Analysis of MicroRNA in Bile Cytologic Samples Is Useful for Detection and Diagnosis of Extrahepatic Cholangiocarcinoma.

OBJECTIVES: This study aimed to develop reliable biomarkers that improve the ability of bile cytology to diagnose cholangiocarcinoma vs benign biliary lesions. METHODS: Many studies indicate that microRNAs (miRNAs) are potential candidates for the early diagnosis of cancer. We analyzed the expression of five tumor-associated miRNAs (miR-31-5p, miR-122-5p, miR-378d, miR-182-5p, and miR-92a-3p) in cytology samples using quantitative reverse transcription polymerase chain reaction. We collected 52 surgically resected tissue samples, 84 cytologic specimens from smears (53 cases of cancer and 31 cases of noncancer), and 40 residual sediments after smearing for routine cytology at Hiroshima University Hospital. RESULTS: The expression of miR-31-5p, miR-378d, and miR-122-5p was significantly higher in cancer tissues than those in normal tissues, while miR-182-5p expression was lower. The expression of miR-31-5p, miR-378d, miR-182-5p, and miR-92a-3p was significantly higher in detached cell samples from smears of cholangiocarcinoma cases than in those from noncancer cases. CONCLUSIONS: These results suggest that the analysis of miRNAs in bile cytologic specimens is a promising auxiliary tool for distinguishing cholangiocarcinoma from benign biliary lesions.

Sources, species and secondary formation of atmospheric aerosols and gaseous precursors in the suburb of Kitakyushu, Japan.

The simultaneous assessment of source apportionment and secondary formation processes was comprehensively studied in a suburban area located on the western edge of Japan by combining year-round daily observation using a filter-pack method with model calculations. Secondary formation was the most important pollution source, accounting for ca. 45% (23% (secondary sulfates) + 22% (secondary nitrates)) of the sources of total atmospheric aerosol mass. For the secondary aerosol composition at this suburban site in western Japan, the secondary sulfates were mainly derived from volcanic eruptions (Sakurajima volcano and/or Aso volcano), the oxidation of SO2 from industrial combustion, ship emissions in the Kyushu area, and long-distance transportation from several coastal cities in Eastern China. Multiple regression results further revealed that the secondary sulfate formation process was significantly influenced by and related to HNO3, HCl, and the relative humidity (RH) (p < 0.01). While the potential pollution source region of secondary nitrates was located in the northwest region of the sampling site, where air masses pass through Mongolia and Northern China, the formation mechanism of secondary nitrates was more complicated, with the important driving factors being Ox, NO2, NH3, HCl, temperature (T), and RH. In addition, if the presence of atmospheric HNO3 was ignored, the nitrogen oxidation rate (NOR) would be significantly underestimated, especially at relative humidity levels less than 60% and temperatures greater than 16 °C. The results of this study clearly demonstrate the source contribution and characteristics of secondary aerosols in the suburban area of western Japan and can be adopted as the important basis to mitigate particle pollution.

The extracellular volume status predicts body fluid response to SGLT2 inhibitor dapagliflozin in diabetic kidney disease.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are an antihyperglycemic drug with diuretic action. We recently reported that the SGLT2 inhibitor dapagliflozin ameliorates extracellular volume expansion with a mild increase in urine volume. However, the impact of the pretreatment extracellular volume status on the body fluid response to SGLT2 inhibitors remains unclear. METHODS: Thirty-six diabetic kidney disease (DKD) patients were treated with dapagliflozin. The body fluid volume, including intracellular water (ICW), extracellular water (ECW) and total body water (TBW), were measured on baseline and day 7 using a bioimpedance analysis (BIA) device. The ECW/TBW and ECW were used as markers of the extracellular volume status. For a comparison, the extracellular volume status responses to loop diuretic furosemide (n = 16) and vasopressin V2 receptor antagonist tolvaptan (n = 13) were analyzed. RESULTS: The body weight, brain natriuretic peptide and body fluid parameters measured by a BIA (ICW, ECW, TBW, and ECW/TBW) were significantly decreased for 1 week after dapagliflozin administration. The change in the ECW/TBW in the high-ECW/TBW group (over the median value of 0.413) was significantly higher than in the low-ECW/TBW group (- 2.1 ± 0.4 vs. - 0.5 ± 0.4%, p = 0.006). Only with dapagliflozin treatment (not furosemide or tolvaptan treatment) was the baseline ECW/TBW significantly correlated with the changes in the ECW/TBW (r = - 0.590, p < 0.001) and ECW (r = - 0.374, p = 0.025). CONCLUSIONS: The pretreatment extracellular volume status predicts the body fluid response to the SGLT2 inhibitor dapagliflozin in DKD patients. The diminished extracellular fluid reduction effect of dapagliflozin in patients without severe extracellular fluid retention may contribute to maintaining a suitable body fluid status.

Impact of serum albumin levels on the body fluid response to tolvaptan in chronic kidney disease patients.

PURPOSE: Tolvaptan exerts an aquaretic effect by blocking vasopressin V2 receptor. Although tolvaptan ameliorates body fluid retention even in patients with chronic kidney disease (CKD), predictors of body fluid reduction induced by tolvaptan remain unclear. We, therefore, examined the clinical parameters associated with the effect of tolvaptan on fluid volume in CKD patients. METHODS: Twelve CKD patients (stage 3-5) with fluid retention were treated with tolvaptan in addition to conventional diuretic treatment. Patients were divided into low and high responders by the median change in total body water (TBW) for 1 week measured by a bioimpedance analysis (BIA) device, and clinical parameters were compared between the groups. RESULTS: The body weight significantly decreased by 2.0 ± 2.3 kg (p = 0.005), but the estimated glomerular filtration rate (eGFR) was not significantly changed (16.9 ± 11.9 vs. 17.4 ± 12.4 mL/min/1.73 m2, p = 0.139) after 1 week. The BIA showed that the intracellular water (ICW) decreased by 6.0% ± 4.7% (p < 0.001), the extracellular water (ECW) decreased by 6.7% ± 5.4% (p = 0.001), and the TBW decreased by 6.3% ± 4.9% (median value - 6.02%, p < 0.001). The serum albumin level in the high responders was significantly lower than in the low responders (2.3 ± 0.5 vs. 3.3 ± 0.8 g/dL, p = 0.013). Significant partial correlations adjusted for the eGFR were observed between the baseline serum albumin level and changes in the ICW (r = 0.440, p = 0.048), ECW (r = 0.593, p = 0.009) and TBW (r = 0.520, p = 0.020). CONCLUSIONS: Serum albumin levels predict the body fluid response to tolvaptan in CKD patients. Tolvaptan may be a promising therapeutic option for ameliorating body fluid retention, especially in patients with hypoalbuminemia.

Different Effects on Fluid Distribution between Tolvaptan and Furosemide in a Liver Cirrhosis Patient with Chronic Kidney Disease.

A 73-year-old man with liver cirrhosis and advanced chronic kidney disease was admitted to our hospital due to bilateral lower leg edema and appetite loss. Furosemide to treat fluid retention markedly decreased extracellular water compared with intracellular water, but the addition of tolvaptan equally decreased both with a greater diuretic response than furosemide alone. Furthermore, tolvaptan administration increased the plasma colloid osmotic pressure, which might facilitate the shift of fluid from the extravascular space to the intravascular space. This is the first case showing different effects on the fluid distribution between furosemide and additional tolvaptan in the same patient.

Effects of the sodium-glucose cotransporter 2 inhibitor dapagliflozin on fluid distribution: A comparison study with furosemide and tolvaptan.

AIM: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are an antihyperglycemic drug with diuretic properties. We recently reported that an SGLT2 inhibitor ameliorated extracellular fluid expansion with a transient increase in urinary Na+ excretion. However, the effects of SGLT2 inhibitors on fluid distribution in comparison to conventional diuretics remain unclear. METHODS: Forty chronic kidney disease patients with fluid retention (average estimated glomerular filtration rate 29.2 ± 3.2 mL/min per 1.73 m2 ) were divided into the SGLT2 inhibitor dapagliflozin (DAPA), loop diuretic furosemide (FR) and vasopressin V2 receptor antagonist tolvaptan (TLV). The body fluid volume was measured on days 0 and 7 using a bioimpedance analysis device. RESULTS: In all three groups, body weight was significantly and similarly decreased, and urine volume numerically increased for 7 days. Bioimpedance analysis showed that the changes in intracellular water were similar, but that there were significant changes in the extracellular water (ECW) (DAPA -8.4 ± 1.7, FR -12.5 ± 1.3, TLV -7.4 ± 1.5%, P = 0.048). As a result, the change in the ratio of ECW to total body water in the DAPA group was significantly smaller than that in the FR group, but numerically larger than that in the TLV group (DAPA -1.5 ± 0.5, FR -3.6 ± 0.5, TLV -0.5 ± 0.4%, P < 0.001). CONCLUSION: Sodium-glucose cotransporter 2 inhibitor DAPA predominantly decreased the ECW with a mild increase in urine volume, but the change in the ECW/total body water was smaller than that in patients treated with FR, and larger than that in patients treated with TLV, suggesting that the effects of SGLT2 inhibitors on fluid distribution may differ from those of conventional diuretics.

Kartagener syndrome complicated by immunoglobulin A nephropathy.

We herein report the case of a 36-year-old woman with Kartagener syndrome (KS), which is an autosomal recessive disorder defined by a triad of bronchiectasis, sinusitis, and situs inversus, with complications of asymptomatic microhematuria and proteinuria. She was finally diagnosed with biopsy-proven immunoglobulin (Ig) A nephropathy. KS constitutes a subgroup of primary ciliary dyskinesia (PCD) characterized by structural and/or functional ciliary abnormalities resulting in sinopulmonary involvement with varying severity. Our case does not allow us to corroborate the clinical impact of KS and/or PCD as a pathogenic basis for the IgA nephropathy, and each disease might develop independently. However, systematic studies on this topic are quite lacking, so we strongly recommend the accumulation of more cases similar to our own, which would allow us to clarify the nature of this disease state more precisely.

Hemolytic Uremic Syndrome: An Increasingly Recognized Public Health Problem.

A 28-year-old man was referred and admitted to our hospital due to Escherichia coli O157-mediated hemorrhagic colitis with severe thrombocytopenia. A systemic workup concluded that the patient had acute pancreatitis as well as hemolytic uremic syndrome. The patient was ultimately discharged, with his platelet count having recovered. Our case serves an illustrative example of potentially serious complications of an increasingly recognized public health problem. Systemic studies on this topic are insufficient, and we strongly recommend the further accumulation of more experiences like ours. Several diagnostic and management concerns that emerged in this case are also discussed.

Valacyclovir Neurotoxicity and Nephrotoxicity in an Elderly Patient Complicated by Hyponatremia.

A 66-year-old women with no history of renal disease was admitted due to a coma and acute kidney injury with a serum creatinine level of 7.44 mg/dL which were ascribed to valacyclovir neurotoxicity and nephrotoxicity, respectively. She had received valacyclovir at a standard dosage for the treatment of herpes zoster and was finally discharged, having fully returned to her normal baseline mental status with a recovered serum creatinine level of 0.68 mg/dL. We feel that awareness of this pathology remains a challenge for physicians and therefore strongly recommend the further accumulation of experiences similar to our own. Our experience underscores the pitfalls of administering valacyclovir to elderly patients who barely appear to have a favorable renal function. Several concerns regarding the therapeutic management, including blood purification strategies, that emerged in this case are also discussed.

Nephrotic Syndrome and a Retroperitoneal Mass: A Case Report of a Patient with Recurrent Invasive Thymoma.

A 68-year-old man was admitted to our hospital to undergo an examination for nephrotic syndrome while concurrently complicated with recurrent thymoma in the parietal pleura and retroperitoneum. He had been diagnosed with invasive thymoma and had undergone thymo-thymectomy seven years previously. Based on the renal biopsy findings, his nephrotic syndrome was ascribed to minimal change disease. He was treated with corticosteroid monotherapy, which resulted in complete remission six months later, despite the fact that the recurrent thymoma remained. The role of thymoma in the pathogenesis of paraneoplastic glomerulopathy and the therapeutic concerns that emerged in this case are also discussed.

Rehabilitation improves prognosis and activities of daily living in hemodialysis patients with low activities of daily living.

BACKGROUND: Activities of daily living (ADL) in aged hemodialysis patients decrease by many factors as hemodialysis therapy, various disease-related complications and underlying disease for rehabilitation. But the correlation between low ADL and mortality remains unclear. We assessed the levels of ADL and effects of rehabilitation in hemodialysis patients with low ADL. Moreover, the association between the baseline functional independence measure (FIM) or rehabilitation treatment effects and all-cause mortality were investigated. METHODS: This prospective cohort study included 182 inpatients on maintenance hemodialysis, who underwent rehabilitation for a decline in ADL. Before and after initiating rehabilitation, ADL were assessed using FIM. RESULTS: The total baseline FIM was 65.1±26.9 (motor items: 39.5±18.7; cognitive items: 25.6±10.7). After rehabilitation, the total FIM increased to 77.1±33.1 (motor items: 50.9±24.4; cognitive items: 26.1±10.8). The baseline FIM, presence or absence of FIM increase, and albumin were significantly associated with mortality. Moreover, the mortality hazard ratio in patients with FIM ≤67 and no FIM increase was 20-fold significantly higher than that in patients with FIM ≥68 and FIM increase. The cognitive items and albumin were significantly associated with the rehabilitation effects in multivariate analysis. CONCLUSIONS: Although the FIM decreased by half in hemodialysis patients, rehabilitation improved their FIM (particularly the motor items). The FIM was a novel predictive marker of 3-year mortality in these patients, and an increased FIM after rehabilitation resulted in better prognosis. Moreover, the effectiveness of rehabilitation may depend on maintaining cognitive functions.

Retroperitoneal Bleeding: An Experience During Prophylactic Anticoagulation in a Patient With Nephrotic Syndrome.

The association between nephrotic syndrome (NS) and a hypercoagulable state has been demonstrated. Controlling the blood clotting activity may therefore be attractive for patients with nephrosis in terms of thromboembolism prophylaxis. We herein report a 75-year-old woman with minimal change disease who developed pains in the right back, groin, and thigh because of retroperitoneal bleeding during prophylactic anticoagulation with unfractionated heparin. Although this procedure has not been accepted as the standard of care for patients with nephrosis, pharmacologic prophylaxis may already be practiced empirically, as in the present patient. We believe that our experience highlights the pitfalls of such a management in patients with nephrosis, implying the need for a diagnostic strategy for identifying those patients with NS who can benefit from prophylactic anticoagulation. Several concerns that emerged in this case are also discussed.

Dual Impact of Tolvaptan on Intracellular and Extracellular Water in Chronic Kidney Disease Patients with Fluid Retention.

Objective Tolvaptan, an oral selective V2-receptor antagonist, is a water diuretic that ameliorates fluid retention with a lower risk of a worsening renal function than conventional loop diuretics. Although loop diuretics predominantly decrease extracellular water (ECW) compared with intracellular water (ICW), the effect of tolvaptan on fluid distribution remains unclear. We therefore examined how tolvaptan changes ICW and ECW in accordance with the renal function. Methods Six advanced chronic kidney disease patients (stage 4 or 5) with fluid retention were enrolled in this study. Tolvaptan (7.5 mg/day) added to conventional diuretic treatment was administered to remove fluid retention. The fluid volume was measured using a bioimpedance analysis device before (day 0) and after (day 5 or 6) tolvaptan treatment. Results Body weight decreased by 2.6%±1.3% (64.4±6.5 vs. 62.8±6.3 kg, p=0.06), and urine volume increased by 54.8%±23.9% (1,215±169 vs. 1,709±137 mL/day, p=0.03) between before and after tolvaptan treatment. Tolvaptan significantly decreased ICW (6.5%±1.5%, p=0.01) and ECW (7.5%±1.4%, p=0.02), which had similar reduction rates (p=0.32). The estimated glomerular filtration rate remained unchanged during the treatment (14.6±2.8 vs. 14.9±2.7 mL/min/1.732 m, p=0.35). Conclusion Tolvaptan ameliorates body fluid retention, and induces an equivalent reduction rate of ICW and ECW without a worsening renal function. Tolvaptan is a novel water diuretic that has a different effect on fluid distribution compared with conventional loop diuretics.

Comparison of the wound healing efficacy of polyglycolic acid sheets with fibrin glue and gelatin sponge dressings in a rat cranial periosteal defect model.

Oral surgical procedures occasionally require removal of the periosteum due to lesions, and these raw bone surfaces are prone not only to infection but also to scar formation during secondary healing. The objective of this study was to identify successful methods for reconstruction using periosteal defect dressings. We created 1-cm2 defects in the skin and cranial periosteum of 10-week-old male Wistar rats under isoflurane anesthesia. The animals were assigned to three defect treatment groups: (1) polyglycolic acid sheets with fibrin glue dressing (PGA-FG), (2) Spongel® gelatin sponge dressing (GS), and (3) open wound (control). Postoperative wound healing was histologically evaluated at 2, 4, and 6 weeks. The moist conditions maintained by the GS and PGA-FG treatments protected the bone surface from the destructive effects of drying and infection. Complete wound healing was observed in the GS group but not for all animals in the PGA-FG and control groups. Histologically, osteoblast proliferation on bone surfaces and complete epithelialization with adnexa were observed in the GS group at 6 weeks after surgery. In contrast, PGA sheets that had not been absorbed inhibited osteoblast proliferation and delayed wound healing in the PGA-FG group. Wound surface dressings maintain a moist environment that promotes wound healing, but PGA materials may not be suitable for cases involving exposed periosteum or bone surfaces due to the observed scar formation and foreign-body reaction.

Subclinical growth of an arteriovenous fistula associated with renal biopsy: a case report.

BACKGROUND: Renal biopsy is not free from complications and patients who undergo this procedure are usually hospitalized to receive intensive care for several days after biopsy. In contrast, after this period, routine follow-up to detect biopsy-associated complications is rarely scheduled, unless the patient develops a clinical manifestation. We describe a case of marked enlargement of arteriovenous fistula in the kidney that occurred many years after renal biopsy. In contrast to the previous cases requiring interventional radiology, our patient showed subclinical growth of fistula over about nine years. CASE PRESENTATION: A 24-year-old man with a history of percutaneous renal biopsy was hospitalized for interventional radiology. Gross hematuria emerged shortly after biopsy, but completely disappeared with administration of hemostatic agents and bed rest. Subsequently, the patient had few symptoms for many years. A giant fistula (a gourd-shaped mass, size 26 × 22 and 12 × 11 mm) was unexpectedly detected by ultrasonography performed for examination of an unrelated disorder (slight elevation of serum transaminase) at 9 years after the original biopsy. The fistula was successfully treated with radiological intervention. Thus, subclinical development of complications associated with renal biopsy should be considered, even in an uneventful course. CONCLUSIONS: This case provides a platform to discuss the importance of long-term follow-up of patients after renal biopsy despite of its difficulty.

Therapeutic Challenges to End-Stage Kidney Disease in a Patient with Tetralogy of Fallot.

In this report, we describe the case of an end-stage kidney disease patient with tetralogy of Fallot (TOF). A 33-year-old female with TOF was admitted to our hospital with complaints of general fatigue and appetite loss probably due to uremic milieu. She was ultimately treated with peritoneal dialysis (PD) with a favorable clinical course. TOF patients with chronic kidney disease are not exceptional, although the currently available information regarding the association between TOF and renal failure severe enough to require dialysis treatment is limited. We also discuss the complex processes of how and why PD was selected as a mode of chronic renal replacement therapy in this case.

Preliminary tests of a prototype FES control system for cycling wheelchair rehabilitation.

The cycling wheelchair "Profhand" developed by our research group in Japan has been found to be useful in rehabilitation of motor function of lower limbs. It is also expected for rehabilitation of paraplegic subjects to propel the cycling wheelchair by lower limbs controlled by functional electrical stimulation (FES). In this paper, a prototype FES control system for the cycling wheelchair was developed using wireless surface stimulators and wireless inertial sensors and tested with healthy subjects. The stimulation pattern that stimulated the quadriceps femoris and the gluteus maximus at the same time was shown to be effective to propel the Profhand. From the analysis of steady state cycling, it was shown that the cycling speed was smaller and the variation of the speed was larger in FES cycling than those of voluntary cycling. Measured angular velocity of the crank suggested that stimulation timing have to be changed considering delay in muscle response to electrical stimulation and cycling speed in order to improve FES cycling. It was also suggested that angle of the pedal have to be adjusted by controlling ankle joint angle with FES in order to apply force appropriately.

Single electron transfer-induced cross-coupling reaction of alkenyl halides with aryl Grignard reagents.

Alkenyl halides were found to undergo coupling with aryl Grignard reagents to give the corresponding styrene derivatives in a stereo-retained manner. The cross-coupling reaction is considered to proceed through a single electron transfer mechanism.

A novel anti-human HB-EGF monoclonal antibody with multiple antitumor mechanisms against ovarian cancer cells.

PURPOSE: Heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) is a member of the EGF family and plays a pivotal role in tumor progression in ovarian cancer. We developed an anti-HB-EGF monoclonal antibody (mAb) and investigated its antitumor activities in vitro and in vivo to evaluate its potential as a therapeutic antibody against ovarian cancer. EXPERIMENTAL DESIGN: We prepared mAbs from HB-EGF null mice immunized with recombinant human soluble HB-EGF and evaluated their binding and neutralizing activity against HB-EGF. Next, we generated a mouse-human chimeric antibody and examined its in vitro and in vivo antitumor activities. RESULTS: Two murine anti-HB-EGF mAbs were developed, and one of them, KM3566, was revealed to have a high binding reactivity for membrane-anchored HB-EGF (pro-HB-EGF) expressed on the cell surface, as well as neutralizing activity against growth promoting activity of soluble HB-EGF. The mouse-human chimeric counterpart for KM3566 (cKM3566) induced dose-dependent antibody-dependent cellular cytotoxicity (ADCC) against cancer cells expressing HB-EGF in vitro, and significantly inhibited tumor growth in severe combined immunodeficient mice inoculated with MCAS or ES-2 human ovarian cancer cells. CONCLUSIONS: A novel anti-HB-EGF chimeric antibody, cKM3566, with two antitumor mechanisms, neutralization and ADCC, exhibits potent in vivo antitumor activity. These results indicate that cKM3566 is a promising antiovarian cancer therapeutic antibody.

Synthesis of anthracene-stacked oligomers and polymer.

Anthracene-stacked oligomers and a polymer were synthesized using a xanthene skeleton as the scaffold, and their structures and properties were fully characterized. Intramolecular pi-pi stacking of the anthracene rings in the ground state and excited state was observed.