [odds ratio (OR) 2.523; 95% confidence interval (CI) 1.238-5.142], liver cirrhosis (OR 13.195; 95% CI 3.502-49.711), chronic renal failure (OR 6.796; 95% CI 1.598-28.904) and valvular heart disease (OR 6.425; 95% CI 1.028-40.165) were identified as significant predictors of the presence of colonic angiectasia. Eight patients were diagnosed with bleeding from angiectasia. Cardiovascular disease (OR 22.047; 95% CI 1.063-457.345) and multiple angiectasias (P-value 0.0019) were identified as significant risk factors for active bleeding. Medication and a large size were not associated with an increased risk of bleeding. CONCLUSION: The presence of colonic angiectasia was associated with valvular heart disease, liver cirrhosis and chronic renal failure. Valvular heart disease and multiple lesions increased the risk of bleeding.

Permanent cerebral bypass approach for lung cancer resection with aortic arch invasion.

We report a case of a 54-year-old man with T4N0M0 non-small cell lung cancer directly invading the thoracic wall and aortic arch. He underwent neoadjuvant chemotherapy followed by en bloc resection of the tumor, lung, chest wall and aortic arch. Perfusion was maintained through femoral-femoral cardiopulmonary bypass, with permanent bypass to the arch vessels to avoid separate extracorporeal cerebral circulation. Total reconstructions of the chest wall and aortic arch were completed without the need for cardiac arrest. The final pathological diagnosis was squamous cell carcinoma, T4N0M0. The patient was discharged without major complications and has been free of disease for 20 months postoperatively.

Association between lipoprotein subfraction profile and the response to hepatitis C treatment in Japanese patients with genotype 1b.

Pegylated interferon and ribavirin combination therapy is the standard treatment for patients with chronic hepatitis C (CHC). Some groups have reported a relation between lipid values and response while others have reported that microsomal triglyceride transfer protein, a key enzyme in the assembly and secretion of lipoproteins, was related to hepatitis C virus (HCV). The aim of this study was to investigate the association between the lipoprotein profiles, classified according to size, and hepatitis C treatment and the usefulness for predicting the outcome of treatment. Forty-four patients with CHC (27 men and 17 women) were included in the study. The serum cholesterol and triglyceride (TG) levels in the lipoprotein subclasses were determined using high-performance liquid chromatography with gel permeation columns, which classified lipoproteins into 20 subfractions based on particle size. According to a univariate analysis, those who achieved an sustained viral response (SVR) had a significantly higher serum total cholesterol level, higher cholesterol levels in the low-density lipoprotein subfraction (25.5 nm in diameter) and the very low-density lipoprotein (VLDL) subfraction (44.5 and 36.8 nm), and a higher serum TG level in the VLDL subfraction (44.5 nm), compared with the corresponding values in the non-SVR group. Higher serum cholesterol and TG concentrations in the lipoprotein subfractions were predictive of an SVR to therapy for HCV infection with genotype 1b prior to the start of interferon treatment.

Association between phospholipids and free cholesterol in high-density lipoprotein and the response to hepatitis C treatment in Japanese with genotype 1b.

Pegylated interferon and ribavirin combination therapy is the standard treatment for patients with chronic hepatitis C (CHC), but treatment failure can be difficult to predict. We and others have reported a relation between lipid values and sustained viral responses in patients with CHC. However, the relationship between lipid values and treatment failure has not been previously reported. The present study investigated the association between the profiles of phospholipids and free cholesterol (FC), the main constitutive ingredients of the surface of lipoprotein, classified according to particle size and hepatitis C treatment, and determined the usefulness of these parameters for predicting the outcome of treatment. Fifty-five patients with CHC (33 men and 22 women) were included in the study. The serum total cholesterol, triglyceride, phospholipids, and FC levels in the lipoprotein subclasses were determined using high-performance liquid chromatography with gel permeation columns, enabling the lipoproteins to be classified into 13 subclasses according to particle size. According to a univariate analysis, the treatment failure group had a significantly higher serum phospholipid level overall in the high-density lipoprotein (HDL) and medium HDL fractions as well as a higher serum FC level in the HDL fraction and all HDL subclass fractions compared with the corresponding values in the non-nonvirological response group. Higher serum phospholipid and FC concentrations in the HDL subclasses were predictive of a failure to respond in patients with genotype 1b.

Clinical factors affecting the efficacy of vancomycin in methicillin-resistant Staphylococcus aureus pneumonia.

OBJECTIVE: Methicillin-resistant Staphylococcus aureus (MRSA) is a major nosocomial pathogen. Patients with risk factors such as long hospital admission and compromised hosts are prone to MRSA infection, particularly MRSA pneumonia that is not resolved effectively and causes significant mortality. To identify the factors affecting the efficacy of vancomycin (VCM) therapy on MRSA pneumonia, a retrospective investigation was carried out. METHODS: Severity rating of pneumonia, pharmacokinetic parameters of VCM, clinical improvement following VCM therapy, clinical data and patient's background were investigated in 40 patients from January 2003 to March 2008. The outcome was evaluated 30 days after the initiation of VCM therapy, and multivariate logistic regression analysis was performed. RESULTS: The 30 day mortality rate was 15.0% (6 patients). As a result of multivariate logistic regression analysis, underlying malignancy and parenteral nutrition as the route of feeding during VCM therapy (odds ratio (OR) = 22.3, 95% confidence interval (CI) = 1.55-322; OR = 12.6, 95% CI = 1.15-139, respectively) were found to be significant factors affecting the survival. No pharmacokinetic parameters of VCM and severity of pneumonia were significant. CONCLUSION: Underlying malignancy and parenteral nutrition, which were associated with nutrition and the immune system, were found to affect the survival after 30 days of VCM therapy.

Non-invasive estimation of hepatic glucose uptake from [18F]FDG PET images using tissue-derived input functions.

PURPOSE: The liver is perfused through the portal vein and hepatic artery. Quantification of hepatic glucose uptake (HGU) using PET requires the use of an input function for both the hepatic artery and portal vein. The former can be generally obtained invasively, but blood withdrawal from the portal vein is not practical in humans. The aim of this study was to develop and validate a new technique to obtain quantitative HGU by estimating the input function from PET images. METHODS: Normal pigs (n = 12) were studied with [18F]FDG PET, in which arterial and portal blood time-activity curves (TAC) were determined invasively to serve as reference measurements. The present technique consisted of two characteristics, i.e. using a model input function and simultaneously fitting multiple liver tissue TACs from images by minimizing the residual sum of square between the tissue TACs and fitted curves. The input function was obtained from the parameters determined from the fitting. The HGU values were computed by the estimated and measured input functions and compared between the methods. RESULTS: The estimated input functions were well reproduced. The HGU values, ranging from 0.005 to 0.02 ml/min per ml, were not significantly different between the two methods (r = 0.95, p < 0.001). A Bland-Altman plot demonstrated a small overestimation by the image-derived method with a bias of 0.00052 ml/min per g for HGU. CONCLUSION: The results presented demonstrate that the input function can be estimated directly from the PET image, supporting the fully non-invasive assessment of liver glucose metabolism in human studies.

Specific early-G1 blocks accompanied with stringent response in Saccharomyces cerevisiae lead to growth arrest in resting state similar to the G0 of higher eucaryotes.

Growth arrests of Saccharomyces cerevisiae cells in early G1 phase brought by various means were classified into two types according to the mode of growth recovery after release of the restraints against growth. The first type, including arrests caused by cdc25, cdc33, cdc35, and ils1 mutations at the nonpermissive temperature and also by sulfur starvation, showed a subsequent delay in the onset of budding when shifted back to permissive conditions. The length of the delay was positively correlated with the time that cells had been arrested. The second type, including those caused by cdc28 and cdc24 mutations and by alpha factor, did not affect the mode of growth recovery after the shift to permissive conditions irrespective of the time that cell proliferation had been restricted. Growth arrests of the first type seem to allow yeast cells to enter a resting state equivalent to the G0 state of higher eucaryotes because features of the G0 shown with lymphocytes and other cultured cells including unusually long delay before the growth recovery (L.H. Augenlicht and R. Baserga, 1974, Exp. Cell Res., 89:255-262; and Kumagai, J., H. Akiyama, S. Iwashita, H. lida, and I. Yahara, 1981, J. Immunol., 126:1249-1254) appeared to be associated with this type. We have noted that arrests of the first type were always accompanied with a stringent response of macromolecular synthesis and its partial release by cycloheximide. Mapping of arrest points along the path of the cell cycle by the reciprocal shift experiment suggested that arrest points in G1 that led to the G0-like arrest precede or are near the step sensitive to alpha-factor.

A heat shock-resistant mutant of Saccharomyces cerevisiae shows constitutive synthesis of two heat shock proteins and altered growth.

A heat shock-resistant mutant of the budding yeast Saccharomyces cerevisiae was isolated at the mutation frequency of 10(-7) from a culture treated with ethyl methane sulfonate. Cells of the mutant are approximately 1,000-fold more resistant to lethal heat shock than those of the parental strain. Tetrad analysis indicates that phenotypes revealed by this mutant segregated together in the ratio 2+:2- from heterozygotes constructed with the wild-type strain of the opposite mating type, and are, therefore, attributed to a single nuclear mutation. The mutated gene in the mutant was herein designated hsr1 (heat shock response). The hsr1 allele is recessive to the HSR1+ allele of the wild-type strain. Exponentially growing cells of hsr1 mutant were found to constitutively synthesize six proteins that are not synthesized or are synthesized at reduced rates in HSR1+ cells unless appropriately induced. These proteins include one hsp/G0-protein (hsp48A), one hsp (hsp48B), and two G0-proteins (p73, p56). Heterozygous diploid (hsr1/HSR1+) cells do not synthesize the proteins constitutively induced in hsr1 cells, which suggests that the product of the HSR1 gene might negatively regulate the synthesis of these proteins. The hsr1 mutation also led to altered growth of the mutant cells. The mutation elongated the duration of G1 period in the cell cycle and affected both growth arrest by sulfur starvation and growth recovery from it. We discuss the problem of which protein(s) among those constitutively expressed in growing cells of the hsr1 mutant is responsible for heat shock resistance and alterations in the growth control.

Durable synthesis of high molecular weight heat shock proteins in G0 cells of the yeast and other eucaryotes.

We report that eucaryotic cells were induced to synthesize a specific class of heat shock proteins (hsps) when they entered the resting state, G0. This finding was originally made with Saccharomyces cerevisiae cells by taking advantage of the system in which we can distinguish between G1 arrests leading to G0 and those that do not result in G0 (Iida, H., and I. Yahara, 1984, J. Cell Biol. 98:1185-1193). Similar observations were subsequently made with higher eucaryotic cells including chick embryonic fibroblasts (CEF), mouse T lymphocytes, and Drosophila GM1 cells. The induction of hsps in G0 cells was distinct from that in heat-shocked cells in two respects. First, hsps with molecular weight around 25,000 were not induced in G0 cells, whereas most, if not all, high molecular weight (HMW) hsps were commonly induced both in G0 cells and in heat-shocked cells. Second, in contrast to the transient synthesis of hsps in heat-shocked cells, G0 cells continued to synthesize hsps at the stimulated rate for a relatively long period. These results suggest the possibility that high molecular weight hsps might function in a transition from the proliferating state to G0 or in maintaining G0 in the eucaryote.

Molecular identification of a eukaryotic, stretch-activated nonselective cation channel.

Calcium-permeable, stretch-activated nonselective cation (SA Cat) channels mediate cellular responses to mechanical stimuli. However, genes encoding such channels have not been identified in eukaryotes. The yeast MID1 gene product (Mid1) is required for calcium influx in the yeast Saccharomyces cerevisiae. Functional expression of Mid1 in Chinese hamster ovary cells conferred sensitivity to mechanical stress that resulted in increases in both calcium conductance and the concentration of cytosolic free calcium. These increases were dependent on the presence of extracellular calcium and were reduced by gadolinium, a blocker of SA Cat channels. Single-channel analyses with cell-attached patches revealed that Mid1 acts as a calcium-permeable, cation-selective stretch-activated channel with a conductance of 32 picosiemens at 150 millimolar cesium chloride in the pipette. Thus, Mid1 appears to be a eukaryotic, SA Cat channel.

A method to measure PET scatter fractions for daily quality control.

PURPOSE: Regular monitoring of PET scanner performance is mandatory to assure quality of acquired data. While extensive performance measurements include many scanner characteristics such as resolution, count rate, uniformity, sensitivity, and scatter fraction (SF), most daily QC protocols are limited to uniformity and sensitivity measurements. These measurements may be too insensitive to detect more subtle drifts in detector gains that could lead to reduced detection of primary and increased detection of scattered events. Current methods to measure SF, such as those prescribed by the NEMA protocols (SF-NEMA), however, require specially designed phantoms and are too cumbersome to be performed on a daily basis. METHODS: In this study, a simple and versatile method to determine SF is described. This method (SF-DAILY) does not require additional measurements, making it suitable for daily QC. The method was validated for four different scanners by comparing results with those obtained with the NEMA 1994 protocol. RESULTS: For all scanner types and acquisition modes, excellent agreement was found between SF-NEMA and SF-DAILY. CONCLUSIONS: The proposed method is a very practical and valuable addition to current daily QC protocols. In addition, the method can be used to accurately measure SF in phantoms with other dimensions than the NEMA phantom.

Aperitif effects on gastric emptying: a crossover study using continuous real-time 13C breath test (BreathID System).

The aim of this study was to determine whether there is a correlation between aperitif and gastric emptying. Ten healthy male volunteers participated in this randomized, two-way crossover study. Under two conditions (after drinking an aperitif versus not), the (13)C breath test was performed for 4 h with a liquid meal (200 kcal/200 ml) containing 100 mg (13)C acetate. We used 50 ml of umeshu as the aperitif. This is a traditional Japanese plum liqueur, and contains 7 ml alcohol (14%). In the aperitif group, T(1/2), T(lag), and T(peak) were significantly delayed [T(1/2) (132: 113-174) versus (112: 92-134) (P = 0.0069); T(lag) (80: 63-94) versus (55: 47-85) (P = 0.0069); and T(peak) (81: 62-96) versus (54: 34-84) (P = 0.0069), (median: range, aperitif versus control, min)]. Gastric emptying was significantly delayed in the aperitif group as compared with the control group. This study revealed that even a small amount of alcohol such as an aperitif may contribute to delayed gastric emptying.

Risk factors for the progression of endoscopic Barrett's epithelium in Japan: a multivariate analysis based on the Prague C & M Criteria.

PURPOSE: To determine the prevalence and progression of Barrett's epithelium and associated risk factors in Japan. METHODS: The study population comprised 869 cases. Endoscopic Barrett's epithelium was diagnosed based on the Prague C & M Criteria. The correlations of clinical factors with the prevalence and progression of endoscopic Barrett's epithelium were examined. RESULTS: Endoscopic Barrett's epithelium was diagnosed in 374 cases (43%), in the majority of which the diagnosis was short-segment Barrett's esophagus. The progression of Barrett's epithelium was identified in 47 cases. In univariate and multiple logistic regression analyses, aging, smoking habit, and erosive esophagitis were significantly associated with the prevalence of Barrett's epithelium, whereas aging and erosive esophagitis, especially severe erosive esophagitis, were significant contributing factors to the progression of Barrett's epithelium. CONCLUSIONS: Forty-three percent of the total study population was diagnosed as having endoscopic Barrett's epithelium. During the follow-up period, 12.6% of the cases with Barrett's epithelium exhibited progression which was associated with aging and severe erosive esophagitis.