Mumefural prevents insulin resistance and amyloid-beta accumulation in the brain by improving lowered interstitial fluid pH in type 2 diabetes mellitus.

The present study tried to clarify if mumefural would prevent hyperglycemia, one of the typical symptoms of type 2 diabetes mellitus (T2DM), since mumefural is an extract from Japanese apricots preventing hyperglycemia. To clarify if mumefural would prevent T2DM pathogenesis, we used Otsuka Long-Evans Tokushima fatty (OLETF) rats, T2DM model. Mumefural diminished hyperglycemia, HOMA-IR and plasma triglyceride concentration in OLETF rats under fasting conditions. In addition, mumefural elevated protein expression of sodium-coupled monocarboxylate transporter 1 (SMCT1) in the distal colon participating in absorption of weak organic acids, which behave as bases but not acids after absorption into the body. Mumefural also increased the interstitial fluid pH around the brain hippocampus lowered in OLETF rats compared with non-T2DM LETO rats used as control for OLETF rats. Amyloid-beta accumulation in the brain decreased in accordance with the pH elevation. On the one hand, mumefural didn't affect plasma concentrations of glucagon, GLP-1, GIP or PYY under fasting conditions. Taken together, these observations indicate that: 1) mumefural would be a useful functional food improving hyperglycemia, insulin resistance and the lowered interstitial fluid pH in T2DM; 2) the interstitial fluid pH would be one of key factors influencing the accumulation of amyloid-beta.

Possibility of Venous Serum Cl- Concentration ([Cl-]s) as a Marker for Human Metabolic Status: Correlation of [Cl-]s to Age, Fasting Blood Sugar (FBS), and Glycated Hemoglobin (HbA1c).

The HCO3- concentration in venous serum ([HCO3-]s) is a factor commonly used for detecting the body pH and metabolic conditions. To exactly detect [HCO3-]s, the venous CO2 pressure should be kept as it is in the vein. The [HCO3-]s measurement is technically complicated to apply for huge numbers of almost heathy persons taking only basic medical examinations. The summation of [HCO3-]s and the venous serum Cl- concentration ([Cl-]s) is approximately constant; therefore, we studied if [Cl-]s could be a marker detecting metabolic conditions instead of [HCO3-]s. Venous blood was obtained from persons taking basic medical examinations (the number of persons = 107,630). Older persons showed higher values of [Cl-]s, fasting blood sugar (FBS), and glycated hemoglobin (HbA1c) than younger ones. [Cl-]s showed positive correlation to age and negative correlation to FBS and HBA1c. The negative correlation of [Cl-]s to FBS/HbA1c was obvious in persons with high FBS/HbA1c, leading us to an idea that persons with high FBS/HbA1c show high [HCO3-]s, which might be caused by low activity of carbonic anhydrase in the lung observed in persons with diabetes mellitus under acidotic conditions. Taken together, an easily measured serum electrolyte, [Cl-]s, could be a useful marker estimating metabolic conditions.

Essential requirement of complex number for oscillatory phenomenon in intracellular trafficking process.

Intracellular protein trafficking processes consisting of three intracellular states are described by three differential equations. To solve the equations, a quadratic equation is required, and its roots are generally real or complex. The purpose of the present study is to clarify the meanings of roots of real and complex numbers. To clarify the point, we define that: 1) ' k I ' is the insertion rate from an insertion state trafficking to the plasma membrane state; 2) ' k E ', the endocytotic rate from the plasma membrane state trafficking to a recycling state; 3) ' k R ', the recycling rate from the recycling state trafficking to the insertion state. Amounts of proteins in three states are expressed as α e lt + ß e mt + γ with α , ß , γ  = constant and l and m are roots of a quadratic equation, r 2 + k I + k E + k R r + k I k E + k I k R + k E k R = 0 . When l and m are real k I 2 + k E 2 + k R 2 > 2 k I k E + k E k R + k R k I , amounts of proteins in three states shows no oscillatory change but a monotonic change after a transient increase (or decrease); when l and m are complex k I 2 + k E 2 + k R 2 < 2 k I k E + k E k R + k R k I , amounts of proteins in three states are expressed as α e lt + ß e mt + γ = 2 g 2 + h 2 sin b t + σ e at + γ ( α , ß , l , m  = complex and γ , a , b , g , h , σ  = real: α , ß  = conjugate each other; l , m  = conjugate each other), showing an oscillatory change with time. The frequency of oscillatory change appearance is evaluated to be 60% at random combinations of three trafficking rates, k I , k E and k R . The present study indicates that complex numbers have an essentially important meaning in appearance of oscillatory phenomena in bodily and cellular function.

Tentative diagnostic criteria and disease severity classification for Castleman disease: A report of the research group on Castleman disease in Japan.

OBJECTIVES: To determine the tentative diagnostic criteria and disease severity classification for Castleman disease (CD) and describe the clinical and pathologic features among human herpesvirus 8 (HHV-8) negative idiopathic multicentric CD (iMCD) in the Japanese population. METHODS: We established the working groups for the research of CD in Japan and had meetings to discuss and define the tentative diagnostic criteria and disease severity classification for CD. We subsequently analyzed 142 patients classified into iMCD by using the nationwide Japanese patient registry. RESULTS: We proposed the preliminary diagnostic criteria and disease severity classification for CD based on our discussion. In addition, we made a proposal for the disease activity score. We identified clinical and pathological features of patients with iMCD diagnosed by these diagnostic criteria. In the disease severity classification, 37, 33 and 30% patients were categorized into mild, moderate and severe diseases, respectively. CONCLUSION: This is the first proposal for diagnosis and classification of CD by the Japanese group. Further studies are required to validate whether they can distinguish CD from other inflammatory diseases and to determine their sensitivity and specificity.

Pretreatment Prediction of Individual Rheumatoid Arthritis Patients' Response to Anti-Cytokine Therapy Using Serum Cytokine/Chemokine/Soluble Receptor Biomarkers.

UNLABELLED: The inability to match rheumatoid arthritis (RA) patients with the anti-cytokine agent most efficacious for them is a major hindrance to patients' speedy recovery and to the clinical use of anti-cytokine therapy. Identifying predictive biomarkers that can assist in matching RA patients with more suitable anti-cytokine treatment was our aim in this report. The sample consisted of 138 RA patients (naïve and non-naïve) who were administered tocilizumab or etanercept for a minimum of 16 weeks as a prescribed RA treatment. Pretreatment serum samples were obtained from patients and clinical measures of their disease activity were evaluated at baseline and 16 weeks after treatment commenced. Using patients' pretreatment serum, we measured 31 cytokines/chemokines/soluble receptors and used multiple linear regression analysis to identify biomarkers that correlated with patients' symptom levels (DAS28-CRP score) at week 16 and multiple logistic analyses for biomarkers that correlated with patients' final outcome. The results revealed that sgp130, logIL-6, logIL-8, logEotaxin, logIP-10, logVEGF, logsTNFR-I and logsTNFR-II pretreatment serum levels were predictive of the week 16 DAS28-CRP score in naïve tocilizumab patients while sgp130, logGM-CSF and logIP-10 were predictive in non-naïve patients. Additionally, we found logIL-9, logVEGF and logTNF-α to be less reliable at predicting the week 16 DAS28-CRP score in naïve etanercept patients. Multiple linear regression and multiple logistic regression analyses identified biomarkers that were predictive of remission/non-remission in tocilizumab and etanercept therapy. Although less reliable than those for tocilizumab, we identified a few possible biomarkers for etanercept therapy. The biomarkers for these two therapies differ suggesting that their efficacy will vary for individual patients. We discovered biomarkers in RA pretreatment serum that predicted their week 16 DAS28-CRP score and clinical outcome to tocilizumab therapy. Most of these biomarkers, especially sgp130, are involved in RA pathogenesis and IL-6 signal transduction, which further suggests that they are highly reliable. TRIAL REGISTRATION: UMIN-CTR Clinical Trial UMIN000016298.

IFN production ability and healthy ageing: mixed model analysis of a 24 year longitudinal study in Japan.

OBJECTIVE: To track changes in interferon (IFN) production in healthy individuals to shed light on the effect these changes have on the course of healthy ageing. DESIGN: Study is based on data that were collected over 24 years from a cohort of individuals whose IFN-α production was quantified as a part of their annual routine health check-up. SETTING: All individuals in this study underwent regular health check-ups at Louis Pasteur Center for Medical Research. PARTICIPANTS: 295 healthy individuals (159 males and 136 females) without a history of cancer, autoimmune diseases and hepatitis C virus (HCV) whose IFN-α production was quantified more than five times within 24 years were selected. Finally, 29 males and 4 females whose IFN-α production was quantified more than 25 times were selected and their data were analysed using a mixed model. MAIN OUTCOME MEASURES: HVJ stimulated IFN-α  production was quantified. Healthy individual's periodical log transformed IFN-α values (y) were plotted versus age (x) and fitted to linear (y=mx+n) and quadratic formula (y=ax(2)+bx+c) expressions to reveal changes in the IFN-α  production in these healthy individuals. RESULTS: The linear expression showed that log (IFN-α) had a slight tendency to decline (3% over 10 years). However, the quadratic formula analysis showed the quadratic expression to be more positive than negative (a concave U-shaped pattern) which means that individuals' once declining IFN production recovered as they aged. CONCLUSIONS: Although we observed a marginal decline in IFN-α  production, we also observed that IFN production recovered even in individuals in their mid50s to early 60s. These results combined with our previous cross-sectional studies of patients with various diseases suggest that in healthy individuals, the impairment of IFN production is triggered more by the onset of disease (notwithstanding the cause) rather than by ageing.

An approach to predict the risk of glaucoma development by integrating different attribute data.

Primary open-angle glaucoma (POAG) is one of the major causes of blindness worldwide and considered to be influenced by inherited and environmental factors. Recently, we demonstrated a genome-wide association study for the susceptibility to POAG by comparing patients and controls. In addition, the serum cytokine levels, which are affected by environmental and postnatal factors, could be also obtained in patients as well as in controls, simultaneously. Here, in order to predict the effective diagnosis of POAG, we developed an "integration approach" using different attribute data which were integrated simply with several machine learning methods and random sampling. Two data sets were prepared for this study. The one is the "training data set", which consisted of 42 POAG and 42 controls. The other is the "test data set" consisted of 73 POAG and 52 controls. We first examined for genotype and cytokine data using the training data set with general machine learning methods. After the integration approach was applied, we obtained the stable accuracy, using the support vector machine method with the radial basis function. Although our approach was based on well-known machine learning methods and a simple process, we demonstrated that the integration with two kinds of attributes, genotype and cytokines, was effective and helpful in diagnostic prediction of POAG.

Pre-operative intracellular glutathione levels of peripheral monocytes as a biomarker to predict survival of colorectal cancer patients.

The ability to predict anti-tumor immune responses at local tumor growing sites using only peripheral blood specimens would be helpful in determining therapeutic options for patients with solid tumors. Here, we show that the glutathione intracellular content (icGSH) of peripheral monocytes (Mo) correlates positively with T cell infiltration within tumor islets and overall survival in patients with colorectal carcinoma. IcGSH redox status was determined in CD14(+) Mo prior to surgery by staining with monochlorobimane. The tumor-infiltrating T cells (TIL) were quantified as CD45RO(+) T cells in resected tumors using paraffin sections. A positive association was found between the GSH index and TIL in tumor islets (P < 0.001). The 50% cut-off value for the GSH index, that is the determinant between TIL presence or absence in tumor islets, was calculated to be almost 0.7 through logistic regression analysis. Mo with a GSH index of > or =0.7 were termed reductive (R)-Mo, and those with <0.7 were designated as oxidative (O)-Mo. Cox's proportional hazards regression analysis of patients with R-Mo or O-Mo prior to surgery, and the presence or absence of TIL, was found to correlate significantly with the overall survival rate of stage II and III patients. Kaplan-Meier analysis also showed a significant correlation. These results indicate that the Mo icGSH index is a useful biomarker parameter for better understanding the host/tumor relationship prior to surgery, thereby enabling the development of an individual patient-oriented therapeutic strategy.

Association between capacity of interferon-alpha production and metabolic parameters.

A prompt and regulated interferon (IFN) system is critical for host defense against infectious pathogens. Although increased susceptibility to infection has been observed in subjects with diabetes or obesity, little is known about the relationship between metabolic disorders and increased susceptibility to infection. In order to evaluate the association between immune function and metabolic parameters, we examined the relationship between capacity of IFN-alpha production and metabolic parameters including fasting plasma glucose (FPG), lipids, uric acid, body mass index (BMI), and blood pressure in 575 healthy subjects. Linear regression analysis showed that log(IFN-alpha production) was positively correlated with log(triglyceride) (r = 0.088, P = 0.03) and uric acid (r = 0.091, P = 0.03), and negatively correlated with age (r = -0.158, P = 0.0001) and FPG (r = -0.088, P = 0.03). Multiple regression analysis showed that log(IFN-alpha production) was independently determined by age (beta = -0.148, P < 0.0001), sex (beta = -0.240, P = 0.0003), and FPG (beta = -0.096, P = 0.0209), suggesting that lesser degrees of hyperglycemia also affect IFN-alpha production. We conclude that hyperglycemia but not BMI, hypertension, or hyperlipidemia may be associated with decreased capacity of IFN-alpha production and glycemic control is critical even for both subjects without any medication for diabetes and subjects under the diagnosis of diabetes on infectious diseases.

A correlative electrophysiologic study of nerve fiber involvement in carpal tunnel syndrome using current perception thresholds.

OBJECTIVE: To relate clinical severity of idiopathic carpal tunnel syndrome (CTS) to current perception threshold (CPT). METHODS: Subjects were 51 patients with CTS (involving 51 hands), and 50 healthy control subjects (50 hands). Involved hands were grouped into three clinical grades (mild, moderate, severe). Using a neurometer (Neurotron, Baltimore, MD), we investigated the relationship between clinical grade and CPT abnormalities. RESULTS: In the mild CTS group, most hands showed CPT abnormalities only at 2000 Hz stimulation. The moderate group included a higher percentage of hands showing abnormalities at both 2000 and 250 Hz stimulation increased. The severe group included the highest percentage of hands with abnormal values at all frequencies tested. CONCLUSIONS: CPT showed abnormalities appear progressively from 'higher to lower' frequency stimulations relative to the increasing severity of CTS. SIGNIFICANCE: Sensory nerve fiber dysfunction apparently begins in larger fibers, extending stepwise to smaller fibers as the clinical grade of CTS progresses.

Objective evaluation of sensory function in patients with carpal tunnel syndrome using the current perception threshold.

The purpose of this study was to determine the sensitivity and specificity for the current perception threshold (CPT) test during clinical examination of idiopathic carpal tunnel syndrome (CTS). We studied 71 patients (102 hands) with CTS; 50 healthy individuals (100 hands) served as a control group. Using a neurometer, we investigated standard CPT values to obtain the sensitivity and specificity of the CPT test in the clinical examination of CTS. In the CTS group, cases that had abnormal values in the range analysis, the ratio analysis, or both were called "true-positive CPTs"; in the control group cases that had normal values in the range and ratio analyses were called "true-negative CPTs." We defined the sensitivity as the percentage of true-positive CPTs in the CTS group and the specificity as the percentage of true-negative CPTs in the control group. The sensitivity of the CPT test using both range and ratio analyses was 73%, and its specificity was 74%. Based on these results we concluded that the CPT test is a reliable quantitative sensory function test.

Evaluation of sensory function after median nerve decompression in carpal tunnel syndrome using the current perception threshold test.

The recovery level for sensory function after carpal tunnel release for the treatment of idiopathic carpal tunnel syndrome (CTS) was assessed with the current perception threshold (CPT) test. Seventeen CTS patients (21 hands) were followed, and the CPTs at the index finger of each patient was measured preoperatively and at 1, 3, and 6 months postoperatively. After carpal tunnel release, there was significant recovery of CPT at all stimulation frequencies, indicating improvement of all sensory functions including sensations of temperature, pain, touch, and vibration.

Magnetic resonance perfusion-weighted imaging of acute cerebral infarction: effect of the calculation methods and underlying vasculopathy.

BACKGROUND AND PURPOSE: Various calculation methods are available to estimate the transit-time on MR perfusion-weighted imaging (PWI). Each method may affect the results of PWI. Steno-occlusive disease in the parent vessels is another factor that may affect the results of the PWI. The purpose of this study was to elucidate the effect of the calculation methods and underlying vasculopathy on PWI. METHODS: From a pool of 113 patients who had undergone PWI during the study period, a total of 12 patients with nonlacunar ischemic strokes who were scanned within 24 hours after onset of symptom were selected for the study. The patient population consisted of 6 patients who had extracranial internal carotid artery stenosis (>70%) and 6 individuals without stenosis. Seven different postprocessing methods were evaluated: first moment, ratio of area to peak, time to peak (TTP), relative TTP, arrival time, full-width at half-maximum, and deconvolution methods. Follow-up MR or CT images were used to determine the areas that evolved into infarcts, which served as the gold standard. Sensitivity and specificity of each transit time technique were calculated. RESULTS: Calculation methods with high sensitivity were the first moment (sensitivity, 74%), TTP (sensitivity, 77%), and deconvolution methods (sensitivity, 81% to 94%). Between the 2 groups with and without internal carotid artery stenosis, the specificity of most of the techniques was lower in the internal carotid artery stenosis group. The first moment and deconvolution methods maintained relatively high specificity even in the stenosis group. CONCLUSIONS: The calculation technique and presence of underlying vasculopathy have a direct impact on the results of PWI. The methods with high sensitivity even in the presence of steno-occlusive disease were the first moment and deconvolution methods with arterial input function derived from the peri-infarct arteries; the deconvolution method was the superior choice because of higher lesion conspicuity.