Linear discriminant analysis on electrocardiogram achieved classification of cardiac involvement status in amyloid light-chain amyloidosis.

OBJECTIVES: Cardiac amyloidosis (CA) is the most crucial determinant of amyloid light-chain (AL) amyloidosis patients' prognosis. We attempted cardiac involvement prediction by 12­lead electrocardiograph (ECG) and echocardiography (UCG) in AL amyloidosis patients. MATERIALS AND METHODS: Fifty patients with histologically confirmed AL amyloidosis underwent gadolinium-enhanced magnetic resonance imaging (Gd-MRI), and CA was assessed using late gadolinium enhancement. ECG and UCG parameters were measured on admission. Fisher's linear discriminant analysis was used to create a model for predicting CA using the ECG and UCG parameters. RESULTS: Prediction by five ECG parameters [QTc(B), QRS-T-angle, III-QRS, aVF-QRS, and V3-R] showed the best performance. Average sensitivity and specificity in the modeling sets, utilizing a linear discriminator based on these five variables, were 99.2 % and 96.8 % and in validation sets, 94.2 % and 90.3 %, respectively. In addition, we tested this model on an additional 26-patient cohort and survival analysis using the Kaplan-Meier method, and significant differences between CA positively predicted and negatively predicted patients were observed. CONCLUSION: Here, we suggest the application of a condensed classical multivariate statistical technique for the diagnosis of CA. It can be used as a guide to invasive endomyocardial biopsy for those in whom Gd-MRI is contraindicated and as a guide for repeat Gd-MRI in follow-up of AL amyloidosis.

Cardiac and renal AL amyloidosis controlled by autologous stem cell transplantation for 17 years accompanying late onset atrial fibrillation and complete atrioventricular block.

Amyloid light chain (AL) amyloidosis is a rare hematologic disease that may involve multiple organs. Amongst the organs, cardiac involvement causes the greatest concern as its treatment is challenging. Diastolic dysfunction rapidly progresses to decompensated heart failure, pulseless electrical activity, and atrial standstill due to electro-mechanical dissociation resulting in death. High-dose melphalan plus autologous stem cell transplantation (HDM-ASCT) is the most radical treatment but its risk is very high and thus only less than 20% of patients can receive this therapy under criteria that can suppress treatment-related mortality. In substantial proportion of patients, levels of M protein remain elevated, and organ response cannot be achieved. Moreover, relapse may occur, making prediction of treatment response and judgement of disease eradication very difficult. Herein we report a case of AL amyloidosis who was treated with HDM-ASCT, resulting in preserved cardiac function and resolution of proteinuria for more than 17 years after HDM-ASCT ensuing atrial fibrillation and complete atrioventricular block required management by catheter ablation and pacemaker implantation 10 years and 12 years after transplantation, respectively.

Optimization of the Thin Waveguide for Double-Parabolic-Reflectors Ultrasonic Transducers (DPLUS) for Thermal Ablation.

OBJECTIVE: Interstitial and intracavitary ultra- sound applicators had been developed and studied for minimally invasive treatments (MIT). However, the acoustic outputs are limited by the small-size PZT. We therefore studied the acoustic waveguide (AW) applicator which enables the use of a large-size PZT, and we aimed to advance AW applicators towards thermal ablation applications. METHODS: Double parabolic reflectors wave-guided ultrasonic transducer (DPLUS) was introduced which has two parabolic reflectors for enhancing the acoustic output. Theoretical modeling was conducted for optimizing the DPLUS thin waveguide. RESULTS: Modeling results showed that optimal a/Λ (thin waveguide radius/wavelength) can be found and the optimal a depends on the excitable vibration amplitude in the thin waveguide. A local optimal a/Λ= 0.2392 was considered the best choice, which results in the optimal frequency of 2.2 MHz at the radius a of 0.6 mm. To verify this optimal frequency, experiments under two working frequencies of 1.0282 MHz and 2.2579 MHz were conducted. Temperature rise curves in the chicken breast tissue showed good agreements between experiments and modeling results, which proved the effectiveness of the modeling. In addition, experiments showed an ablated area with a diameter of 1.03±0.12 mm under continuous excitation of 2.2579 MHz and 5 s. CONCLUSION: The developed DPLUS advanced the AW applicators towards thermal ablation applications. SIGNIFICANCE: This study provides the evidence for recognizing AW applicators as a technique for thermal ablation.

Vincristine, Doxorubicin, and Dexamethasone Induction before Autologous Stem Cell Transplantation in Patients with AL Amyloidosis: A Retrospective Comparison with Frontline Stem Cell Transplantation.

Objective High-dose melphalan and autologous stem cell transplantation (ASCT) therapy for AL amyloidosis are now associated with reduced mortality based on the application of strict criteria. However, there is no long-term evidence concerning the performance of induction therapy with newer agents, such as bortezomib or daratumumab. Concerns regarding long-term relapse despite treatment with ASCT exist, and missing the opportunity to perform ASCT might occur if induction proves to not be efficacious and cardiac amyloidosis progression deprives the patients of a chance to receive ASCT. We herein report good amyloid control by vincristine, doxorubicin, and dexamethasone (VAD) induction therapy and argue the importance of induction therapy before ASCT. Methods We compared patients who underwent VAD induction and ASCT (VAD+ASCT) with patients who underwent frontline ASCT in our hospital. Patients A total of 26 patients with histologically proven AL amyloidosis were included (18 in the VAD+ASCT group and 8 in the frontline ASCT). Results In the VAD+ASCT group, the 10-year overall survival and renal response rates were 82% and 43%, respectively. The renal response rate at two years in the VAD+ASCT group was significantly better than that in the frontline ASCT group. Although there was no significant difference in the survival rates between the two groups, the time to next treatment or death was significantly better in the VAD+ASCT group than in the the frontline ASCT group. Acute kidney injury was the most frequent reason for failure to receive two courses of VAD, and early mortality was mainly due to gastrointestinal complications. Conclusion Considering that only those who underwent 2 courses of VAD experienced a 10-year renal response, induction therapy was deemed to be directly related to the long-term control of AL amyloidosis.

Double-Parabolic-Reflectors Ultrasonic Transducer With Flexible Waveguide for Minimally Invasive Treatment.

OBJECTIVE: To treat tissues that are difficult to access, ultrasound based minimally invasive treatment (MIT) is promising. However, high-power ultrasound delivery through waveguides had been difficult which can increase treatment duration. It is our effort to design the waveguide that can transmit powerful ultrasound. METHODS: The waveguide with two parabolic reflectors was proposed by us to produce high-energy-density plane wave. Use of flexible and long thin waveguide was demonstrated here. RESULTS: Double Parabolic refLectors wave-guided high-power Ultrasonic tranSducer (DPLUS) including a ϕ1 mm ×1 m Nitinol thin waveguide was fabricated. It was shown that high-power ultrasound between 1 to 2 MHz can be propagated through the thin waveguide. Low-loss waveguide material was confirmed to be important to enhance output. As ultrasound is transmitted into working medium, energy mainly flows from the side surface. Temperature of target soft tissue was demonstrated to drastically increase by 10 degree in 30 seconds. CONCLUSION: The developed DPLUS makes high-power ultrasound transmission in long and flexible thin waveguide possible. SIGNIFICANCE: The concept of DPLUS for delivering high-power ultrasound is powerful in the field of Ultrasonics.

A patient with congenital nephrogenic diabetes insipidus due to AVPR2 mutation complicated by persisting polydipsia under hemodialysis treatment.

A 17-year-old boy was referred to our institution for a re-evaluation of congenital nephrogenic diabetes insipidus. A water restriction test revealed no urine concentration or volume reduction and a subsequent pitressin test revealed a lack of an anti-diuretic response. Nephrogenic diabetes insipidus was confirmed, and the patient was treated using trichlormethiazide 4 mg, indomethacin 175 mg, and desmopressin 20 µg. His blood pressure and weight were not controlled owing to polydipsia and polyuria secondary to acquired excessive water drinking behavior. Repeated admissions for weight control were necessary and despite consultation with a psychiatrist for his obsessive water drinking behavior, he had end-stage renal failure after 30 years of treatment. Genetic testing revealed AVPR2 mutation (c. T866C: p. L289P) that had previously been reported as a pathogenic mutation. His excessive drinking behavior persisted, leading to hyponatremia even after initiation of hemodialysis. There was also difficulty in achieving body weight control, which was managed by repeated admissions with restriction of water intake, being the mainstay of management.

Candida albicans and Staphylococcus lugdunensis superinfection of liver cysts in a patient with autosomal dominant polycystic kidney disease under prednisolone treatment.

We report a case of superinfection of liver cysts caused by Candida albicans and Staphylococcus lugdunensis in a patient with autosomal dominant polycystic kidney disease. A 69-year-old man with chief complaints of headache and blurred vision was admitted to the former institution for the evaluation of suspected temporal arteritis. He was prescribed oral prednisolone (55 mg/day) as a preemptive treatment; however, he became febrile and presented with bilateral flank pain during prednisolone tapering. Blood culture revealed fungemia as a result of Candida famata infection; thus, micafungin treatment was started. Thereafter, recrudescence of the C-reactive protein level ensued. Then a cyst infection as visualized on magnetic resonance imaging led to cyst aspiration sclerotherapy. Cyst aspirate culture revealed the presence of C. albicans in one of the cysts and S. lugdunensis in two of the cysts. The patient was clinically stabilized with an additional 3 weeks of antibiotic and antifungal drug administration.

Wideband Multimode Excitation by a Double-Parabolic-Reflector Ultrasonic Transducer.

This research presents double-parabolic-reflector wave-guided ultrasonic transducers in order to realize wideband (0-2.5 MHz), multiharmonic mode excitations (over 20 modes), and to obtain large mechanical/acoustic outputs. The double-parabolic-reflector mechanism serves as a horn structure at low frequencies and acoustic-focusing structure at high frequencies to enhance the energy density of the incident ultrasound. Upon combining simulation and experimental methods, we examined and verified the basic performance and working mechanisms of the double-parabolic-reflector waveguides: multimode excitation belongs to the harmonic modes from the thin waveguide. At the megahertz range near the thickness mode of the piezoelectric element (PZT), energy density of the incident ultrasound is enhanced by double-parabolic reflections, and the amplification ranges 10 to 40× between 1 and 2.5 MHz. At burst excitations, the amplification performance is independent of the length of the thin waveguide. Compared with conventional Langevin transducers and high-intensity focused ultrasound (HIFU) transducers, our transducers possess a wide working frequency with large mechanical/acoustic outputs and large vibration velocity amplification. By introducing these new features, our proposed method is a promising candidate for examining basic physics parameters, such as frequency dependence, in the fields of medicine, biology, industry, etc.

Double-parabolic-reflectors acoustic waveguides for high-power medical ultrasound.

High intensity focused ultrasound therapeutics are widely used to noninvasively treat various types of primary tumors and metastasis. However, ultrasound penetration depth is shallowed with increasing frequency which limits the therapeutic accuracy for deep tissues. Although acoustic waveguides are commonly inserted into tissue for localized therapy, powerful ultrasound delivery is difficult. Here, we invent double-parabolic-reflectors acoustic waveguides, where high-power ultrasound emission and large mechanical vibration enhance the therapeutic efficiency. High-energy-density ultrasound with around 20 times amplification by two parabolic reflectors propagates through the thin waveguide between 1 to 2 MHz, and wideband large mechanical vibration at the waveguide tip from 1 kHz to 2.5 MHz accelerates the therapeutics. This fundamental work serves as a milestone for future biomedical applications, from therapeutics to diagnostics. Since the high-power ability at high frequencies, our waveguide will also open up new research fields in medical, bio, physics and so on.

An Orofaciodigital Syndrome 1 Patient and Her Mother Carry the Same OFD1 Mutation but Have Different X Chromosome Inactivation Patterns.

Orofaciodigital syndrome 1 (OFD-1) is a rare, X-linked, dominantly inherited disorder caused by an OFD1 mutation that can cause polycystic kidneys. A 37-year-old woman on hemodialysis therapy was admitted to our hospital for trans-catheter arterial embolization therapy for enlarged polycystic kidneys. Lobulated tongue and brachydactyly were noticed, prompting an OFD1 sequencing analysis. Sequencing revealed a causal four-base-pair deletion in exon 13, both in the patient and in her mother, whose renal function had been retained. The peripheral leukocyte X chromosome inactivation pattern was skewed in the patient but not in her mother, suggesting some role in their phenotypic difference.

Lupus Nephritis with Thymoma Managed by Thoracoscopic Surgery and Prednisolone.

A 48-year-old woman was admitted to our hospital to undergo evaluation for fatigue, severe weight loss, and nephrotic range proteinuria. Light microscopy of a renal biopsy specimen revealed class III (A) lupus nephritis, while immunofluorescence and electron microscopy only showed sparse immune deposits with findings that were not typical of lupus nephritis. Computed tomography revealed a mass in the anterior mediastinum, which was resected. The examination of the surgical specimen revealed type A noninvasive thymoma. In combination with thymomectomy, postoperative steroid therapy achieved the prompt remission of lupus nephritis. In this patient, thymoma-related autoimmunity may have contributed to the exacerbation of lupus nephritis.

Prediction of hepatic cyst recurrence after minocycline hydrochloride aspiration sclerotherapy using cyst computed tomography values.

AIM: Polycystic liver disease (PLD) occasionally leads to abdominal pain, distention, and discomfort due to massively enlarged cysts. Patients with a small number of large liver cysts, which correspond to Gigot's classification type 1 PLD, are reported to be good candidates for treatment by aspiration sclerotherapy. However, there is a 21% reported recurrence rate of an enlarged cyst. A rule to predict outcome of aspiration sclerotherapy is explored in this study. METHODS: The medical records of patients with autosomal dominant polycystic kidney disease or isolated polycystic liver disease, who underwent minocycline hydrochloride cyst aspiration sclerotherapy for their symptomatic PLD, were retrospectively analyzed. Changes in the volume of cysts from before to 1 year after treatment were calculated using computed tomography (CT) images. Mean CT values of the largest planes of cysts were also calculated. Specific gravity and other laboratory parameters of aspirated cyst fluid were also retrospectively investigated. RESULTS: In total, 12 patients were selected and 21 cysts were analyzed that received aspiration sclerotherapy. Mean CT values more than 13.34 HU were predictive for 1-year non-sustainability of a cyst volume of less than 30% compared with the volume prior to the therapy. Specific gravity had good positive correlation with mean CT value and other laboratory parameters indicating exudative properties were also high in recurred cysts. CONCLUSIONS: The CT values of cysts may become an aid in appropriate selection of therapy in patients with symptomatic polycystic disease by distinguishing cysts that are resistant to aspiration sclerotherapy.

Daughter and mother with orofaciodigital syndrome type 1 and glomerulocystic kidney disease.

A 35-year-old woman was admitted to our hospital for evaluation of end-stage renal failure. Diagnostic imaging, including ultrasonography and magnetic resonance imaging, showed polycystic kidneys and peribiliary hepatic cysts, but the renal cysts were isointense and her kidneys were smaller than the end-stage kidneys of patients with autosomal dominant polycystic kidney disease. Glomerulocystic kidney disease was diagnosed by renal biopsy. Clinical examination revealed findings such as a missing maxillary canine, lingual anomalies, and brachydactyly. Genetic testing gave a diagnosis of orofaciodigital syndrome type 1 with a 5 nucleotide deletion indicating a frameshift mutation in exon 9. The patient's mother had the same mutation and similar clinical findings. This case is useful for understanding kidney and liver involvement in orofaciodigital syndrome type 1.

Ursodeoxycholic Acid for Treatment of Enlarged Polycystic Liver.

Patients with autosomal dominant polycystic kidney disease and polycystic liver disease (PLD) often have elevated serum levels of alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (GGT). Ursodeoxycholic acid (UDCA) is used to treat biliary tract diseases, but its effect on PLD remains unclear. UDCA was administered for 1 year at a dose of 300 mg daily to seven PLD patients with elevated ALP or GGT levels who were selected for this treatment by experienced clinicians. Laboratory data and liver volumes were compared among three time points: 1 year before UDCA treatment, at the start of UDCA therapy, and 1 year after the start of therapy. Median GGT did not show a significant change between 1 year before UDCA (180 IU/L) and the start of UDCA therapy (209 IU/L), but it decreased significantly to 98 IU/L after 1 year of UDCA therapy (P = 0.015 vs. the start of therapy). ALP showed a significant increase from 1 year before UDCA (456 IU/L) to the start of UDCA therapy (561 IU/L), and then decreased significantly after 1 year of UDCA therapy (364 IU/L). Median liver volume did not show any significant changes among these three time points of assessment. UDCA may be effective for reducing biliary enzyme levels and inhibiting the growth of liver cysts in patients with PLD.

Tocilizumab for AA Amyloidosis after Treatment of Multicentric Castleman Disease with Steroids, Chemotherapy and Rituximab for Over 20 Years.

We herein report the long-term outcome (30 years) of a human immunodeticiency virus- and human herpesvirus 8-negative Japanese man who was diagnosed to have multicentric Castleman disease (MCD) of the plasmacytic type after investigation of generalized lymphadenopathy at 34 of age in 1983. He received chemotherapy based on lymphoma regimens (combinations of prednisolone, vincristine, vindesine, cyclophosphamide, etoposide, melphalan, and ranimustine, etc.) for over 20 years. Although the systemic lymphadenopathy resolved, AA amyloidosis-related nephropathy occurred, with a serum creatinine (Cre) level of 0.9 mg/dL and urinary protein excretion (UP) of 7.5 g daily. Rituximab was started, but Cre increased to 2.6 mg/dL in 2010 and UP was unchanged. Therefore, treatment with tocilizmab was started. As a result, his hypergammaglobulinemia was well controlled, C-reactive protein became normal, UP decreased to 3.5 g daily, and Cre remained at 2.5 mg/dL in 2013. When AA amyloid nephropathy occurred after long-term chemotherapy, lituximab could not control it, but tocilizmab stopped the progression of nephropathy. This case suggests that MCD and AA amyloidosis may both have a close relationship to the overproduction of interleukin-6.

Tocilizumab improves systemic rheumatoid vasculitis with necrotizing crescentic glomerulonephritis.

We report a Japanese woman with systemic rheumatoid vasculitis (SRV) complicated by necrotizing crescentic glomerulonephritis (NCGN). Rheumatoid arthritis first occurred at the age of 19 years, followed by interstitial pneumonia, hepatitis, rheumatoid nodules, mononeuritis multiplex, and hypocomplementemia in chronological order. At the age of 51 years, rapidly progressive renal failure occurred with nephrotic proteinuria, and NCGN with subepithelial deposits was revealed by renal biopsy. Severe destructive changes of multiple joints and scleritis were detected, but anti-neutrophil cytoplasmic antibody was negative on enzyme-linked immunosorbent assays and indirect immunofluorescence. SRV was diagnosed due to involvement of multiple extra-articular organs. An anti-interleukin (IL)-6 receptor antibody (tocilizumab) was started at dosage of 280 mg (8 mg/kg) monthly. After 18 months, her serum creatinine decreased from 1.7 to 1.3 mg/dL, and urinary protein excretion declined from 5.2 to 1.2 g daily. Tocilizumab may be a therapeutic option for SRV associated with NCGN.

Transmission of 100-MHz-range ultrasound through a fused quartz fiber.

PURPOSE: This paper describes an investigation into direct observation of microscopic images of tissue using a thin acoustic wave guide. METHODS: First, the characteristics of the ultrasonic wave propagated in a fused quartz fiber were measured using the reflection method in order to study the insertion loss and the frequency shift of the ultrasonic wave transmitted from the transducer. Next, a receiving transducer was placed close to the end of the fiber, and the characteristics of the ultrasonic waves propagated through the acoustic coupling medium were measured using the penetration method in order to study the insertion loss and the frequency-dependent attenuation of the penetrated waves. Finally, a C-mode image was obtained by optimizing the measuring conditions using the results of the above measurements and scanning the ultrasonic beams on a target (coin) in water. RESULTS: A reflected wave with a peak frequency of approximately 220 MHz was obtained from the end of the fiber. The transmitted ultrasonic waves propagated through the acoustic coupling medium were detected with a frequency range of approximately 125-170 MHz, and the maximum detectable distance of the waves was approximately 1.2 mm within the 100-MHz frequency range. Finally, a high-frequency C-mode image of a coin in water was obtained using a tapered fused quartz fiber. CONCLUSION: The results suggest that it is necessary to improve the signal-to-noise ratio and reduce the insertion loss in the experimental system in order to make it possible to obtain microscopic images of tissue.

Short-step synthesis of a resveratrol derivative from commercially available 1,3-dimethoxybenzene and 4-vinylanisole.

An efficient synthesis of tri-O-methylated resveratrol is presented using an advanced Heck reaction promoted by Pd(dba)(2) in the presence of P(t-Bu)(3).

Influence of Pb and La contents on the lattice configuration of La-substituted Pb(Zr,Ti)O3 films fabricated by CSD method.

The influence of Pb and La contents on the lattice configuration in La-substituted Pb(Zr0(.65),Ti0(.35))O3 (La- PZT) films was systematically investigated. La-PZT films with various La and Pb contents were fabricated on Pt/Ti/SiO(2)/Si substrates by chemical solution deposition (CSD). In the La- PZT films with a Pb content ratio of 125% relative to a stoichiometric value, La ions were substituted for not only A-site ions but also B-site ions at La contents greater than 3 mol%. La substitution for B-site seems to cause larger reduction of the unit cell size. In addition, we found that in the La-PZT films with a La content of 3 mol%, the Pb content of 116 mol% (120% relative to a stoichiometric value) was optimum from the viewpoint of site occupancy. This indicates that excess Pb prevented the A-site substitution of La ions.

Synthesis of (-)-epicatechin 3-(3-O-methylgallate) and (+)-catechin 3-(3-O-methylgallate), and their anti-inflammatory activity.

A concise synthesis of (-)-epicatechin 3-(3-O-methylgallate) (1; ECG3''Me), which is a minor constituent of tea, and (+)-catechin 3-(3-O-methylgallate) (2; CG3''Me) via condensation of equimolar amount of catechin and gallate derivatives has been achieved. The anti-inflammatory effect of the synthetic compounds on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation of mouse ears was examined. Compounds 1 and 2 suppressed the TPA-induced inflammation of mouse ears by 50 and 43%, respectively, at a dose of 200 microg. Their activities are stronger than those of indomethacin and glycyrrhetinic acid, the normally used anti-inflammatory agents.