Eriko Sumi

Expression of Smad1 is directly associated with mesangial matrix expansion in rat diabetic nephropathy.

Diabetic nephropathy is the leading cause of end-stage renal disease, and glomerular mesangial matrix expansion is the hallmark in diabetic nephropathy. However, the precise mechanism for the development of mesangial matrix expansion has remained unknown. The key component involved in mesangial matrix expansion is type IV collagen (Col4). Recently, we have reported that Smad1 transcriptionally regulates expression of Col4 under diabetic conditions in vitro. Here we show that this direct regulator of Col4 also plays a crucial role for mesangial matrix expansion in vivo. Streptozotocin-induced diabetic rats are the model of incipient diabetic nephropathy, and showed various levels of mesangial matrix expansion at 24 weeks. The glomerular expression of Smad1 was significantly increased in diabetic rats with more mesangial matrix expansion by Western blot and immunohistochemical analysis. Furthermore, the glomerular expression of Smad1 was closely correlated with the glomerular expression of Col4 and smooth muscle alpha actin (α-SMA), while albuminuria or glomerular filtration rate was not correlated with mesangial matrix expansion. We also found that urinary excretion of Smad1 was closely associated with the severity of mesangial matrix expansion. In cultured mesangial cells expression of Smad1 upregulated the transcriptional activity of key molecules in mesangial matrix expansion, such as Col4 and α-SMA. These data indicate the critical involvement of Smad1 in mesangial matrix expansion in the early phase of diabetic nephropathy. Our data imply that urinary Smad1 might be a representative diagnostic marker for mesangial matrix expansion in diabetic nephropathy.

Angiotensin II-dependent Src and Smad1 signaling pathway is crucial for the development of diabetic nephropathy

Angiotensin II (Ang II) is known to play a pivotal role in the development of diabetic nephropathy. However, the precise mechanism of Ang II-mediated effects on diabetic nephropathy is still unknown. We have reported that Smad1 plays a key role in diabetic mesangial matrix expansion and directly regulates the transcription of type IV collagen (Col4) in vitro and in vivo. Here we examined the effect of Ang II on the expression of Smad1 and mesangial matrix expansion in streptozotocin (STZ)-induced diabetic rats in vivo, using Ang II type 1 receptor blocker, olmesartan. We also examined the signaling mechanism by which Ang II induces mesangial matrix expansion in vitro. Treatment of diabetic rats with low-dose olmesartan for 20 weeks reduced albuminuria and hyperfiltration without affecting blood pressure and inhibited mesangial matrix expansive changes and the expression of Col4 and smooth muscle alpha actin compared with those in untreated rats. Immunohistochemical staining and Western blotting showed that the increased expression of Smad1, phospho-Smad1, and phospho-Src was inhibited by olmesartan. Ang II induced Col4 synthesis and increased expression of phospho-Src and phospho-Smad1 in cultured mesangial cells, which was blocked by olmesartan. PP2, a Src tyrosine kinase inhibitor, and overexpression of dominant negative Src also reduced the phosphorylation of Smad1. Moreover, addition of small-interfering RNA against Src significantly reduced the phosphorylation of Smad1 and synthesis of Col4. Taken together, these results indicate that Ang II can regulate the development of mesangial matrix expansion in the early phase of diabetic nephropathy through Src and Smad1.

EFFECTS OF GHRELIN TREATMENT ON PATIENTS UNDERGOING TOTAL HIP REPLACEMENT FOR OSTEOARTHRITIS: DIFFERENT OUTCOMES FROM STUDIES IN PATIENTS WITH CARDIAC AND PULMONARY CACHEXIA

non-dominant hemisphere anterior lesions. In posterior watershed infarctions, hemi-anopsia is common. Watershed infarctions in the bilateral frontal lobes can cause severe dementia. PV is a chronic, myeloproliferatieve disorder, predominantly presenting in elderly patients with an incidence rate of 23.5 per 100,000 person-years. Symptoms are due to hyperviscocity. A feared complication of PV is thrombosis (venous or arterial). Together with transformation into myelofibrosis, acute leukemia, or both, thrombosis is the main cause of death. The median survival of treated patients exceeds 10 year. This case history illustrates that an unusual course of cognitive impairment necessitates in-depth clinical investigation.

Risk of osteomyelitis of the jaw induced by oral bisphosphonates in patients taking medications for osteoporosis: A hospital-based cohort study in Japan

Oral bisphosphonates (BPs) represent the first line of prevention and treatment for osteoporosis. However, several studies have reported osteonecrosis of the jaw (ONJ), also known as osteomyelitis of the jaw (OMJ), as a side effect of these drugs. Although absolute risk is suggested to be low, information to date on the relative risk or attributable risk has in fact been limited. Here, we estimated risk of oral BPs for OMJ in osteoporosis patients taking oral BPs compared with other osteoporosis drugs. Using an electronic medical records retrieval system and manual confirmation of OMJ, we conducted a retrospective cohort study of patients taking medications for osteoporosis at Kyoto University Hospital between November 2000 and October 2010. To evaluate relative risks of oral BPs for OMJ, logistic regression analysis was performed and odds ratios (ORs) and 95% confidence interval (CIs) were estimated. In addition, sensitivity analyses were performed according to hierarchical diagnosis. A total of 4129 patients (59.6%) were prescribed BPs while 2794 (40.3%) received other osteoporosis drugs. Absolute risk for OMJ was estimated to range from 0.46% to 0.99% (95% CIs: 0.25-0.66 to 0.69-1.2) among patients receiving oral BPs and 0.071% to 0.17% (95% CIs: 0-0.17 to 0.022-0.33) among patients receiving other osteoporosis drugs. The attributable risks of oral BPs for OMJ were estimated to range from 0.38% to 0.81% (95% CIs: 0.38-0.39 to 0.80-0.81). ORs (95% CIs) adjusted for confounding factors were 5.0 (1.9-12.9) to 6.0 (1.3-26.1) for confirmed cases only. In terms of absolute and attributable risks, the risk of oral BPs for OMJ is considered to be less than 1% in patients with osteoporosis. However, oral BPs may increase the risk of OMJ compared with patients treated with other osteoporosis medications and the risk of side effects should be kept in mind.

An eClinical trial system for cancer that integrates with clinical pathways and electronic medical records

Background Various information technologies currently are used to improve the efficiency of clinical trials. However, electronic medical records (EMRs) are not yet linked to the electronic data capture (EDC) system. Therefore, the data must be extracted from medical records and transcribed to the EDC system. Clinical pathways are planned process patterns that are used in routine clinical practice and are easily applicable to the medical care and evaluation defined in a trial protocol. However, few clinical pathways are intended to increase the efficiency of clinical trials. Purpose Our purpose is to describe the design and development of a new clinical trial process model that enables the primary use of EMRs in clinical trials by integrating clinical pathways and EMRs. Methods We designed a new clinical trial model that uses EMR data directly in clinical trials and developed a system to follow this model. We applied the system to an investigator-initiated clinical trial and examined whether all data were extracted correctly. At the protocol development stage, our model measures endpoints based on clinical pathways with the same diagnosis. Next, medical record descriptions and the format of the statistical data are defined. According to these observations, screens for entry of data, which are used both in clinical practice and for study, are prepared into EMRs with an EMR template, and screens are prepared for data checks on our EMR retrieval system (ERS). In an actual trial, patients are registered and randomly assigned to a protocol treatment. The protocol treatment is executed according to clinical pathways, and the data are recorded to EMRs using EMR templates. The data are checked by a local data manager using reports created by the ERS. After edit checks and corrections, the data are extracted by the ERS, archived in portable document format (PDF) with an electronic signature, and transferred in comma-separated values (CSV) format to a coordinating centre. At the coordinating centre, the data are checked, integrated, and made available for a statistical analysis. Results We verified that the data could be extracted correctly and found no unexpected problems. Limitation To execute clinical trials in our system, the EMR template and efficient ERSs are required. Additionally, to execute multi-institutional clinical trials, it is necessary to create templates appropriate for EMRs at all participating sites and for the coordinating centre to validate local templates and procedures. Conclusion We proposed and pilot tested a new eClinical trial model. Because our model is integrated with routine documentation of clinical practice and clinical trials, redundant data entries were avoided and the burden on the investigator was minimised. The reengineering of the clinical trial process would facilitate the establishment of evidence in the future.

A pragmatic method for electronic medical record-based observational studies: developing an electronic medical records retrieval system for clinical research

Objective The use of electronic medical record (EMR) data is necessary to improve clinical research efficiency. However, it is not easy to identify patients who meet research eligibility criteria and collect the necessary information from EMRs because the data collection process must integrate various techniques, including the development of a data warehouse and translation of eligibility criteria into computable criteria. This research aimed to demonstrate an electronic medical records retrieval system (ERS) and an example of a hospital-based cohort study that identified both patients and exposure with an ERS. We also evaluated the feasibility and usefulness of the method. Design The system was developed and evaluated. Participants In total, 800 000 cases of clinical information stored in EMRs at our hospital were used. Primary and secondary outcome measures The feasibility and usefulness of the ERS, the method to convert text from eligible criteria to computable criteria, and a confirmation method to increase research data accuracy. Results To comprehensively and efficiently collect information from patients participating in clinical research, we developed an ERS. To create the ERS database, we designed a multidimensional data model optimised for patient identification. We also devised practical methods to translate narrative eligibility criteria into computable parameters. We applied the system to an actual hospital-based cohort study performed at our hospital and converted the test results into computable criteria. Based on this information, we identified eligible patients and extracted data necessary for confirmation by our investigators and for statistical analyses with our ERS. Conclusions We propose a pragmatic methodology to identify patients from EMRs who meet clinical research eligibility criteria. Our ERS allowed for the efficient collection of information on the eligibility of a given patient, reduced the labour required from the investigators and improved the reliability of the results.

Implication of sensorimotor integration in the generation of periodic dystonic myoclonus in subacute sclerosing panencephalitis (SSPE).

To clarify the mechanism of periodic dystonic myoclonus in subacute sclerosing panencephalitis (SSPE), a 22‐year‐old patient with a clinical diagnosis of SSPE was electrophysiologically investigated. Involuntary movements consisted of generalized dystonic posturing which occurred quasi‐periodically once every 4 to 8 seconds. Effects of sensory stimuli and voluntary movements were studied by means of polygraphic recording of surface electromyogram (EMG), scalp electroencephalogram (EEG), and magnetoencephalogram (MEG). EEG showed quasi‐periodic, generalized, transient complexes synchronous to each dystonic myoclonus, which were preceded by a slow negative EEG shift at the parietal region by approximately 5 seconds. Neither external stimuli nor self‐paced movements alone influenced the periodicity of dystonic myoclonus or EEG complexes. In the reaction time task, however, the external stimuli given as an imperative cue to execute a motor task elicited dystonic myoclonus and generalized EEG complexes only if they were presented in the latter segment of the interval between the two successive EEG complexes while the slow negative EEG shift appeared. These findings suggest that EEG complexes and periodic movements spontaneously occur when cortical excitability reaches a certain critical level, but both phenomena are elicited even before if the sensory stimuli as an imperative signal requiring motor execution are presented. This finding most likely implies involvement of the sensorimotor integration mechanism in these periodic phenomena.

The correlation between the number of eligible patients in routine clinical practice and the low recruitment level in clinical trials: a retrospective study using electronic medical records

BackgroundA number of clinical trials have encountered difficulties enrolling a sufficient number of patients upon initiating the trial. Recently, many screening systems that search clinical data warehouses for patients who are eligible for clinical trials have been developed. We aimed to estimate the number of eligible patients using routine electronic medical records (EMRs) and to predict the difficulty of enrolling sufficient patients prior to beginning a trial.MethodsInvestigator-initiated clinical trials that were conducted at Kyoto University Hospital between July 2004 and January 2011 were included in this study. We searched the EMRs for eligible patients and calculated the eligible EMR patient index by dividing the number of eligible patients in the EMRs by the target sample size. Additionally, we divided the trial eligibility criteria into corresponding data elements in the EMRs to evaluate the completeness of mapping clinical manifestation in trial eligibility criteria into structured data elements in the EMRs. We evaluated the correlation between the index and the accrual achievement with Spearmans rank correlation coefficient.ResultsThirteen of 19 trials did not achieve their original target sample size. Overall, 55% of the trial eligibility criteria were mapped into data elements in EMRs. The accrual achievement demonstrated a significant positive correlation with the eligible EMR patient index (r = 0.67, 95% confidence interval (CI), 0.42 to 0.92). The receiver operating characteristic analysis revealed an eligible EMR patient index cut-off value of 1.7, with a sensitivity of 69.2% and a specificity of 100.0%.ConclusionsOur study suggests that the eligible EMR patient index remains exploratory but could be a useful component of the feasibility study when planning a clinical trial. Establishing a step to check whether there are likely to be a sufficient number of eligible patients enables sponsors and investigators to concentrate their resources and efforts on more achievable trials.

The increase in prescriptions of bisphosphonates and the incidence proportion of osteonecrosis of the jaw after risk communication activities in Japan: a hospital-based cohort study.

The purpose of this study was to investigate the impact of risk communication about bisphosphonate (BP)‐related osteonecrosis of the jaw (ONJ) on the number of reported cases to the Drug Adverse Reactions Reporting System and on the incidence proportion of ONJ in a hospital‐based cohort study in Japan.

Comprehensive Geriatric Assessment for outpatients is important for the detection of functional disabilities and depressive symptoms associated with sensory impairment as well as for the screening of cognitive impairment

Background:  The Comprehensive Geriatric Assessment (CGA) for inpatients is very useful to improve the outcomes of elderly patients. However, most of the elderly patients are provided their care by general practitioners in primary care settings without comprehensive assessment. Concise and practical assessment is necessary for the detection of geriatric problems and sufficient care in the outpatient clinic.