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A 16-year-old boy who was a non-smoker presented with a prolonged severe dry cough and malaise of 3 months in duration. Despite an increase in the patient's inflammatory marker levels, no respiratory lesions were radiologically or serologically detected. We suspected that the cough reflex pathway had been stimulated by large vessel vasculitis (LVV, a non-respiratory inflammatory condition) and diagnosed the patient with Takayasu arteritis. While inflammation of either the ascending pharyngeal or pulmonary artery have been reported to cause cough in patients with LVV, the present case shows that intense inflammation of the aortic arch and the starting portion of its main branches may stimulate a vagus nerve branch as a novel mechanism causing cough.

Objectives: The case history is an important part of diagnostic reasoning. The patient management problem method has been used in various studies, but may not reflect the actual reasoning process because a list of choices is given to the subjects in advance. This study investigated the contribution of the history to making the correct diagnosis by using clinical case simulation, in which students obtained clinical information by themselves. Methods: A prospective study was conducted. Ninety-four fifth-year medical students from Chiba University who underwent supervised clinical clerkships in 2009 were surveyed. Each student randomly selected 1 of 4 test cases and attempted to make a diagnosis through medical interview, physical examination, and laboratory tests, while the teacher acted as a patient. The student ranked the disease(s) diagnosed at each stage of the process. Diagnostic accuracy rates were compared using analysis of the χ2-test. Results: Sixty students (63.8%) made a correct diagnosis, which was based on the history in 43 students (71.7%), physical findings in 11 students (18.3%), and laboratory data in 6 students (10.0%). Compared with students who considered the correct diagnosis in their differential diagnosis after taking a history, students who failed to do so were 5.0 times (95%CI = 2.5-9.8) more likely to make a final misdiagnosis (χ2(1) = 30.73; p

We report a 54-year-old man with osteomalacia due to a bladder reconstruction performed 35 years previously. He had had slowly progressive chest and back pain for 18 months. Osteomalacia due to metabolic acidosis was suspected based on hyperalkalinephosphatasemia and a high serum chloride level, and the diagnosis was confirmed by bone scintigraphy. His symptoms and blood electrolyte levels were improved by oral medication, including sodium hydrogen carbonate. Measurement of the serum chloride level is simple and useful for evaluating acidosis, for which a regular blood test is essential in patients who have undergone bladder reconstruction.

We report a rare case of iliac vein compression syndrome caused by urethral calculus. A 71-year-old man had a history of urethral stenosis. He complained of bilateral leg edema and dysuria for 1 week. Physical examination revealed bilateral distention of the superficial epigastric veins, so obstruction of both common iliac veins or the inferior vena cava was suspected. Plain abdominal computed tomography showed a calculus in the pendulous urethra, distention of the bladder (as well as the right renal pelvis and ureter), and compression of the bilateral common iliac veins by the distended bladder. Iliac vein compression syndrome was diagnosed. Bilateral iliac vein compression due to bladder distention (secondary to neurogenic bladder, benign prostatic hyperplasia, or urethral calculus as in this case) is an infrequent cause of acute bilateral leg edema. Detecting distention of the superficial epigastric veins provides a clue for diagnosis of this syndrome.

Rationale, aims and objectives To investigate the subsequent behaviour of doctor-shopping patients (defined as those attending multiple hospitals for the same complaint) who consulted our department and factors related to cessation of doctor shopping. Methods Patients who presented without referral to the Department of General Medicine at Chiba University Hospital in Japan (our department) completed a questionnaire at their first visit. A follow-up questionnaire was also sent to them in order to assess doctor shopping after 3 months. Then items in the questionnaires were investigated for significant differences between patients who continued or stopped doctor shopping. Logistic regression analysis was performed with items showing a significant difference between patients who stopped doctor shopping and those who continued it, in order to identify independent determinants of the cessation of shopping. Results A total of 978 patients who presented spontaneously to our department consented to this study, and 929 patients (95.0%) completed questionnaires correctly. Among them, 203 patients (21.9%) were identified as doctor shoppers. The follow-up survey was completed correctly by 138 patients (68.0%). Among them, 25 patients (18.1%) were found to have continued doctor shopping, which was a significantly lower rate than before (P

There have been some studies of common primary care diseases in Japan, but no reports on which diseases it is difficult for general physicians to diagnose in daily practice. In this study, we identified diseases that provided a diagnostic challenge for Japanese general physicians in daily practice. The subjects were new undiagnosed patients referred to the General Outpatient Department of Chiba University Hospital during the one-year period from January 2008. We performed a retrospective chart review to identify the referring doctor, patient demographics, the duration of symptoms, the final diagnosis, and the outcome. Final diagnoses were classified according to the International Classification of Primary Care Second Edition (ICPC-2). In addition, the differences between referrals from general physicians and those from other physicians were assessed. Fisher’s exact test and the Bonferroni-Holm correction were used for statistical analysis. A total of 169 patients were referred by general physicians and 239 patients were referred by other physicians. The most common ICPC-2 diagnosis was “General & Unspecified” conditions (35 patients, 20.7%), followed by “Psychological” conditions (31 patients, 18.3%) and “Musculoskeletal” conditions (21 patients, 12.4%). No significant differences of the ICPC-2 category for the final diagnosis and each diagnosis were found between patients referred by general physicians and those referred by other physicians. The hospitalization rate was lower for patients referred by general physicians than for patients referred by other physicians (4 patients, 2.4% vs. 24 patients, 10.0%) (P = 0.002). Japanese general physicians found difficulty in diagnosing “Psychological” conditions, “Musculoskeletal” conditions, variations within the normal range, and viral infections that required diagnosis by exclusion. Because most of the patients referred by general physicians had mild conditions, further education at outpatient departments and clinics is required to improve diagnostic performance. Additionally, it is important to increase the gatekeeper role of general physicians and further development of the medical system by the government to distinguish the functions of clinics and hospitals is expected.

We report a 38-year-old mestizo man with the sudden onset of left upper abdominal pain while climbing Mt. Fuji, which is the highest mountain in Japan. Enhanced computed tomography showed splenic infarction. Although his peripheral blood smear was normal, a hemoglobin S level of 40% established the diagnosis of sickle cell trait (SCT). This trait is common worldwide, but is not well recognized by doctors in Japan because no Japanese patients with SCT have been reported. However, in Japan it is important to consider SCT when assessing foreign patients with splenic infarction.

The (pro)renin receptor [(P)RR] induces the catalytic activation of prorenin, as well as the activation of the mitogen-activated protein kinase (MAPK) signaling pathway; as such, it plays an important regulatory role in the renin-angiotensin system. (P)RR is known to form a homodimer, but the region participating in its dimerization is unknown. Using glutathione S-transferase (GST) as a carrier protein and a GST pull-down assay, we investigated the interaction of several (P)RR constructs with full-length (FL) (P)RR in mammalian cells. GST fusion proteins with FL (P)RR (GST-FL), the C-terminal M8-9 fragment (GST-M8-9), the extracellular domain (ECD) of (P)RR (GST-ECD), and the (P)RR ECD with a deletion of 32 amino acids encoded by exon 4 (GST-ECDd4) were retained intracellularly, whereas GST alone was efficiently secreted into the culture medium when transiently expressed in COS-7 cells. Immunofluorescence microscopy showed prominent localization of GST-ECD to the endoplasmic reticulum. The GST pull-down analysis revealed that GST-FL, GST-ECD, and GST-ECDd4 bound FLAG-tagged FL (P)RR, whereas GST-M8-9 showed little or no binding when transiently co-expressed in HEK293T cells. Furthermore, pull-down analysis using His-tag affinity resin showed co-precipitation of soluble (P)RR with FL (P)RR from a stable CHO cell line expressing FL h(P)RR with a C-terminal decahistidine tag. These results indicate that the (P)RR ECD participates in dimerization.

The (pro)renin receptor [(P)RR] is a single transmembrane protein with a large N-terminal extracellular domain and a short C-terminal cytoplasmic domain. Three molecular forms of (P)RR are known: a full-length form, a C-terminal truncated soluble form [s(P)RR], and an N-terminal truncated transmembrane form (M8-9 fragment). It has been reported that (P)RR forms homodimer, but the region participating in dimerization is unknown. Here we report that the extracellular domain of (P)RR participate in dimerization. Using secretory glutathione S-transferase (GST) as a fusion tag, we developed an in vivo pull-down assay to investigate (P)RR dimerization in the cell. GST-tagged extracellular domain (amino acid residues 17-304) of human (P)RR [GST-ECD], as well as full-length (P)RR [GST-Full] and M8-9 fragment [GST-M8-9], was retained in the cell, while GST alone was efficiently secreted into the culture medium when transiently expressed in COS-7 cells. Consistent with this observation, immunofluorescence microscopy showed prominent localization of GST-ECD to the ER. In vivo GST pull-down experiments revealed that GST-ECD as well as GST-Full bound FLAG-tagged full-length (P)RR, whereas GST-M8-9 bound it little, if any, when transiently coexpressed in HEK293T cells. To investigate whether s(P)RR can form heterodimer with full-length (P)RR, we established a CHO cell line stably expressing human (P)RR with C-terminal 10His-tag. All three forms of (P)RR were detected in the cell lysate and only s(P)RR was detected in the culture medium. Full-length (P)RR and s(P)RR were prominently localized to the ER as observed by immunofluorescence microscopy. Pull down experiment using His-tag affinity resin showed coprecipitation of s(P)RR with full-length (P)RR. These results indicate that the extracellular domain of (P)RR participates in dimerization.

Kazutaka Noda, Masatomi Ikusaka, Yoshiyuki Ohira, Toshihiko Takada, Tomoko TsukamotoDepartment of General Medicine, Chiba University Hospital, Chiba, JapanObjective: Patient medical history is important for making a diagnosis of causes of dizziness, but there have been no studies on the diagnostic value of individual items in the history. This study was performed to identify and validate useful questions for suspecting a diagnosis of benign paroxysmal positional vertigo (BPPV).Methods: Construction and validation of a disease prediction model was performed at the outpatient clinic in the Department of General Medicine of Chiba University Hospital. Patients with dizziness were enrolled (145 patients for construction of the disease prediction model and 61 patients for its validation). This study targeted BPPV of the posterior semicircular canals only with a positive Dix–Hallpike test (DHT + BPPV) to avoid diagnostic ambiguity. Binomial logistic regression analysis was performed to identify the items that were useful for diagnosis or exclusion of DHT + BPPV.Results: Twelve patients from the derivation set and six patients from the validation set had DHT + BPPV. Binomial logistic regression analysis selected a "duration of dizziness ≤15 seconds" and "onset when turning over in bed" as independent predictors of DHT + BPPV with an odds ratio (95% confidence interval) of 4.36 (1.18–16.19) and 10.17 (2.49–41.63), respectively. Affirmative answers to both questions yielded a likelihood ratio of 6.81 (5.11–9.10) for diagnosis of DHT + BPPV, while negative answers to both had a likelihood ratio of 0.19 (0.08–0.47).Conclusion: A "duration of dizziness ≤15 seconds" and "onset when turning over in bed" were the two most important questions among various historical features of BPPV.Keywords: benign paroxysmal positional vertigo, likelihood ratio, diagnosis, screening, prediction rules

In January, 2007, a 58-year-old woman presented to our department with a 2-year history of severe paroxysmal hip pain. She had a 30-year history of anorexia nervosa. The pain originated near the pubis and radiated to the right or left hip, with right-sided pain being more frequent. The pain often occurred after urination or defecation, and lasted from several minutes to several hours. She could not walk because of the severity of the pain, and had to lie supine with the aff ected thigh fl exed to obtain some relief. Our patient had presented to emergency departments several times, receiving a diagnosis of psychogenic pain or osteoarthritis because of degenerative changes shown on hip radiographs. On examination, she was asymptomatic but severely emaciated with a height of 159 cm and weight of 32 kg (body-mass index 12·7 kg/m2). There was no tenderness, swelling, or restricted movement of her hip joints, making the diagnosis of degenerative arthritis unlikely. Just after examination, left-sided pain occurred on urination. Emergency CT of the pelvis showed intrusion of the bowel into the left obturator canal (fi gure). Her pain soon subsided, and elective surgery was scheduled. After 1 month, severe right-sided pain occurred and she had an emergency laparotomy. Bilateral obturator hernia was diagnosed and mesh repair surgery done. In August, 2009, at 32-month follow-up she had not experienced any pain since the operation. Obturator hernia is most common in emaciated elderly women between 70 and 90 years old. Women are aff ected six times more frequently than men because they have a wider pelvis with a larger obturator canal. Emaciation is an important risk factor because the loss of preperitoneal fat overlying the obturator canal increases the risk of herniation. Obturator hernia is relatively rare, with a reported incidence of 0·073% of all abdominal hernias and bilateral obturator hernia has an incidence of only 0·013%. The hernia is more common in multiparous women and Asians, and occurs less frequently on the left side because the sigmoid colon can cover the left obturator foramen, preventing herniation. The usual presention is with the clinical features of acute small bowel obstruction, but obstruction can also be partial and resolve spontaneously. Approximately one third of the patients have a history of intermittent previous attacks. Patients can present with groin, thigh, knee, or hip pain due to compression of the obturator nerve by the hernia (Howship-Romberg sign), which is seen in 15–50% of patients. The pain is exacerbated by extension, abduction, or medial rotation of the thigh, while fl exion usually relieves it. Our patient with bilateral hernia was relatively young, but she had severe emaciation due to anorexia nervosa. Bowel herniation induced the HowshipRomberg sign, resulting in her curious paroxysmal hip pain. Diagnosis of obturator hernia is challenging, although CT or ultrasonography can be useful, the correct diagnosis is made preoperatively in only 21·5% to 31·3% of cases. Diffi culty in establishing the diagnosis leads to a high mortality rate of up to 25%, so early accurate diagnosis is crucial. Although obturator hernia is a rare disease, it must be considered when any underweight woman, not only the elderly, complains of unexplained pain in the groin, thigh, knee, or hip.

Objective Carnett's test is a simple clinical test in which abdominal tenderness is evaluated while the patient tenses the abdominal muscles. It is useful for differentiating abdominal wall pain from intra-abdominal pain. However, no study has reported its association with psychogenic abdominal pain. We evaluated its diagnostic usefulness in psychogenic abdominal pain. Methods Two physicians performed Carnett's test on each patient, but only one received the medical history. The other physician only conducted the test. Based on the final diagnosis, patients were categorized into 3 groups: psychogenic pain, abdominal wall pain, or intra-abdominal pain. Each group was analyzed in association with the results of Carnett's test conducted by the blinded physician. Patients A total of 130 outpatients with the chief complaint of abdominal pain who had abdominal tenderness. Results There were 22 patients with psychogenic abdominal pain, 19 with abdominal wall pain and 62 with intra-abdominal pain. In patients with psychogenic pain or abdominal wall pain, Carnett's test was usually positive, whereas the test was usually negative in patients with intra-abdominal pain (p

To investigate the subsequent behaviour of doctor-shopping patients (defined as those attending multiple hospitals for the same complaint) who consulted our department and factors related to cessation of doctor shopping.Patients who presented without referral to the Department of General Medicine at Chiba University Hospital in Japan (our department) completed a questionnaire at their first visit. A follow-up questionnaire was also sent to them in order to assess doctor shopping after 3 months. Then items in the questionnaires were investigated for significant differences between patients who continued or stopped doctor shopping. Logistic regression analysis was performed with items showing a significant difference between patients who stopped doctor shopping and those who continued it, in order to identify independent determinants of the cessation of shopping.A total of 978 patients who presented spontaneously to our department consented to this study, and 929 patients (95.0%) completed questionnaires correctly. Among them, 203 patients (21.9%) were identified as doctor shoppers. The follow-up survey was completed correctly by 138 patients (68.0%). Among them, 25 patients (18.1%) were found to have continued doctor shopping, which was a significantly lower rate than before (P0.001). Logistic regression analysis selected the following factors as independent determinants of the cessation of doctor shopping: 'confirmation of the diagnosis' (odds ratio: 8.12, 95% confidence interval: 1.46-45.26), and 'satisfaction with consultation' (odds ratio: 2.07, 95% confidence interval: 1.42-3.01).Doctor shopping decreased significantly after patients consulted our department, with 'confirmation of the diagnosis' and 'satisfaction with consultation' being identified as contributing factors.

Kiyoshi Shikino, Masatomi Ikusaka, Yoshiyuki Ohira, Masahito Miyahara, Shingo Suzuki, Misa Hirukawa, Kazutaka Noda, Tomoko Tsukamoto, Takanori Uehara Department of General Medicine, Chiba University Hospital, Chiba, Chiba Prefecture, Japan Background: This study aimed to clarify the influence of predicting a correct diagnosis from the history on physical examination by comparing the diagnostic accuracy of auscultation with and without clinical information. Methods: The participants were 102 medical students from the 2013 clinical clerkship course. Auscultation was performed with a cardiology patient simulator. Participants were randomly assigned to two groups. Each group listened to a different simulated heart murmur and then made a diagnosis without clinical information. Next, a history suggesting a different murmur was provided to each group and they predicted the diagnosis. Finally, the students listened to a murmur corresponding to the history provided and again made a diagnosis. Correct and incorrect diagnosis rates of auscultation were compared between students with and without clinical information, between students predicting a correct or incorrect diagnosis from the history (correct and incorrect prediction groups, respectively), and between students without clinical information and those making an incorrect prediction. Results: For auscultation with or without clinical information, the correct diagnosis rate was 62.7% (128/204 participants) versus 54.4% (111/204 participants), showing no significant difference (P=0.09). After receiving clinical information, a correct diagnosis was made by 102/117 students (87.2%) in the correct prediction group versus 26/87 students (29.9%) in the incorrect prediction group, showing a significant difference (P=0.006). The correct diagnosis rate was also significantly lower in the incorrect prediction group than when the students performed auscultation without clinical information (54.4% versus 29.9%, P

A greater QT dispersion in patients with chronic heart failure (CHF) appears to be a non-invasive marker of susceptibility to malignant ventricular arrhythmias. We evaluated whether QT dispersion in CHF patients is modified by the patients' recumbent position. In 12 CHF patients, and age and sex-matched 12 normal subjects, a single 12-lead surface ECG was recorded in each postural position [left lateral decubitus position (L), supine position (S), and right lateral decubitus position (R)]. In normal subjects, the QT dispersion was comparable in the three recumbent positions [L: 47+/-15 (SD) ms, S: 40+/-9 ms, R: 38+/-14 ms, P=NS]. In contrast, in CHF patients, QT dispersion was significantly shorter in R than those in L and S (L: 93+/-42 ms*, S: 81+/-29 ms*, R: 63+/-24 ms, *P

Takanori Uehara,1,2 Masatomi Ikusaka,1 Yoshiyuki Ohira,1 Mitsuyasu Ohta,1,2 Kazutaka Noda,1 Tomoko Tsukamoto,1 Toshihiko Takada,1 Masahito Miyahara11Department of General Medicine, Chiba University Hospital, 2Division of Rotated Collaboration Systems for Local Healthcare, Graduate School of Medicine, Chiba University, Chiba, JapanPurpose: To compare the diagnostic accuracy of diseases predicted from patient responses to a simple questionnaire completed prior to examination by doctors with different levels of ambulatory training in general medicine.Participants and methods: Before patient examination, five trained physicians, four short-term-trained residents, and four untrained residents examined patient responses to a simple questionnaire and then indicated, in rank order according to their subjective confidence level, the diseases they predicted. Final diagnosis was subsequently determined from hospital records by mentor physicians 3 months after the first patient visit. Predicted diseases and final diagnoses were codified using the International Classification of Diseases version 10. A “correct” diagnosis was one where the predicted disease matched the final diagnosis code.Results: A total of 148 patient questionnaires were evaluated. The Herfindahl index was 0.024, indicating a high degree of diversity in final diagnoses. The proportion of correct diagnoses was high in the trained group (96 of 148, 65%; residual analysis, 4.4) and low in the untrained group (56 of 148, 38%; residual analysis, -3.6) (χ2=22.27, P

Background Appropriate long-term drinking of red wine is associated with a reduced risk of cardiovascular disease. Resveratrol, a well-known SIRT1 activator is considered to be one of the beneficial components contained in red wine, and also developed as a drug candidate. We previously demonstrated that resveratrol protects brain against ischemic stroke in mice through a PPARα-dependent mechanism. Here we report the different effects of the oligomers of resveratrol. Methods We evaluated the activation of PPARs by ε-viniferin, a resveratrol dimer, and vaticanol C, a resveratrol tetramer, in cell-based reporter assays using bovine arterial endothelial cells, as well as the activation of SIRT1. Moreover, we tested the metabolic action by administering vaticanol C with the high fat diet to wild-type and PPARα-knockout male mice for eight weeks. Results We show that vaticanol C activates PPARα and PPARβ/δ in cell-based reporter assays, but does not activate SIRT1. ε-Viniferin shows a similar radical scavenging activity as resveratrol, but neither effects on PPARs and SIRT-1. Eight-week intake of vaticanol C with a high fat diet upregulates hepatic expression of PPARα-responsive genes such as cyp4a10, cyp4a14 and FABP1, and skeletal muscle expression of PPARβ/δ-responsive genes, such as UCP3 and PDK4 (pyruvate dehydrogenase kinase, isoform 4), in wild-type, but not PPARα-knockout mice. Conclusion Vaticanol C, a resveratrol tetramer, activated PPARα and PPARβ/δ in vitro and in vivo. These findings indicate that activation of PPARα and PPARβ/δ by vaticanol C may be a novel mechanism, affording beneficial effects against lifestyle-related diseases.