Cost-Effectiveness Analysis of the Diagnosis and Treatment of Primary Aldosteronism in Japan.

Approximately 10% of cases of hypertension in Japan are caused by primary aldosteronism (PA), amounting to about 4 million patients in total. Primary aldosteronism due to unilateral aldosterone hypersecretion is potentially curable by adrenalectomy. The clinical benefits of identifying and treating PA have been reported internationally, but its cost-effectiveness is unclear. We examined whether diagnosing and treating hidden PA in hypertensive population was cost-effective compared with suboptimal treatment. Our hypothetical patient was a 50-year-old man diagnosed with stage I-III hypertension. We established a Markov decision model based on plausible clinical pathways and prognoses of PA. We applied cost-effectiveness analysis comparing a comprehensive diagnostic strategy for PA (measurement of plasma aldosterone/renin ratio, 2 loading tests, imaging, and selective adrenal venous sampling) with a suboptimal strategy to manage hypertension by medication unless the typical signs of PA or other complication were manifest. Outcome measures were expected costs, expected effectiveness, and incremental cost-effectiveness ratio. The robustness of the findings was established by one-way and scenario sensitivity analyses. The comprehensive PA diagnostic strategy increased the expected costs by 64 004 JPY and expected life-years by 0.013 compared with standard treatment. The incremental cost-effectiveness ratio for the diagnosis of PA was 4 923 385 JPY per year. Our findings were sensitive to the outcomes of screening and treatment, and the costs of continuous or periodic medication for hypertension and the treatment of stroke and its complications.

Development of novel treatment with a bioabsorbable esophageal patch for benign esophageal stricture.

Using a large animal model, we examined whether circumferential stricture after esophageal endoscopic submucosal dissection (ESD) can be treated by grafting a bioabsorbable esophageal patch. Circumferential ESD was performed on the thoracic esophagus in pigs (n = 6) to create a stricture, for which one of the following interventions was performed: (1) the stricture site was longitudinally incised, and an artificial esophageal wall (AEW) was grafted after placing a bioabsorbable stent (AEW patch group, n = 3); (2) endoscopic balloon dilation (EBD) was performed every other week after stricture development (EBD group, n = 3). In both groups, esophageal fluoroscopy was performed 8 weeks after the interventions, and the esophagus was excised for histological examination of the patched site. In the AEW patch group, esophageal fluoroscopy revealed favorable passage through the patched site. Histologically, the mucosal epithelium and lamina propria had regenerated as in the normal area. In the EBD group, the circumferential stricture site showed marked thickening, and there were hypertrophic scars associated with epithelial defects on the luminal surface. Histologically, defects of the mucosal epithelium and full-thickness proliferation of connective tissue were observed. AEW patch grafting was suggested to be a potentially novel treatment strategy for post-ESD esophageal circumferential stricture.

What is the utility of routine ANA testing in predicting development of biological DMARD-induced lupus and vasculitis in patients with rheumatoid arthritis? Data from a single-centre cohort.

OBJECTIVE: To determine whether serial ANA testing predicts biological disease modifying antirheumatic drugs (bDMARD)-associated ANA/dsDNA production in patients with rheumatoid arthritis (RA). METHODS: Serial autoantibody profiles, bDMARD treatment sequences and clinical data were collected from patients identified from our database that since 2005 received (i) a first bDMARD (tumour necrosis factor inhibitor (TNFi)) and (ii) tocilizumab and/or abatacept. RESULTS: Of over 1000 patients, 454 RA patients received a first TNFi. Infliximab group demonstrated higher ANA seroconversion rates (31.2%) compared with etanercept (11.8%) and adalimumab (16.1%) (p<0.001). Median (range) treatment duration prior to ANA seroconversion was 10.9 (1.3-80.0) months. Positive anti-dsDNA titres of IgG class (median (range) of 77 IU/mL (65-109)) were noted in six (7.2%) patients, within a median (range) of 2.0 (0.8-4.2) years. Three patients developed classifiable lupus. 4 of 74 (5.4%) primary non-responders and 24 of 111 (21.6%) secondary non-responders developed positive ANA antibodies after TNFi initiation (p=0.003). Seven (9.5%) tocilizumab-treated patients changed to positive ANA; five (8.6%) abatacept-treated patients changed to positive ANA status. CONCLUSIONS: This study demonstrates no utility of serial ANA/dsDNA testing that could be used to predict onset of seroconversion and therefore the development of lupus/vasculitis. An association however between seroconversion and the development of a secondary non-response to bDMARD therapy is suggested.

MRI findings of radiation-induced myocardial damage in patients with oesophageal cancer.

AIM: To evaluate radiation-induced myocardial damage after mediastinal radiotherapy using MRI. MATERIALS AND METHODS: Between May 2010 and April 2011, delayed contrast-enhanced MRI was performed for patients who had maintained a complete response to curative radiotherapy for oesophageal cancer for more than 6 months. The patients received radiotherapy with a median total dose of 66 Gy (60-70 Gy) for the primary tumour and metastatic lymph nodes. Images of MRI were analysed by a 17-segment method recommended by the American Heart Association. A segment included mainly in the 40 Gy dose line was defined as Segment 40 Gy, a segment included mainly in the 60 Gy dose line as Segment 60 Gy, and a segment out of the radiation fields as Segment OUT. The percentage of late gadolinium enhancement (LGE) was examined in those categories. The layer in which LGE was predominantly distributed was evaluated for each patient. RESULTS: Four hundred and eight segments in 24 patients were analysed. The median interval from completion of radiotherapy to MRI was 23.5 months (range 6-88 months). LGE was detected in 12 of the 24 patients. LGE was detected in 15.38% of Segment 40 Gy cases, 21.21% of Segment 60 Gy cases, and 0% of Segment OUT cases. LGE in mid-myocardial and subendocardial layers was detected in 11 patients and one patient, respectively. CONCLUSION: LGE suggesting radiation induced myocardial fibrosis was observed by performing delayed contrast-enhanced MRI. Care should be taken when planning radiotherapy to avoid late cardiac damage.

Zero-dead-time operation of interleaved atomic clocks.

We demonstrate a zero-dead-time operation of atomic clocks. This clock reduces sensitivity to local oscillator noise, integrating as nearly 1/τ whereas a clock with dead time integrates as 1/τ(1/2) under identical conditions. We contend that a similar scheme may be applied to improve the stability of optical clocks.

Simultaneous evaluation of long-lasting knee synovitis in patients undergoing arthroplasty by power Doppler ultrasonography and contrast-enhanced MRI in comparison with histopathology.

OBJECTIVES: We simultaneously assessed ultrasonography (US) and magnetic resonance imaging (MRI) in comparison with histopathological changes in the knee joints of long-lasting arthritis patients. METHODS: We studied 15 patients with rheumatoid arthritis and 5 patients with osteoarthritis, who underwent total knee arthroplasty. On the day before surgery, the joints were examined by US and contrast-enhanced MRI. In US, synovitis was graded with 0-3 grey scale (GSUS) and power Doppler (PDUS). In MRI, synovitis was graded according to OMERACT-RAMRIS (grade 0-3). Synovial tissue samples were obtained during arthroplasty and evaluated on the basis of inflammatory cell infiltrates (grade 0-3), synovial lining layer thickness (grade 0-3) and vascularity (grade 0-3). RESULTS: Positive findings of PDUS and contrast-enhanced MRI were 45% and 85% of 20 operated joints, respectively. GSUS, PDUS and MRI synovitis were well correlated with overall histopathological grades of synovitis (Spearman correlation coefficients 0.48, 0.84 and 0.48, p<0.05, p<0.01 and p<0.05, respectively). Moreover, positive PDUS findings were closely associated with all pathological comportments of synovitis including inflammatory cell infiltrates, synovial lining layer thickness and vascularity. CONCLUSIONS: The present study revealed that positive PDUS findings more faithfully illustrated active synovitis than MRI, whereas contrast-enhanced MRI was more sensitive in detecting synovitis in patients with long-lasting arthritis. It is important to understand distinct features of the both modalities for clinical assessment of chronic joint diseases.

Absolute geodetic rotation measurement using atom interferometry.

We demonstrate a cold-atom interferometer gyroscope which overcomes accuracy and dynamic range limitations of previous atom interferometer gyroscopes. We show how the instrument can be used for precise determination of latitude, azimuth (true north), and Earth's rotation rate. Spurious noise terms related to multiple-path interferences are suppressed by employing a novel time-skewed pulse sequence. Extended versions of this instrument appear capable of meeting the stringent requirements for inertial navigation, geodetic applications of Earth's rotation rate determination, and tests of general relativity.

Traumatic mechanisms and therapeutic results of the perilunate injuries.

OBJECTIVE: In this study, eighteen patients who have had perilunate injury with dislocation or fracture, were evaluated and the patho-mechanics and surgical treatment were studied. SUBJECTS AND METHODS: According to the Green and O'Brien's classification, type 1 injury occurred in one patient, type 2 in nine, type 4A in five, type 4C in one and type 4D in one. The other one case could not be classified using the Green and O'Brien's criteria. RESULTS: According to the Evans scoring system, good results were achieved in thirteen patients, fair results, in four, poor results in one and very poor results in none. When the patho-mechanics was estimated based on the Mayfield's criteria, seventeen patients were classified as stage 3. However only one case was extremely unusual and should be classified as a subtype of stage 2. CONCLUSION: The results were good in the majority of patients who had repair of perilunate injury.

Therapeutic results of the modified Cadenat procedure for acromioclavicular joint separations compared with the modified Dewar procedure.

AIM AND BACKGROUND: The surgical treatment for acromioclavicular joint dislocations is recommended for Rockwood's classification types 4, 5 and 6. In this study we evaluate the therapeutic results of the modified Cadenat procedure on type 5 acromioclavicular joint dislocation, and report on a comparative study of the modified Dewar procedure also on type 5 acromioclavicular joint dislocation. SUBJECTS AND METHODS: The modified Cadenat procedure was performed on 73 patients (66 males and 7 females, group C). The mean age at the time of the surgery was 35.4 years. On the other hand, the modified Dewar procedure was performed on 55 patients (51 males and 4 females, group D). The mean age at the time of the surgery was 34.5 years. RESULTS: The mean therapeutic results were 28.2 points in group C and 27.3 in group D according to the UCLA scoring system. In group C, the subluxation that represented less than 5 mm superior translation of the clavicle, occurred only in 18 of 73 patients. Meanwhile, in group D, the subluxation that represented less than 5 mm, occurred only in 14; that which represented 5 to 10 mm was in seven patients, and the complete dislocation occurred in three patients. Also, the occurrence of osteoarthritic changes in the acromioclavicular joint was nine patients in group C and 20 in group D, respectively. CONCLUSION: The modified Cadenat procedure could provide satisfactory therapeutic results and avoid postoperative failure of reduction compared to the modified Dewar procedure. However the modified Cadenat procedure does not aim to restore the anatomical coracoclavicular ligaments. It is believed that anatomic restoration of both coracoclavicular ligaments could best restore the function of the acromioclavicular joint.

Induction of G1 arrest by down-regulation of cyclin D3 in T cell hybridomas.

The relationship between activation-induced growth inhibition and regulation of the cell cycle progression was investigated in T cell hybridomas by studying the function of the cell cycle-regulating genes such as G1 cyclins and their associated kinases. Activation of T cell hybridomas by anti-T cell receptor antibody induces growth arrest at G1 phase of the cell cycle and subsequently results in activation-driven cell death. Rapid reduction of both messenger RNA and protein level of the cyclin D3 is accompanied by growth arrest upon activation. Although the residual cyclin D3 protein forms a complex with cdk4 protein, cyclin D3-dependent kinase activity is severely impaired. Stable transfectants engineered to express cyclin D3 override the growth arrest upon activation. These results imply that the activation signal through T cell receptor induces the down-regulation of cyclin D3 expression and cyclin D3-dependent kinase activity, leading to growth arrest in G1 phase of the cell cycle in T cells.

Oral steroid therapy for frozen shoulder.

BACKGROUND: Since frozen shoulder is characterized by spontaneous recovery, no precise treatment strategy exists. Both conservative therapy and arthroscopic surgery is available, but the time required for recovery varies considerably. This study looks at the possible early symptom relief with oral steroid therapy. SUBJECTS AND METHODS: The subjects were 76 patients aged 33 to 73 years at the beginning of the study. The duration of the frozen shoulder was one to 15 months (mean 5.7 months) and hypertension was noted in 13 patients as a complicated disorder. A single course of steroid therapy consisted of a total dose of 105 mg of prednisolone over approximately a three-week period by the dose-tapering method. The number of courses varied with the degree of symptom relief but the rest period between courses was always approximately four weeks. The results were assessed on the basis of the Japanese Orthopaedic Association (JOA) score, but the principal evaluations were pain and range of motion. RESULTS: The average ranges of motion before treatment were 102.8 degrees of forward flexion 11.3 degrees of external rotation and internal, rotation was at the buttocks. However, after one course of treatment, forward flexion was 136 degrees, external rotation was 33.7 degrees, and internal rotation was limited to the buttocks in only six cases. CONCLUSION: The results of oral steroid therapy for frozen shoulder were highly satisfactory. However, sufficient care is required in explaining the method of administration and the adverse effects such as the osteonecrosis of the femoral head or osteoporosis.

Pathology and therapeutic results in patients with intraosseous ganglia of the carpal bone.

This study evaluated the pathology and therapeutic results of seven patients with intraosseous ganglia of the carpal bone. The mean age at the time of surgery was 27.6 years. The lesions were localized in the proximal carpal row in six patients and in the distal carpal row in only one. Surgical treatment was performed in all patients with good bone union. None had pain during activity or at rest and no recurrence had occurred. The intraosseous ganglia in four patients was of the idiopathic type, and in the other three patients was of the penetrating type. Although intraosseous ganglia of the carpal bone is reported as a rare disease, there were 159 cases in the literature. The pathology was intra- or extraosseous development, showing variation, but most cases were localized in the proximal carpal row.

The usefulness of latissimus dorsi transfer for reconstruction for malignant fibrous histiocytoma in the infraspinatus muscle region: a case report.

Malignant fibrous histiocytoma (MFH) is a type of highly malignant soft tissue sarcoma with a predilection for the extremities of adults. We report a patient with MFH in the infraspinatus muscle for which wide resection including total resection of the infraspinatus muscle was performed, followed by transfer of the latissimus dorsi muscle for shoulder reconstruction in a one-stage operation with good postoperative function.

Sex-specific 24-h acetylcholine release profile in the medial prefrontal cortex: simultaneous measurement of spontaneous locomotor activity in behaving rats.

The difference in visual object recognition by males and females suggests a sex-specific function in the medial prefrontal cortex (mPFC). In the present study, we performed an in vivo microdialysis study in three groups of rats (males, diestrous females, and proestrous females) to examine the potential sex difference in acetylcholine (ACh) release in the mPFC. The dialysate was automatically collected from the mPFC every 20 min for 24 h under freely moving conditions and the spontaneous locomotor activity was simultaneously monitored. Although ACh release in the mPFC during the dark phase was significantly greater than during the light phase in both sexes, the female rats consistently exhibited a significantly greater mean ACh release than the males. Spontaneous locomotor activity during the dark phase was also significantly greater than during the light phase in both sexes, but the females exhibited significantly greater spontaneous locomotor activity than the males. In addition, both sexes of rats were found to have significant positive correlations between ACh release and spontaneous locomotor activity, but females were found to have significantly greater correlation coefficients than males. Stereological methods were used to examine the number of choline acetyltransferase immunoreactive cells in the nucleus basalis magnocellularis and the horizontal diagonal band of Broca. The number of choline acetyltransferase immunoreactive cells in the nucleus basalis magnocellularis was also greater in females than males, suggesting a contribution to the higher ACh release in females. In contrast, no sex difference in the choline acetyltransferase immunoreactive cells was observed in the horizontal diagonal band of Broca. This is the first report to show a sex difference in the 24-h ACh release profile in the mPFC of behaving rats.

Infectious complications in patients receiving autologous CD34-selected hematopoietic stem cell transplantation for severe autoimmune diseases.

Long-term analysis of infectious complication after high-dose immunosuppressive therapy with CD34-selected autologous hematopoietic stem cell transplantation for patients with severe autoimmune diseases (AD) was performed. Theoretically, CD34 selection can reduce the risk of reinfusion of autoreactive lymphocytes. However, it is also associated with a significant reduction in T cells, natural killer cells, and monocytes, which in turn may compromise immune reconstitution, thereby increasing the risk of infection. Moreover, AD compromises host immunity and causes organ damage resulting in dysfunction of the cutaneous or mucosal barrier. In this study, the incidence rate of infections is reported in 14 patients who underwent high-dose (200 mg/kg) cyclophosphamide therapy followed by reinfusion of CD34-selected autologous peripheral blood stem cells. Bacterial complication occurred in 3 of 14 (21%) patients. Cytomegalovirus reactivation and adenovirus hemorrhagic cystitis were observed in 9 (64%) and 2 (14%) patients, respectively. As for late infectious complications, 7 patients (50%) developed dermatomal varicella zoster virus infection. No infection-related mortality was seen in this case series. Because the risk for infections approaches that seen in allogeneic transplant recipients, infection surveillance, diagnostic workup, and prophylactic strategies similar to those applicable to allogeneic recipients are warranted.

Outcomes after switching from one bisphosphonate to another in 146 patients at a single university hospital.

UNLABELLED: Most patients who switched to a second bisphosphonate continued their treatment long term, although those who stopped their first drug because of adverse events were likely to discontinue the second drug for the same reason. Switching to another bisphosphonate is a reasonable treatment option for some patients with treatment failure. INTRODUCTION: Patients who experience treatment failure with a bisphosphonate because of adverse events (AEs) or other reasons might receive a second bisphosphonate. However, the frequency and benefits of switching bisphosphonates are unknown. METHODS: We retrospectively evaluated 197 men and 1110 women newly treated with bisphosphonates between 1 January 2000 and 30 June 2005 at our university hospital. RESULTS: Among the 497 patients who discontinued bisphosphonate treatment, 146 were switched to a second bisphosphonate. The cumulative probabilities of persistence of treatment after 3 years were 45% with the first bisphosphonate and 65% with the second (P = 0.017). Age >or=65 years, switching bisphosphonates because of AEs, and male gender were associated (P < 0.05) with low persistence of treatment with the second bisphosphonate. Discontinuation of the first drug because of AEs was associated with an increased rate of discontinuation of the second drug because of AEs (hazard ratio, 4.2; 95% confidence interval, 2.1-8.4). CONCLUSIONS: Patients who switched bisphosphonates had high rates of persistence of therapy. Those who stopped their first bisphosphonate because of AEs were at risk of discontinuing the second drug for the same reason. Switching to another bisphosphonate is a reasonable treatment option for some patients with treatment failure.

Isolation, characterization and quantitation of canine alpha-1-acid glycoprotein.

The present study was designed to investigate the physicochemical properties of canine alpha-1-acid glycoprotein (AGP), and to establish a method for measuring serum AGP in canine. Fifty-three normal beagles were used in the study. AGP was purified from normal canine sera by successive ammonium sulfate precipitation, ion-exchange chromatography and gel filtration. The serum AGP concentration was measured by single radial immunodiffusion (SRID). Canine AGP had a molecular weight of 42,000 +/- 2,000 Da and contained 40.9% carbohydrate. Gel isoelectric focusing revealed microheterogeneity with 6-7 bands in a pI range (isoelectric points) of 3.2-3.8. AGP migrated to the alpha1-globulin region on immunoelectrophoresis. The serum AGP level of 35 normal beagles was 283.4 +/- 113.3 microg/ml. Canine AGP was isolated, and its physicochemical properties were clarified. SRID may be a useful method for quantification of serum AGP in canine.

Inhibition of metastin (kisspeptin-54)-GPR54 signaling in the arcuate nucleus-median eminence region during lactation in rats.

Follicular development and ovulation are suppressed during lactation in various mammalian species, mainly due to the suppression of pulsatile GnRH/LH secretion. Metastin (kisspeptin-54), a KiSS-1 gene product, is an endogenous ligand for GPR54, a G-protein-coupled receptor, and suggested to play a critical role in regulating the gonadal axis. The present study therefore aims to determine whether metastin (kisspeptin-54)-GPR54 signaling in discrete brain areas is inhibited by the suckling stimulus that causes suppression of LH secretion in lactating rats. Quantitative RT-PCR revealed that the KiSS-1 mRNA level was significantly lower in the arcuate nucleus (ARC)-median eminence region in lactating ovariectomized (OVX) and estrogen-treated OVX rats than in nonlactating controls. KiSS-1 mRNA in the anteroventral periventricular nucleus was kept at a low level in both lactating and nonlactating rats despite estrogen treatment. GPR54 mRNA levels were significantly lower in lactating than nonlactating rats in the anteroventral periventricular nucleus, but the levels in lactating mothers of the preoptic area and ARC-median eminence were comparable with nonlactating controls. Although KiSS-1 mRNA-expressing cells or metastin (kisspeptin-54) immunoreactivities were densely located in the ARC of nonlactating controls, few were found in the ARC of lactating OVX animals. Various doses of metastin (kisspeptin-54) (0.02, 0.2, and 2 nmol) injected into the third ventricle caused a significant increase in LH secretion in both lactating and nonlactating OVX rats, suggesting that lactating rats are responsive to metastin (kisspeptin-54) stimulus. Thus, the present study demonstrated that KiSS-1 mRNA/metastin (kisspeptin-54) expression is inhibited in the ARC by the suckling stimulus, suggesting that the inhibition is most probably involved in suppressing LH secretion in lactating rats.

Rituximab does not compromise the mobilization and engraftment of autologous peripheral blood stem cells in diffuse-large B-cell lymphoma.

To investigate effects of the preautografting administration of rituximab on the mobilization and engraftment of peripheral blood stem cells (PBSC), we retrospectively analyzed the outcomes of 43 newly diagnosed diffuse-large B-cell lymphoma patients who received CHOP chemotherapy with or without rituximab as a first-line treatment before autologous PBSC transplantation (PBSCT). There was no difference in the number of CD34(+) cells among PBSC between the non-rituximab and the rituximab groups. Although B-cells were completely depleted from PBSC in the rituximab group, we found no difference in the expression of CXCR-4, VLA-4 and c-Kit on PBSC, indicating that rituximab did not affect the expression of these adhesion molecules, which might be involved in the mechanism of mobilization. There was no significant difference in the recovery of neutrophils and platelets, transplant-related toxicity and post-transplant complications between the two groups. Despite the short follow-up, there was no significant difference in progression-free survival between the two groups. These results indicated no adverse effect of rituximab on the mobilization and engraftment of PBSC. Larger studies are required to determine the impact of rituximab on the mobilization and function of PBSC as well as whether a survival advantage exists in patients who undergo auto-PBSCT with rituximab.

Highly gate-tuneable Rashba spin-orbit interaction in a gate-all-around InAs nanowire metal-oxide-semiconductor field-effect transistor.

III-V semiconductors have been intensively studied with the goal of realizing metal-oxide-semiconductor field-effect transistors (MOSFETs) with high mobility, a high on-off ratio, and low power consumption as next-generation transistors designed to replace current Si technology. Of these semiconductors, a narrow band-gap semiconductor InAs has strong Rashba spin-orbit interaction, thus making it advantageous in terms of both high field-effect transistor (FET) performance and efficient spin control. Here we report a high-performance InAs nanowire MOSFET with a gate-all-around (GAA) structure, where we simultaneously control the spin precession using the Rashba interaction. Our FET has a high on-off ratio (104~106) and a high field-effect mobility (1200 cm2/Vs) and both values are comparable to those of previously reported nanowire FETs. Simultaneously, GAA geometry combined with high- κ dielectric enables the creation of a large and uniform coaxial electric field (>107 V/m), thereby achieving highly controllable Rashba coupling (1 × 10-11 eVm within a gate-voltage swing of 1 V), i.e. an operation voltage one order of magnitude smaller than those of back-gated nanowire MOSFETs. Our demonstration of high FET performance and spin controllability offers a new way of realizing low-power consumption nanoscale spin MOSFETs.