Due to a change in disease spectrum in aged countries, the primary role of geriatricians should be directed to an appropriate management and prevention of 1) cognitive decline and dementia, 2) swallowing and aspiration pneumonia and 3) falls and fractures. Management of dementia constitutes a central part in the practice of geriatric medicine in order to support independence of life in elderly people. The current paradigm of cognitive function-based testing for the diagnosis and treatment of Alzheimer's disease (AD) is going to drastically shift to a biomarker-based test approach, a shift that will correspond to the emergence of disease-modifying drugs. In addition, a new molecular imaging technique that visualizes neuronal protein deposits or pathological features has been developed in Japan and the U.S.A. Based on these achievements, the Alzheimer's Disease Neuroimaging Initiative (ADNI) was proposed and initiated in 2005. The ADNI is a long-term observational study being conducted in the U.S.A., Europe, Australia, and Japan using identical protocols. The objectives of ADNI are: 1) to establish methodology which will allow standard values related to long-term changes in imaging data, such as MRI and PET, in patients with AD and mild cognitive impairment and normal elderly persons; 2) to obtain clinical indices, psychological test data, and blood/cerebrospinal fluid biomarkers to demonstrate the validity of image-based surrogate markers; and 3) to establish optimum methods to monitor the therapeutic effects of disease-modifying drugs for AD. Patient enrollment in the Japanese ADNI has begun in July 2008. Imaging of AD pathology not only acts as a reliable biomarker with which to assay curative drug development by novel pharmaceutical companies, but it also helps health promotion toward AD prevention.
Mycobacterium tuberculosis, the causative agent of tuberculosis, is a tenacious and remarkably successful pathogen that has latently infected one third of the world's population, according to the World Health Organization (WHO) statistics. It is anticipated that 10% of these infected individuals will develop active tuberculosis at some point in their lifetime. The long-term use of the current drug regimen, the emergence of drug-resistant strains, and HIV co-infection have resulted in a resurgence of research efforts to address the urgent need for new anti-tuberculosis drugs. A number of potential candidate drugs with novel modes of action have entered clinical trials in recent years, and these are likely to be effective against anti-tuberculosis drug-resistant strains. They include neuroquinolone derivatives, a modified ethambutol, nitro-imidazole groups and so on. This mini-review summarizes the latest information about eight new anti-tuberculosis drug candidates and describes their activities, pharmacokinetics, mechanisms of action, and mechanisms of drug-resistance induced by these drug candidates.
Aldehyde dehydrogenase-2 (ALDH2) is a key enzyme of alcohol metabolism, catalyzing the conversion of aldehyde to acetic acid. The G-to-A polymorphism in exon 12 of the ALDH2 gene, which causes Glu-to-Lys substitution at codon 504, has been shown to be an independent risk factor for acute myocardial infarction (AMI). We investigated the possible role of the G-to-A polymorphism in the severity of the myocardial damage in the early phase of AMI by measuring plasma levels of inflammatory markers, including high-sensitivity C-reactive protein (hs-CRP). A total of 226 Han Chinese patients with AMI were divided into two groups: subjects without A allele (GG, n = 144) and subjects with A allele (GA and AA, n = 82), and the blood samples were collected within 12 hours after the onset of AMI. The results displayed that high-density lipoprotein cholesterol (HDL-C) was higher in GG group than that in GA and AA group (p < 0.05). The body mass index (BMI) and the concentration of hs-CRP were lower in GG group than that in GA and AA group (p < 0.05). Multivariate logistic regression analysis showed that subjects with the A allele were at an increased risk for the high level of hs-CRP (> 3 mg/L) compared with those with GG genotype (OR = 4.908, 95% CI = 1.57∼20.98). Thus, the A allele in ALDH2 gene is associated with the elevated plasma levels of hs-CRP after the onset of AMI, suggesting a higher susceptibility of the myocardium to ischemic injuries.
Short-bowel syndrome (SBS) is defined as the malabsorptive state that occurs after extensive resection of the small intestine. In patients with SBS, oral administration of drugs usually becomes difficult because of the severity of intestinal failure. We describe a successful living related renal transplantation (LRRTx) in an 18-year-old male with SBS. Shortly after birth, the patient developed necrotizing enterocolitis requiring massive resection of the small intestine, which resulted in SBS. At seven years of age, the patient developed proteinuria and was diagnosed as focal segmental glomerulosclerosis (FSGS). His kidney function was gradually deteriorated toward the end-stage renal failure. The patient received LRRTx at age of 18 years. To evaluate the absorption capacity of the patient, we investigated pharmacokinetics of calcineurine inhibitors (tacrolimus and cyclosporine). The drug concentration, which is sufficient to provide effective immunosuppression, was achieved with cyclosporine, but not with tacrolimus. The patient therefore received a triple immunosuppressive therapy with oral cyclosporine, methyl-prednisolone and mycophenolate mofetil. To prevent both recurrent FSGS and rejection, we repeatedly analyzed the trough level and the pharmacokinetics of cyclosporine after LRRTx. The patient was successfully treated with oral immunosuppression for over 5 years, without hemodialysis. To our knowledge, this is the first report showing the long-term outcome of LRRTx treated with oral cyclosporine in a patient with SBS.
The relationship between Behçet's disease (BD) and platelet aggregation has not sufficiently been investigated yet. Mean platelet volume (MPV) is a marker of platelet function, and the increase in MPV has been identified as an independent risk factor of recurrent vascular events. BD is characterized by a relapsing vasculitis of the venous as well as arterial thrombosis. However, the precise pathogenic mechanisms underlying thrombotic tendency in BD are not known. We hypothesized that there might be an association between thrombotic complication and MPV in these patients. Therefore, we investigated activation of platelets in patients with BD using a simple marker, MPV, the most accurate measure of platelet size. A total of 60 patients with BD and 40 age- and gender-matched controls were included. The BD patients were divided into subgroups based on the presence (n = 22) or absence of thrombosis (n = 38) and clinically active (n = 30) or inactive (n = 30) state. MPV was higher in patients with BD than controls (8.14 ± 0.8 vs. 7.48 ± 0.3 fl, p = 0.001). Among BD patients, MPV was larger in patients with thrombosis than those without thrombosis (8.45 ± 1.0 vs. 7.96 ± 0.7 fl, p = 0.038). However, there was no significant difference in MPV between BD patients with active and inactive states. The increase in MPV is independent of the disease activity, and the presence of thrombosis is associated with higher MPV in BD patients. Therefore, antiplatelet therapy may be useful to prevent thrombotic complications in BD patients.
Interstitial cells of Cajal (ICC) are distributed throughout the gastrointestinal (GI) tract and have important functions in the control of GI motility. Loss of ICC is associated with several GI motility disorders; yet, the mechanisms modulating ICC survival and proliferation are not fully understood. Hydrogen sulfide (H2S) has been reported to be a gaseous transmitter that regulates cellular proliferation. This study aims to establish whether H2S participates in regulation of ICC proliferation. The effect of H2S was studied in primary cultures of ICC, prepared from the mouse small intestine. To determine the extent of ICC proliferation, we used immunofluorescent staining to study alterations in the number of cells expressing c-Kit+ and CD44+, markers for mature ICC. Phosphorylation of Akt was measured by Western blot analysis. Treatment with low concentrations of NaHS (H2S donor, 1-30 μM) showed no apparent toxicity, as judged from cell numbers. Importantly, treatment with NaHS (15 μM) for 24 hours increased the numbers of c-Kit+/CD44+ ICC by 23.3 ± 1.4% (P < 0.05). Moreover, NaHS increased Akt phosphorylation, which was prevented with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 (5 μM). LY294002 also blocked the NaHS-mediated increase in the number of ICC. In addition, H2S enhanced the proliferation of mature ICC in the in vitro culture system used here in a concentration-dependent manner. The present study suggests that H2S may be a critical factor in maintaining ICC numbers and may have a novel, Akt-dependent role in proliferation of mature ICC.
Several studies have suggested a potential effect of serum bilirubin as an antioxidant and cytoprotectant factor. For the results presented here, we evaluated the correlation between serum bilirubin and diabetes mellitus (DM) or chronic kidney disease originated from DM (DMCKD) in a Korean population. We used a cross-sectional, population-based design to examine 93,909 subjects (aged 18-96 years, 53.0% male). The trend of P values in the odds ratios for being DM and DMCKD was calculated using patients separated into five groups based on individual serum bilirubin concentrations. The prevalence of DM and DMCKD was 6.7% and 0.8%, respectively. Higher serum bilirubin levels were significantly associated with decreased prevalence of DM in both men (P trend < 0.001) and women (P trend = 0.014). The risk of DMCKD also decreased as bilirubin levels increased in women (P trend = 0.011), but not in men (P trend = 0.467). Serum bilirubin level was inversely related to insulin resistance using the homeostasis model assessment (HOMA-IR), serum insulin, and C-reactive protein (CRP) levels in multiple linear regression analyses. The regression coefficients (B) of log-HOMA-IR, log-insulin, and log-CRP were as follows: −0.09, −0.13, and −0.60 in men; −0.07, −0.09, and −0.50 in women, respectively. All the regressions were statistically significant (P < 0.001). These results indicate that serum bilirubin might have some protective function against DM and DMCKD, although the association between high serum bilirubin and decreased prevalence of DMCKD is observed only in women.
Mesenchymal stem cells (MSCs) can potentially differentiate along multiple lineages and be expanded in vitro, making them highly attractive candidates for cell therapy and tissue engineering applications. This study sought to investigate the critical proteins involved in osteogenic differentiation of mesenchymal stem cells derived from umbilical cord blood (UCB-MSCs). MSCs, which were isolated from three different preparations of human UCB, were osteoinduced, and total proteins were extracted from the cells. Two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) was performed on the day (d) of induction d0, and on d2, d7, and d21 of differentiation. The optical density (OD) of each spot was measured, and spots with a mean OD of three cell lines of MSCs that increased > 30 or decreased < 0.1 relative to a previous time point were selected. Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF/MS) was used to identify the proteins. Through database searches, the properties and functions of the proteins were investigated and then classified according to the Gene Ontology classification. Among the 308 spots observed in the 2-D gel, 16 proteins with a mean OD ratio > 30, and 20 proteins with a mean OD ratio < 0.1 were identified during the differentiation process. Additionally, the distribution of differentially expressed proteins according to cellular component and molecular function criteria differed depending on whether protein expression increased or decreased during differentiation. The results of this study will comprise an initial proteomic database for UCB-MSCs differentiation.
It has been reported that treatment with branched chain amino acids (BCAAs) increases the survival rates in cirrhotic patients. In this study, we investigated the effect of L-valine, one of BCAAs, on liver fibrosis in rat. To induce liver fibrosis, male Wistar rats were injected carbon tetrachloride (CCl4) intraperitoneally (2.0 mL/kg) twice a week for 12 weeks. The rats (seven to fifteen rats for each group) were then administered 1.688 g/kg/day of L-valine intravenously for 7 days or 10% amino acid preparation that provided the same amount of nitrogen. Seven days after the last administration, blood platelet counts and bone marrow megakaryocyte counts were significantly higher in the valine group than in the control group (131.2 ± 38.3 vs. 106.3 ± 14.5 × 104/μL, p = 0.04; 18.0 ± 2.1 vs. 13.5 ± 2.2 per field, p < 0.01, respectively). Importantly, the mRNA level of thrombopoietin, a key regulator of thrombopoiesis, was significantly higher in the liver of the valine group than the control group. Furthermore, hepatic fibrosis was significantly reduced in the valine group, and the mRNA levels of factors associated with liver fibrosis such as procollagen α1(III), transforming growth factor-β1 and connective tissue growth factor were significantly lower in the liver of the valine group 10 days after the last administration. These results indicate that L-valine treatment ameliorates liver fibrosis and restores thrombopoiesis in rats exposed to CCl4. Therefore, L-valine supplementation may be helpful for patients with liver cirrhosis.
Joint immobilization is commonly used for the treatment of joint injuries and diseases, but it also causes unfavorable outcomes such as joint contracture. The purpose of this study was to examine the morphological changes of the synovial membrane that is suspected as a cause of joint contracture, and localization of type A (macrophage-like) and type B (fibroblast-like) synoviocytes in the capsule after joint immobilization. Male Sprague-Dawley rats were used in this study. Unilateral knee joints were rigidly immobilized at 150° of flexion with internal fixators for 3 days, 1, 2, 4, 8, and 16 weeks (7 rats/each immobilized group), while 42 rats were sham-operated. Sagittal sections of 5 μm were prepared from the medial midcondylar region of the knee joints and assessed with histological, histomorphometric, and immunohistochemical methods. Adhesions were observed both in the anterior and posterior synovial membranes in the immobilized group after 2 weeks. In the adhesion area, the cells were mainly composed of type A synoviocytes that were positive for CD68 and type B synoviocytes positive for prolyl 4-hydroxylase subunit beta. The length of synovial membrane in the immobilized group was significantly shorter than that in the control group after 2 and 4 weeks. After 8 weeks, the adhesion area in the immobilized group became fibrous and hypocellular. The staining intensity of hyaluronic acid-binding protein was increased after 16 weeks. Adhesion and shortening of the synovial membrane and the structural changes of the adhesion area may contribute to the development of joint contracture.
Although mitral annular velocity assessed by tissue Doppler echocardiography has been established as a parameter of left ventricular (LV) diastolic function, aortic annular velocity has never been investigated as a parameter of cardiovascular function. We investigated whether aortic annular velocity can be measured using the same tissue Doppler echocardiographic method that is used for measuring mitral annular velocity, as well as the correlation between the aortic annular velocity thus measured and arterial stiffness that was assessed by the cardio-ankle vascular index (CAVI). Sixty-three patients (69 ± 13 years) with hypertension, diabetes, or dyslipidemia, who had no overt heart disease, were enrolled. The mitral and aortic annular velocities were measured at the mitral and aortic annuluses, respectively, using tissue Doppler echocardiography. Aortic annular velocity was successfully obtained in all patients. The correlation between the peak early diastolic aortic annular velocity (r = −0.803, p < 0.001) and CAVI as an index of arterial stiffness was greater than that of the peak early diastolic mitral velocity and CAVI (r = −0.649, p < 0.001). Stepwise regression analysis showed that the age (β coefficient = 0.488, p = 0.002) and the peak early diastolic aortic annular velocity (β coefficient = −0.405, p = 0.008) were independent determinants of the CAVI. The strong inter-relationship was found between left ventricular diastolic function assessed by the aortic annular velocity and arterial stiffness assessed by CAVI. In conclusion, the aortic annular velocity may be helpful for assessing arterial stiffness in patients with cardiovascular risk factors.