Fibroblast growth factor (FGF) 23 has been identified as the last member of FGF family. FGF23 reduces serum phosphate level by suppressing proximal tubular phosphate reabsorption and intestinal phosphate absorption. FGF23 is produced by bone and acts on the kidney through a specific receptor system which is composed of Klotho and certain subtypes of FGF receptors. Excess actions of FGF23 cause several hypophosphatemic diseases characterized by impaired renal phosphate reabsorption and rickets/osteomalacia. In contrast, deficient actions of FGF23 result in hyperphosphatemic tumoral calcinosis with enhanced renal phosphate reabsorption. These results indicate that FGF23 works as a hormone to regulate the serum phosphate level.

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Lung epithelium is the primary site of lung damage in interstitial lung diseases. Although there are various initiating factors, the terminal stages are characterized by pulmonary fibrosis. Conventional therapy consisting of glucocorticoids or immunosuppressive drugs is usually ineffective. Epithelial cell apoptosis have been considered to be initial events in interstitial lung diseases. The death receptor-mediated signaling pathway directly induces caspase activation and apoptosis. Other stresses induce the release of cytochrome from mitochondria and caspase activation. Endoplasmic reticulum stress also induces apoptosis. Epithelial cell death is followed by remodeling processes, which consist of epithelial and fibroblast activation, cytokine production, activation of the coagulation pathway, neoangiogenesis, re-epithelialization and fibrosis. Epithelial and mesenchymal interaction plays important roles in these processes. Further understanding of apoptosis signaling may lead to effective strategies against devastating lung diseases. We review the role of epithelial cell apoptosis in the molecular mechanisms of pulmonary fibrosis.

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Objective The aim of this study was to elucidate the efficacy of short-term interferon (IFN) therapy for chronic hepatitis C patients with low virus load.
Methods The present study was a retrospective cohort study. Inclusion criteria were biopsy-proven chronic hepatitis, the serum hepatitis C virus (HCV) RNA level of less than 100 KIU/ml, IFN period of 8weeks or less. One hundred and eleven consecutive patients satisfied above criteria were treated with IFN-beta (dose: 6 MU, daily for 4, 6, or 8 weeks).
Results Background of clinical profiles were as follows: median (range) age=56 (20-73) years, male/female=64/47, genotype 1b/2a/2b=40/68/3, and median (range) HCV-RNA= 34 (4.5-81) KIU/ml. Out of 111, 64 patients (57.7%) had sustained viral response (SVR). Based on the difference of HCV genotype, the SVR rate was 47.5% (19/40) in genotype 1 and 63.3% (45/71) in genotype 2. In genotype 1, the SVR rate in patients treated with the 8-week-regimen was significantly higher than that in patients treated with the 4- or 6-week regimen. In contrast, in genotype 2, the SVR in patients treated with the 8-week regimen was not significantly different from that in patients treated with the 6-week regimen. None of the patients had severe IFN-related side effects.
Conclusions The 6 or 8-week regiment of IFN-beta therapy is one selection of therapy for chronic hepatitis C patients who have tended to have a SVR and who show IFN-related adverse events.

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Objective To compare the effect of delapril/manidipine vs olmesartan/hydrochlorothiazide (HCTZ) combination on insulin sensitivity and plasma fibrinogen in obese hypertensive patients.
Patients and Methods After a 4-week placebo period, 88 obese, hypertensive (DBP >95 and <110 mmHg) outpatients were randomized to delapril 30 mg/manidipine 10 mg combination or to olmesartan 20 mg/HCTZ 12.5 mg combination for 24 weeks according to a prospective, randomized, open-label, blinded endpoint, parallel group design. At the end of the placebo period and treatment period, clinical BP, fasting plasma glucose (FPG), plasma insulin, insulin sensitivity (by euglycemic hyperinsulinemic clamp) and plasma fibrinogen were evaluated. Insulin sensitivity was expressed as the amount of glucose infused during the last 30 minutes (glucose infusion rate, GIR) in mg/Kg/min. The total glucose requirement (TGR) to maintain a steady-state blood glucose level in response to a defined increase in plasma insulin concentration was also evaluated.
Results Both combinations significantly reduced SBP/DBP values (-22.3/16.4 mmHg and -22.6/17.2 mmHg, respectively, all p <0.001 vs placebo). GIR was significantly increased only by delapril/manidipine (+3.01 mg/min/Kg, p=0.038 vs placebo), the difference between treatments being significant (p <0.05). TGR was significantly increased by delapril/manidipine (+9.7 g, p=0.034), while it was unaffected by olmesartan/HCTZ. Plasma insulin as well as fibrinogen were significantly reduced by delapril/manidipine (-17.8 pmol/l, p=0.047 and -67.5 mg/dl, p=0.021, respectively), but not by olmesartan/HCTZ, the difference between the two treatments being statistically significant (p <0.05).
Conclusion In obese hypertensive patients the delapril/manidipine combination but not the olmesartan/HCTZ combination significantly decreased insulin resistance and plasma fibrinogen levels, despite the similar BP lowering efficacy.

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Objective The goal of this study was to evaluate the safety and efficacy of mechanical ventilation (MV), including noninvasive positive pressure ventilation (NPPV) and endotracheal intubation (ETI) in patients with very severe hypoxemia due to refractory heart failure (RHF).
Methods In addition to conventional treatment, eighteen patients with hypoxemia due to RHF were assigned to receive NPPV (n=10) or ETI (n=8) based on the severity of their clinical status. Arterial blood gas, PaO₂/FiO₂, vital signs including respiratory rate (RR), heart rate (HR) and systolic blood pressure (SBP), left ventricular ejection fraction (LVEF) and left ventricular end-diastolic volume (LVEDV) were recorded before and after MV in each group.
Results The patients in the ETI group showed more severe hypoxemia and respiratory acidosis in comparison with the patients in the NPPV group. Both the NPPV and ETI significantly increased PaO₂, PaO₂/FiO₂ and arterial oxygen saturation (SaO₂) (p <0.01) and reduced RR and HR (p <0.01) after MV in comparison to that before MV. Both the NPPV and ETI significantly increased LVEF (p <0.05) and decreased LVEDV (p <0.01) at the time of weaning from MV in comparison to that before MV. Moreover, PaO₂ correlated with LVEF (r=0.882, p=0.01 and r=0.736, p=0.037) while it also inversely correlated with LVEDV (r=-0.645, p=0.044 and r=-0.756, p=0.030) at the time of weaning from MV in the NPPV and ETI groups, respectively. There were two failed cases in the NPPV group. They were transferred immediately to be treated with ETI and were equivalent to the others in the ETI group.
Conclusion Both NPPV and ETI are safe and effective modalities for improving hypoxemia and left heart function in patients with RHF. These results suggest that invasive MV should be applied to very severe patients with RHF as quickly as possible when an expected clinical improvement cannot be obtained by NPPV.

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Background Levofloxacin (LVFX) is widely used against a broad spectrum of bacteria. To prevent the emerging of resistance resulting from its abuse, an optimal method and dosage are needed. In the field of hematological malignancies, LVFX is one of the choices for prophylaxis for febrile neutropenia (FN). There is no consensus about the optimal dosage and method among hematologists.
Aims To determine the population pharmacological parameters based on the population pharmacokinetics of LVFX. We considered the optimal dosage and method of LVFX based on various simulations depicted by personal computer.
Methods We performed population pharmacokinetic analysis for seven patients receiving LVFX as prophylaxis (200 mg, b.i.d.) for FN with blood sampling. One patient received 100 mg t.i.d. All patients were treated at Kyoto Prefectural University of Medicine.
Results Clearance (CL) is 5.8 L/hr, distribution volume (Vd) is 58.5 L, area under the blood concentration-time curve (AUC_0-24) is 69.0 μg·hr/mL, t1/2 is 6.9hr, Cmax is 3.4 μg/mL at administration of 200 mg b.i.d. Cmax (peak) of 500 mg, and q.d. is simulated as 8.54 μg/mL.
Conclusion For LVFX 500 mg q.d. is predicted to be the most effective dosage and method. Because the predicted Cmax value is similar to that of western countries, the frequency of adverse effects is thought to be same as in western countries. 500 mg, q.d., may also be an optimal dosage and method for Japanese.

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Objective To reduce the relapse rate for hematological malignancies after allogeneic hematopoietic stem cell transplantation, we employed a myeloablative regimen comprising thiotepa 400 mg/m², cyclophosphamide 3,600 mg/m² and total body irradiation 10 Gy.
Materials and Methods Subjects comprised 17 patients (median age, 53 years; range, 50-56 years) with hematological malignancies who received allogeneic hematopoietic stem cell transplantation from HLA-identical related (n=6), HLA-mismatched family (n=2) or unrelated donors (n=9). Prophylaxis of acute graft-versus-host disease (GVHD) consisted of short-term methotrexate and cyclosporine (n=4) or short-term methotrexate and tacrolimus (n=13).
Results No grade IV regimen-related toxicities as determined by Bearman's criteria were encountered. Acute grade II-IV GVHD developed in 7 patients, with chronic GVHD in 11 patients. With a median follow-up of 39 months, 3 years survival rate after transplantation was 59%. Two patients died due to infection by 100 days after transplantation. Only 1 patient with Philadelphia-positive acute lymphoblastic leukemia experienced relapse. Eight patients died of non-leukemic causes (sepsis, n=2; liver dysfunction, n=2; idiopathic interstitial pneumonia, n=1; bacterial pneumonia, n=1; bronchiolitis obliterans resulting from chronic GVHD, n=1; and disseminated infection with varicella zoster virus, n=1).
Conclusions This regimen was tolerable, but a large trial is warranted to confirm the efficacy of this conditioning.

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Objective The aim of this study was to reveal whether or not the presence of anti-U1RNP antibodies is associated with a low amount of salivary secretion (ASS).
Subjects and Methods Twenty females (mean age 49±12 years) who had anti-U1RNP but not ACA, anti-Ro, or anti-La antibodies (anti-U1RNP-positive group), and 65 control females (mean age 50±12 years) were included in this study. The saxon test was performed to measure the ASS.
Results After a correction for age by ANCOVA, ASS in the anti-U1RNP-positive group was significantly lower than ASS in the control group (p <0.001). In the control group, ASS was not significantly decreased with advanced age (r=-0.140, p=0.211). In the anti-U1RNP-positive group, ASS was decreased with age, without a significant difference (r=-0.379, p=0.100). In the next analysis, we introduced 'ASS with age correction', assuming that all subjects in the anti-U1RNP-positive group were 49 years of age. A negative correlation between the titers of anti-U1RNP antibodies and the ASS with the age correction in the anti-U1RNP-positive group was noted (r=-0.520, p=0.019). The log of the antinuclear antibodies titers, or titers of rheumatoid factor was significantly correlated with the titers of anti-U1RNP antibodies, respectively (r=0.466, p=0.038 and r=0.595, p=0.006; respectively). The pathological findings of minor salivary gland biopsy in 2 subjects were compatible with Sjögren's syndrome; one subject showed moderate lymphocytic infiltration.
Conclusion The presence of anti-U1RNP antibodies is associated with reduced ASS.

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Objective Chronic kidney disease (CKD) is a major public health problem. There is conflicting evidence concerning whether CKD is an independent risk factor for carotid intima-media thickness (IMT).
Patients and Methods The study subjects were 428 men aged 70±15 (mean±standard deviation) years and 582 women aged 75±12 years enrolled consecutively from patients in the Medical Department of Seiyo Municipal Nomura Hospital. Carotid IMT was derived via B-mode ultrasonography and CKD was evaluated by the estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease Study equation.
Results In men, age (p<0.001), systolic blood pressure (p<0.001), antihypertensive drug use (p<0.001), HDL-C (p=0.006), LDL-C (p=0.004), prevalence of diabetes (p=0.035) and eGFR (p<0.001) were significantly correlated with carotid IMT. In women, age (p<0.001), systolic blood pressure (p<0.001), antihypertensive drug use (p<0.001), HDL-C (p=0.035), LDL-C (p=0.017) and eGFR (p<0.001) were significantly correlated with carotid IMT. Stepwise multiple linear regression analysis using IMT as an objective variable, adjusted by various factors as explanatory variables, showed that eGFR was a significant independent contributing factor along with known risk factors in men (β, -0.096; p=0.018) and women (β, -0.080; p=0.035).
Conclusions Our data suggested that eGFR was associated with an increased prevalence of carotid atherosclerosis independent of common cardiovascular risk factors in both men and women.

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Objective Salt intake restriction is important to health maintenance in subjects tending toward excessive intake. For convenience salt intake is ordinarily estimated at health check up centers using a salt-preference questionnaire, but whether or not the questionnaire identifies excessive salt consumers is unclear.
Methods Daily salt intake in 725 subjects including 452 men examined at our health-check center was estimated by a spot urine method developed by Kawasaki et al (Clin Exp Pharmacol Physiol 20:7-14, 1993). Results from the questionnaire were used to divide into salt preference and non-salt preference groups.
Results Daily salt intake estimated by the spot urine method was 13.5±3.5 g in male subjects and 12.4±3.1 g in female subjects. Salt preference subjects included 42% men and 24% of women. As a daily salt intake of less than 10 g is recommended for the general population in Japan, subjects whose salt intake exceeded 10 g were considered excessive salt consumers. Among men, excessive salt consumers comprised 85% of the salt preference group and 84% of the non-salt preference group. Among women, 88% of the salt preference group and 76% of the non-salt preference group were excessive consumers.
Conclusions A simple questionnaire for salt preference was not effective in identifying excessive salt consumers. Convenient, reliable methods for the estimation of salt intake, such as the spot urine method, are recommended in place of the questionaire.

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We encountered three families that showed NASH accumulation. In family #1, a 21-year-old son and 10-year-old daughter were diagnosed with nonalcoholic steatohepatitis (NASH). They shared two adiponectin-gene single nucleotide polymorphisms (SNP). In family #2, a 51-year-old mother and 27-year-old son were diagnosed with NASH and shared the SNPs of other genes. In family #3, a 66-year-old mother and 34-year-old son were diagnosed with NASH and shared the SNPs of other genes. SNP sites differed among the three families, suggesting that the genes associated with the occurrence of NASH might be different in each patient.

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A 73-year-old man with hepatocellular carcinoma (HCC) had been treated repeatedly with transcatheter arterial embolization (TAE) and percutaneous ethanol injection therapy (PEIT) since 2000. HCC recurrence near the intrahepatic left portal vein was treated by PEIT in 2004. The patient complained of fatigue and upper abdominal pain 28 days later. Abdominocentesis and abdominal computed tomography demonstrated rupture of the recurrent HCC and multiple intrahepatic recurrences. We successfully performed emergency TAE, but the patient died of liver failure. Rapid seeding of multiple intrahepatic tumors after PEIT is a rare event, but such a possibility must be kept in mind.

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Contrary to the widely known view of the insidious, slowly progresive pattern of hepatitis C, a rapidly progressive cirrhotic form can devolop in immunodeficient conditions. Hepatitis C leads to cirrhosis in immunocompetent hosts after 20 years of infection however in hypogammaglobulinemic patients disease progresses faster, leading to cirrhosis and death within 10 years of diagnosis and frequently earlier. Here we present a 57-year-old woman with common variable immunodeficiency infected with hepatitis C after antral and duodenal resection and gastrojejenostomy operation in another hospital for lymphoma mimicking duodenal nodular hyperplasia which then rapidly progressed to decompansated cirrhosis in less than two years.

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Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease primarily affecting middle-aged women. Although little is known about the etiology of PBC, it may be induced by an autoimmune response. Here, we describe a rare case of appearance of PBC following chemotherapy for Hodgkin's lymphoma.

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We report an autopsied 20-year-old man case of intestinal necrosis associated with megacolon from hypoganglionosis, a pseudo-Hirschsprung's disease. The patient had suffered from severe constipation since two years of age, and presented abdominal distention from age ten. Autopsy revealed marked dilatation and necrosis of the entire large intestine. Although ganglion cells in the intestinal plexus were found throughout the large intestine, their number was reduced to 12-20% of that in the normal control. In pseudo-Hirschsprung's disease, there are occasional cases where an acute abdomen first presents itself in adulthood after running its course as chronic constipation.

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A 61-year-old man, consulted the clinic for dyspnea and cough worsening for 15 days. His past medical history was limited to a cutaneous melanoma 15 years previously, treated by surgery. He was thought to be cured, and was relapse free for the subsequent five years. Echocardiography revealed a large intracardiac mass occupying at least three quarters of the right ventricle, extending to the outflow tract. Echocardiography, MRI findings and anatomopathological examination are presented. Melanoma metastatasis is discussed, with particular attention to cardiac localizations.

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We observed a 41-year-old woman with severe central pontine myelinolysis (CPM) and unusually extensive extrapontine myelinolysis (EPM), but without evidence of hyponatremia. Increased alcohol consumption in prior months was the main cause of her CPM/EPM. However, in general, EPM is a rare accompaniment in alcoholic patients with CPM without hyponatremia. With regard to our patient, the EPM was unusually widespread; magnetic resonance imaging (MRI) of her brain showed multiple hyperintense lesions on T2-weighted images distributed symmetrically in bilateral caudate nuclei, lentiform nuclei and thalami. Serial follow-up MRI revealed almost complete resolution of EPM after methylprednisolone pulse therapy. By contrast, marked cavitary hypointensity in the pons remained, but complete remission of neurological symptoms was achieved.

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A 70-year-old man on antiplatelet therapy developed sudden severe back pain in his neck with numbness and weakness in his extremities. On admission, he presented with complete quadriplegia, hypoesthesia, and anuria. Magnetic resonance imaging (MRI) revealed cervical cord compression due to an epidural hematoma posterior to the spinal cord and intramedullary hyperintensity. Surgical evacuation was performed about 12 hours after the onset, but the recovery of neurological deficits was poor. After performing 2 additional administrations of steroid pulse therapy, the patient's motor dysfunction began to improve and spinal MRI showed a recovery as well. These observations suggest that steroid administration should be considered as a post-operative additional therapy for cases with severe neurological deficits even after surgery.

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A 44-year-old woman with mitochondrial encephalomyopathy noticed weakness of the lower extremities at the age of 30 years. She also has type 2 diabetes mellitus, posterior subcapsular cataracts in both eyes, and corpus callosum atrophy. Family history showed that a maternal cousin had a myopathy, 3 maternal aunts had diabetes mellitus, and her mother and 2 maternal aunts had cataracts. External ophthalmoplegia, proximal myopathy, and absent deep tendon reflexes were noted. The mitochondrial DNA 3243 point mutation was negative. Muscle biopsy showed ragged-red fibers, cytochrome c oxidase (COX)-positive fibers, and COX-negative fibers.

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A 41-year-old man with progressive limb weakness manifested fluctuating muscle weakness as seen in myasthenia gravis (MG). Laboratory investigations revealed hyperthyroidism without the complication of MG. Electrophysiological studies demonstrated abnormal features of neuromuscular transmissions resembling those of the Lambert-Eaton myasthenic syndrome rather than those of MG. A CT scan showed a mediastinal mass that suggested thymic hyperplasia which often complicates MG or hyperthyroidism. Medical treatment of hyperthyroidism resulted in resolution of MG-like symptoms and regression of thymic hyperplasia on CT concomitant with normalization of thyroid function. This case highlights the fact that careful investigations are needed to differentiate MG-like symptoms from genuine MG in cases of hyperthyroidism with thymic lesions.

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This report describes a case of hepatic phase Fasciola hepatica infection presenting huge and multilocular lesions. The unique radiological findings mimicked hydatid diseases and also cystic liver neoplasm. Fascioliasis should be included in the differential diagnosis for cystic liver diseases.

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A 50-year-old man without family history of metabolic bone disease was referred to our hospital with a 5-year history of progressively worsening spinal and bilateral diffuse leg pain and proximal muscle weakness. Two years before admission, he was diagnosed as ankylosing spondylitis by a rheumatologist and was maintained on low-dose prednisone therapy without benefit. He developed progressive spinal and thoracic deformities, resulting in a 10 cm loss in height in the preceding 2 years. On physical examination, marked thoracic kyphosis and pectus carinatum was noted. Plain radiograph revealed pseudofracture in the right femoral neck. Laboratory findings showed a normal level of serum calcium, elevated level of serum alkaline phosphatase and inappropriately increased urinary phosphate excretion despite extreme hypophosphatemia. He was diagnosed as adult-onset hypophosphatemic osteomalacia caused by renal phosphate wasting. Serum fibroblast growth factor 23 was the upper limit of normal despite extreme hypophosphatemia and no neoplastic lesion potentially inducing hypophosphatemic osteomalacia could be identified in a thorough search including imaging studies of his entire body. Oral administration of phosphate and activated vitamin D together with dipyridamole relieved the persistent pain and weakness, and he became fully ambulatory.

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We report a case of Mycobacterium intracellulare (M. intracellulare) pulmonary infection with co-existing lung cancer and presenting as a solitary pulmonary nodule requiring differentiation from lung cancer. Computed tomography showed two nodules (20 mm) with spicula formation and pleural indentation on the right lower lobe of the lung (right S6 and S8). Transbronchial biopsies from the right S6 and S8 nodules revealed mycobacteriosis and adenocarcinoma, respectively. Thereafter, a right lower lobectomy was performed. Cases of pulmonary M. intracellulare disease with solitary nodule are rare. Moreover, M. intracellulare pulmonary infection with co-existing lung cancer is extremely rare.

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The syndrome of inappropriate antidiuretic hormone (SIADH) secretion is a common consequence of neurologic and pulmonary infections as well as drug intake and many other clinical situations. This report describes SIADH that developed in an elderly woman with single dermatomal herpes varicella zoster ophthalmicus without evidence of varicella zoster encephalitis or dissemination. A 76-year-old woman was admitted to our department for evaluation of left facial pain, confusion and disorientation. Further investigation revealed hyponatremia 112 mEq/L, low serum osmolality, high urine osmolality, normal renal function, normal adrenal and thyroid hormones, and high plasma vasopressin 40 pg/mL. These results indicate that the hyponatremia in this case was due to SIADH and that SIADH was caused by an increased release of vasopressin probably because of the antiviral drug (acyclovir) or infection of varicella zoster virus(VZV)in a single dermatome.

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Nattokinase is used as a health-promoting medicine for preventing thrombosis due to its fibrinolytic activity. Cerebral microbleed is remnant of blood extravasations from the damaged vessels related to cerebral microangiopathies. We report a patient, having used aspirin for secondary stroke prevention, who had an acute cerebellar hemorrhage after taking nattokinase 400 mg daily for 7 consecutive days. In addition to the hemorrhagic lesion, multiple microbleeds were demonstrated on brain MR images. We suggest that nattokinase may increase risk of intracerebral hemorrhage in patients who have bleeding-prone cerebral microangiopathy and are receiving other antithrombotic agent at the same time.

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The name of the first author, Yasuo Masanori, should have been "Masanori Yasuo". The authors and editors apologize for any confusion this may have caused.

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