Petrous internal carotid artery aneurysm rupture induced by Eustachian tube catheterisation: case report.

BACKGROUND: Petrous internal carotid artery aneurysms are very rare vascular lesions, which may present with otalgia and life-threatening massive otorrhoea. CASE REPORT: An 84-year-old woman presented at a local otolaryngology clinic with progressive otalgia due to an acute exacerbation of chronic otitis media. She was referred with left-sided massive otorrhoea following Eustachian tube catheterisation. She suffered another massive otorrhoea with epistaxis during left-sided ear cleaning at a clinic visit. Contrast-enhanced computed tomography and computed tomography angiography revealed a left-sided aneurysm and adjacent stenosis at the left internal carotid artery. Coil embolisation of the petrous internal carotid artery aneurysm was performed with percutaneous transluminal angioplasty followed by dilatation of the stenosis. CONCLUSION: Computed tomography angiography should be performed immediately when a patient reports massive otorrhoea. Endovascular occlusion is a treatment option as it avoids complications of open surgical ligation procedures.

Peculiar temperature dependence of dynamical sound speed in liquid Se50Te50 by inelastic x-ray scattering.

Inelastic x-ray scattering (IXS) measurements were carried out on liquid Se50Te50 at temperatures up to 1323 K to investigate how the atomic dynamics changes with temperature through the semiconductor-metal transition. The acoustic mode was clearly observed in the dynamic structure factor and its energy was determined using a damped harmonic oscillator model. The dynamical sound speed obtained by IXS for [Formula: see text] nm-1 was found to behave similarly to the temperature dependence of ultrasonic sound velocity with a minimum near the semiconductor metal transition. The results can be explained by taking liquid Se50Te50 to be an inhomogeneous liquid consisting of metallic and semiconducting domains whose size is approximately 3 nm. The relaxation time obtained from frequency dependence of the dynamical sound speed was on a picosecond time scale.

Highly c-axis orientated superconducting core and large critical current density in Ba0.6Na0.4Fe2As2 powder-in-tube tape.

Improvement of the critical current density (Jc) of superconducting wires/tapes is one of the key issues in the field of superconductivity applications. Here we report the fabrication of a silver-sheathed Ba1-xNaxFe2As2 (BaNa-122) superconducting tape by using a powder-in-tube technique and its superconducting properties, in particular transport Jc, as well as the tape-core texture. The optimally-doped BaNa-122 tape with Na concentration x = 0.4 exhibits the superconducting critical temperature (Tc) of 33.7 K and high transport Jc of 4 × 104 A/cm2 at 4.2 K in a magnetic field of 4 T. Patterns of x-ray diffraction for the superconducting core show that the degree of c-axis orientation is significantly enhanced through the tape fabrication process. The tendency of c-axis orientation is advantageous for achieving higher Jc, suggesting the high potential of BaNa-122 for superconducting wire/tape applications.

Oral administration of heat-killed Lactobacillus brevis SBC8803 elevates the ratio of acyl/des-acyl ghrelin in blood and increases short-term food intake.

It is known that gastrointestinal microbiota, probiotics and heat-killed microbes can regulate intestinal immunity; however, their effect on the secretion of gastrointestinal hormones is unclear. The secretion of gastrointestinal hormones can be mediated by the elevation of intracellular Ca2+ concentration, suggesting that these hormones may act through common mechanisms. We have previously shown that heat-killed Lactobacillus brevis SBC8803 (hk-SBC8803) induced the secretion of serotonin and elevated intracellular Ca2+ concentration in serotonin-producing RIN-14B cells, suggesting that hk-SBC8803 could potentially cause the same effect on other gastrointestinal hormones, including hunger hormone ghrelin. Here, we tested this hypothesis by treating cultured cells and experimental animals with hk-SBC8803 and assessing ghrelin secretion, expression of ghrelin-related genes, and food intake. The results indicated that hk-SBC8803 treatment for 30 min significantly upregulated the secretion of acyl ghrelin (active form) (P=0.046) and mRNA expression of the Syt3 (synaptotagmin 3) gene related to ghrelin exocytosis (P<0.05) in primary mouse stomach cells. In addition, oral administration of 500 mg/kg hk-SBC8803 to rats tended to upregulate acyl ghrelin concentration (P=0.10) and significantly increased the ratio of acyl to des-acyl (inactive) ghrelin (P=0.027) in blood, which corresponded to a tendency of stimulating food intake (P=0.087) at 30 min post-treatment. However, when in order to minimise individual differences we normalised the data on food intake to those on one-day food intake prior to food deprivation, the resultant food intake ratio showed a significant increase (by 5% compared to control; P=0.032) at 30 min after hk-SBC8803 treatment, indicating that hk-SBC8803 administration stimulated rats to take more food during the first meal after fasting. These results suggest that hk-SBC8803 induces short-term ghrelin secretion and transiently increases appetite, which is an important effect for individuals with low energy intake.

Drug-induced oral lichenoid reaction during nivolumab therapy.

Oral lichenoid reaction, an immune-related adverse event of immunotherapy, has been reported in very few patients receiving anti-programmed cell death receptor-1 (anti-PD-1) therapy. Here, we describe a case of severe stomatitis (grade ≥3 by the Common Terminology Criteria for Adverse Events, version 4.0) accompanied by pharyngolaryngitis that was observed in a patient receiving nivolumab therapy. The stomatitis was diagnosed as drug-induced lichenoid reaction. Nivolumab therapy was discontinued, and the patient was administered systemic prednisolone (1mg/kg). Most of the patient's mucosal changes in the oral cavity and pharyngolarynx resolved within approximately 3 weeks after starting the prednisolone. Clinicians should be aware that severe oral lichenoid reactions can occur in patients receiving anti-PD-1 therapy.

Tuning the structure of the Josephson vortex lattice in Bi2Sr2CaCu2O8+δ single crystals with pancake vortices.

In extremely anisotropic cuprate superconductors a lattice of stacks of pancake vortices nucleates when a magnetic field is applied perpendicular to the copper oxide layers, while an orthogonal lattice of highly elliptical Josephson vortices forms when the applied field is parallel to the layers. Under tilted magnetic fields these sublattices can interact in complex ways to form systems of vortex chains and composite vortex lattices. Here we have used high-resolution scanning Hall microscopy (SHM) to map the rich tilted-field vortex phase diagram in an underdoped Bi2Sr2CaCu2O8+δ single crystal. We find that the Josephson vortex lattice spacing has an unexpected non-monotonic dependence on the pancake vortex density reflecting the delicate balance between attractive and repulsive vortex interactions, and actually undergoes a field-driven structural transformation with increasing out-of-plane fields. We also identify particularly stable composite structures composed of vortex chains separated by an integer number of rows of interstitial pancake vortex stacks and are able to establish the precise evolution of vortex-chain phases as the out-of-plane field is increased at small in-plane fields. Our results are in good semi-quantitative agreement with theoretical models and could enable the development of vortex ratchets and lenses based on the interactions between Josephson and pancake vortices.

Viscoelastic anomaly accompanying anti-crossing behaviour in liquid As2Se3.

We investigate the dynamic structure factor of the melt of the well known glass former, As2Se3, using inelastic x-ray scattering for temperatures, T, [Formula: see text] K and momentum transfers Q from [Formula: see text] nm-1. An anomaly was observed at Q = 2.7 nm-1 ([Formula: see text] K) with, in the context of a simple model, both an abrupt change in frequency and an increased linewidth reminiscent of an anti-crossing in a solid. Comparison with structural information from reverse Monte Carlo modeling of x-ray diffraction data allows us to associate the disappearance of the anomaly at higher temperatures with a drop in the number of mechanical constraints per atom, n mc, to [Formula: see text] reminiscent of the threshold applicable for glass formation in rigidity theory. It is inferred that the surprising jump in the dispersion in the liquid may be correlated with a stiffness transition in a network glass.

Evaluation of postoperative changes in vascularized iliac bone grafts used for mandibular reconstruction.

Vascularized iliac bone grafts are used for mandibular reconstruction, but the factors affecting graft maintenance are unknown. This study explored the postsurgical changes in vascularized iliac bone grafts in patients who had undergone mandibular reconstruction after segmental resection. The study involved 24 patients (16 men and eight women) with oral tumours or osteoradionecrosis. Thirteen patients required bare bone grafting (BBG) and 11 patients required reconstruction with soft tissue coverage (six with a skin paddle and five with direct closure). The bone graft maintenance rate (with regard to the height of the centre of the graft) was calculated immediately after surgery and at 3, 6, 12, 24, and 36months after surgery. The maintenance rate was significantly lower in the BBG group than in the soft tissue coverage group at 3, 6, 12, 24, and 36months, and in those who were fitted with dentures compared to those who were not at 6, 12, 24, and 36months. Local infection also influenced the maintenance rate, but not significantly so. These findings indicate that the reconstruction technique and denture use can affect the bone graft maintenance rate after mandibular reconstruction with vascularized iliac bone grafts.

Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer.

BACKGROUND: Although some retrospective studies have suggested the value of adjuvant therapy, no recommended standard exists in bile duct cancer. The aim of this study was to test the hypothesis that adjuvant gemcitabine chemotherapy would improve survival probability in resected bile duct cancer. METHODS: This was a randomized phase III trial. Patients with resected bile duct cancer were assigned randomly to gemcitabine and observation groups, which were balanced with respect to lymph node status, residual tumour status and tumour location. Gemcitabine was given intravenously at a dose of 1000 mg/m2 , administered on days 1, 8 and 15 every 4 weeks for six cycles. The primary endpoint was overall survival, and secondary endpoints were relapse-free survival, subgroup analysis and toxicity. RESULTS: Some 225 patients were included (117 gemcitabine, 108 observation). Baseline characteristics were well balanced between the gemcitabine and observation groups. There were no significant differences in overall survival (median 62·3 versus 63·8 months respectively; hazard ratio 1·01, 95 per cent c.i. 0·70 to 1·45; P = 0·964) and relapse-free survival (median 36·0 versus 39·9 months; hazard ratio 0·93, 0·66 to 1·32; P = 0·693). There were no survival differences between the two groups in subsets stratified by lymph node status and margin status. Although haematological toxicity occurred frequently in the gemcitabine group, most toxicities were transient, and grade 3/4 non-haematological toxicity was rare. CONCLUSION: The survival probability in patients with resected bile duct cancer was not significantly different between the gemcitabine adjuvant chemotherapy group and the observation group. Registration number: UMIN 000000820 (http://www.umin.ac.jp/).

Effect of Mouse Strain on Equine Herpesvirus 9 Infection.

The infectivity of equine herpesvirus (EHV)-9 has been studied in different animal models including immunocompromised animals. The current study focused on the infectivity of EHV-9 in different mouse strains (C3H, C57BL, DBA, BALB/c-nu/nu, BALB/c and ICR) by intranasal inoculation of 2 × 106 plaque forming units (PFU). Various organs, including head and lungs, were collected 7 days post infection (dpi) to investigate microscopical lesions and the distribution of EHV-9 antigen. Immunopositivity of tissue sections was scored using ImageJ software. Open reading frame (ORF) 30 expression in lung tissues was quantified using quantitative reverse transcriptase polymerase chain reaction. Pathological examination revealed different degrees of rhinitis in the different mouse strains. Severe rhinitis was detected in C3H and BALB/c-nu/nu strains, moderate rhinitis was observed in C57BL and DBA strains and no lesions were detected in BALB/c mice. Immunopositivity for EHV-9 antigens was detected in the olfactory epithelium of C3H and BALB/c-nu/nu strains. Compared with C57BL, DBA, BALB/c-nu/nu, ICR and BALB/c strains, the C3H strain showed greater expression of EHV-9 antigens in the brain. The proportion of areas with high positive to positive immunoreactivity for EHV-9 were 7.57, 3.42, 3.12, 2.51, 1.79 and 0.03% for C3H, C57BL, DBA, BALB/c-nu/nu, ICR and BALB/c strains, respectively. The proportions of areas with low positive to negative immunoreactivity were 92.42, 96.70, 96.87, 97.48, 98.16 and 99.96%, respectively. The highest relative expression levels for EHV-9 ORF30 in the lungs were in C3H mice. No significant differences in the expression of ORF30 were observed in other strains. In conclusion, of the strains examined, C3H, C57BL, DBA, BALB/c-nu/nu and ICR were the most susceptible to EHV-9 infection, and the BALB/c strain was less susceptible.

Wearing Compression Garment after Endurance Exercise Promotes Recovery of Exercise Performance.

The present study examined the effects of wearing a lower-body compression garment (CG) after endurance exercise on recovery of physiological function. 18 males were divided into 2 experiments, the downhill running (n=10, DHR) experiments and the level running (n=8, LR) experiments. Subjects performed 30 min of DHR (gradient: - 10%) or LR (gradient: 0%) at 70% of ˙VO2max with either wearing a CG (CG trial) or normal garment (CON trial) for 24 h after running. Changes in jump performance (counter movement jump; CMJ, rebound jump; RJ, drop jump; DJ), subjective feelings, circumferences of leg, and blood variables (creatine kinase, myoglobin, interleukin-6, high-sensitivity C-reactive protein) were evaluated before exercise, immediately after exercise, 1, 3 and 24 h following exercise. Running economy was evaluated at 24 h following exercise. CMJ height and RJ index were significantly higher in the CG trial than in the CON trial 24 h after running (P<0.05). Although changes in muscle soreness and blood variables were significantly greater in the DHR experiment than in the LR experiment, there was no significant difference between the trials in either experiment. Wearing a CG following endurance exercise facilitated recovery of jump performance under situations with severe exercise-induced muscle damage.

Factors associated with mothers not vaccinating their children against mumps in Japan.

OBJECTIVES: In Japan, mumps immunization is not mandatory, and the prevalence of mumps immunization among eligible children is only about 30%, raising concerns about increased risk of meningitis, encephalitis and deafness caused by mumps. In 2011, to understand why families are not voluntarily immunizing their children against mumps, we surveyed mothers who were university graduates to examine the factors and barriers influencing mumps vaccination in Japan. STUDY DESIGN: A cross sectional design. METHODS: We sent questionnaires including questions on demographic data and vaccination status, barriers and factors for immunizations to university alumnae to recruit participants. Data were analysed by Student's t-test for continuous variables and by univariate and multivariate analysis to obtain the odds ratio and adjusted odds ratio. RESULTS: Two hundred and twenty-six mothers with children responded with an average (range) age of 44.7 years (SD = 5.02; 30-55 years). Adjusted odds ratios (aOR) from logistic regression analysis identified fear of harmful side-effects (aOR, 2.55; 95% CI, 1.10 to 5.89), the vaccination not being mandatory (aOR, 3.30; 95% CI, 1.41 to 7.72), perceived non-efficacy (aOR, 6.21; 95% CI, 1.85 to 20.91) and being busy (aOR, 3.30; 95% CI, 1.21 to 9.01) were significantly and inversely associated with mumps vaccination. Recommendations from family doctors (aOR, 0.35; 95% CI, 0.17 to 0.71), living abroad when their children would be vaccinated (aOR, 0.10; 95% CI, 0.02 to 0.68) and the maternal age (aOR, 0.91; 95% CI, 0.85 to 0.96) were significant and positively associated with vaccination. CONCLUSIONS: In the absence of mandatory vaccinations, a public education campaign about mumps, their potential consequences and the nature and value of vaccination could improve the prevalence of mumps vaccination among children and prevent the consequences of this disease.

Randomised phase II trial of S-1 plus oxaliplatin vs S-1 in patients with gemcitabine-refractory pancreatic cancer.

BACKGROUND: This randomised, open-label, multicenter phase II study compared progression-free survival (PFS) of S-1 plus oxaliplatin (SOX) with that of S-1 alone in patients with gemcitabine-refractory pancreatic cancer. METHODS: Patients with confirmed progressive disease following the first-line treatment with a gemcitabine-based regimen were randomised to receive either S-1 (80/100/120 mg day(-1) based on body surface area (BSA), orally, days 1-28, every 6 weeks) or SOX (S-1 80/100/120 mg day(-1) based on BSA, orally, days 1-14, plus oxaliplatin 100 mg m(-2), intravenously, day 1, every 3 weeks). The primary end point was PFS. RESULTS: Between January 2009 and July 2010, 271 patients were randomly allocated to either S-1 (n=135) or SOX (n=136). Median PFS for S-1 and SOX were 2.8 and 3.0 months, respectively (hazard ratio (HR)=0.84; 95% confidence interval (CI), 0.65-1.08; stratified log-rank test P=0.18). Median overall survival (OS) was 6.9 vs 7.4 months (HR=1.03; 95% CI, 0.79-1.34; stratified log-rank test P=0.82). The response rate (RR) was 11.5% vs 20.9% (P=0.04). The major grade 3/4 toxicities (S-1 and SOX) were neutropenia (11.4% and 8.1%), thrombocytopenia (4.5% and 10.3%) and anorexia (12.9% and 14.7%). CONCLUSIONS: Although SOX showed an advantage in RR, it provided no significant improvement in PFS or OS compared with S-1 alone.

Is the evidence of the Supreme Court Ruling of gefitinib litigation in Japan scientific?

BACKGROUND: Plaintiffs of the gefitinib (Iressa) lawsuits in Japan started in 2004 were defeated in the Supreme Court in 2013. The Court judged it was not possible to foresee the outbreak of deaths caused by interstitial pneumonia due to gefitinib from death cases before approval of this drug. OBJECTIVE: We attempted to verify validity of this judgment. METHODS: We estimated the 95% confidence interval (CI) of the proportion of onset and death cases among 23 onset and 13 death cases occurring from "within 1 week" to "within 4 weeks" from clinical data before approval of this drug using data admitted to the Court. RESULTS: For death cases, all of the upper limits of the 95% CI exceeded 50% within 1-4 weeks. This fact suggested that the cases of acute interstitial pneumonia were included in the clinical trial before the approval of gefitinib. CONCLUSION: It was possible to foresee the outbreak of death cases after drug approval. This conclusion showed the Court's ruling was not reasonable and was unscientific.

Effect of eccentric contractions of elbow flexor on bone formation and resorption markers.

AIM: This study aimed to investigate the effects of eccentric contractions (ECs) of the biceps brachii muscle on bone metabolism markers. METHODS: Eight untrained subjects (20.0±0.5 years) performed 5 sets of 6 maximal ECs of the elbow flexors with a 2-min rest interval between each set. Blood samples were collected at 6 time points: before (Pre) ECs, immediately after (Post) ECs, and two hours (2 hours), 1 (day 1), 3 (days 3), and 5 days (days 5) after ECs. We measured the levels of the bone formation marker osteocalcin (OC) and the resorption marker tartrate-resistant acid phosphatase 5b (TRACP-5b). In addition, we measured the isometric tetanic torque and the levels of myoglobin (Mb), creatine kinase (CK), blood lactate, and insulin-like growth factor-1 (IGF-1). RESULTS: The results showed 1) CK and Mb levels increased significantly by days 3 and 5 (P<0.05); 2) OC levels significantly decreased in Post and 2 hours (P<0.01) and TRACP-5b levels significantly increased in Post (P<0.01); 3) OC positively correlated with the total work output in Post, 2 hours, and days 5 (Post: r=0.79, P<0.05; 2 hours: r=0.82, P<0.01; days 5: r=0.79, P<0.05); and 4) TRACP-5b levels positively correlated with IGF-1 levels (r=0.69, P<0.01). CONCLUSION: We conclude that a single bout of ECs of the biceps has a negative effect on bone metabolism in the acute phase.

Identification of chemoresistant factors by protein expression analysis with iTRAQ for head and neck carcinoma.

BACKGROUND: Cisplatin and other anticancer drugs are important in the treatment of head and neck squamous cell carcinoma; however, some tumours develop drug resistance. If chemoresistance could be determined before treatment, unnecessary drug administration would be avoided. Here, we investigated chemoresistance factors by comprehensive analyses at the protein level. METHODS: Four human carcinoma cell lines were used: cisplatin-sensitive UM-SCC-23, UM-SCC-23-CDDPR with acquired cisplatin resistance, naturally cisplatin-resistant UM-SCC-81B, and UM-SCC-23/WR with acquired 5-fluorouracil resistance. Extracted proteins were labelled with iTRAQ and analysed by tandem mass spectrometry to identify resistance. Protein expression was confirmed by western blotting and functional analysis was carried out using siRNA. RESULTS: Thirteen multiple-drug resistance proteins were identified, as well as seven proteins with specific resistance to cisplatin, including α-enolase. Differential expression of these proteins in cisplatin-resistant and -sensitive cell lines was confirmed by western blotting. Functional analysis for α-enolase by siRNA showed that cisplatin sensitivity significantly was increased in UM-SCC-81B and slightly in UM-SCC-23-CDDPR but not in UM-SCC-23/WR cells. CONCLUSIONS: We identified proteins thought to mediate anticancer drug resistance using recent proteome technology and identified α-enolase as a true cisplatin chemoresistance factor. Such proteins could be used as biomarkers for anticancer agent resistance and as targets of cancer therapy.

High force eccentric exercise enhances serum tartrate-resistant acid phosphatase-5b and osteocalcin.

We investigated the effects of eccentric contractions (ECs) on bone metabolism markers and the relationship between bone metabolism and skeletal muscle related protein. Seventeen young untrained men were divided into two groups and performed either 60 or 30 maximal ECs. We measured serum levels of osteocalcin (OC), bone alkaline phosphatase, cross-linked N-telopeptide of type I collagen (NTx), and tartrate-resistant acid phosphatase 5b (TRACP-5b), growth hormone (GH), and insulin-like growth factor-1 (IGF-1). Blood samples were collected for up to five days after ECs. OC with 60 ECs were significantly higher than with 30 ECs (2 hours; p<0.05, day 1 and day 5; p<0.01). TRACP-5b with 60 ECs were significantly higher than with 30 ECs (day 3 and day 5; p<0.001). IGF-1 and OC were significantly positively correlated with 60 ECs (2 hours, day 1, and day 5; p<0.05). There were also significant positive correlations between IGF-1 and NTx with 60 ECs (2 hours, p<0.01; day 1, p<0.05). We found that one bout of severe ECs caused increases in OC and TRACP-5b, which promote increased bone metabolism. Our results suggest that contraction-induced IGF-1 may activate OC and NTx in acute response.

Peripheral corticotropin-releasing factor (CRF) induces stimulation of gastric contractions in freely moving conscious rats: role of CRF receptor types 1 and 2.

BACKGROUND: Peripheral corticotrophin-releasing factor (CRF) plays an important role in stress-induced alterations of gastrointestinal motility. CRF injected peripherally inhibits gastric emptying, but its effect on gastric contractions has not been clarified in freely moving conscious rats. METHODS: Intraluminal gastric pressure waves were measured in freely moving conscious non-fasted rats using the perfused manometric method. We assessed the area under the manometric trace as the motor index (MI), and compared this result with those obtained 1 h before and after drug administration. KEY RESULTS: Subcutaneous injection (sc) of CRF (15 µg kg(-1)) increased the MI significantly. Pretreatment with intravenous astressin (100 µg kg(-1)), a non-selective CRF antagonist, blocked the sc CRF (15 µg kg(-1))-induced response, but astressin(2)-B (200 µg kg(-1), sc), a selective CRF receptor type 2 (CRF(2)) antagonist, enhanced the CRF-induced increase in MI significantly. Meanwhile urocortin 2 (15 µg kg(-1), sc), a selective CRF(2) agonist, did not alter the basal MI, but it inhibited the sc CRF (15 µg kg(-1))-induced stimulation of gastric contractions. The intraperitoneal injection of cortagine (30 µg kg(-1)), a selective CRF receptor type 1 (CRF(1)) agonist, mimicked the response induced by sc CRF. CONCLUSIONS & INFERENCES: Peripheral CRF stimulates gastric contractions through CRF(1). CRF(2) activation inhibits the response induced by CRF, suggesting that CRF(2) may have a modulatory action to CRF(1) signaling in gastric motor activity.

Efficacy and effect on plasma B-type natriuretic peptide concentration of losartan-hydrochlorothiazide for hypertension uncontrolled by losartan-based therapy: subanalysis of a Multicentre Prospective Observational Study.

Many patients with hypertension have difficulty achieving their target blood pressure (BP). Therefore combination therapy, for example with an angiotensin II receptor blocker (ARB) and a diuretic, may be recommended. We previously evaluated the efficacy and safety of losartan (LOS) 50 mg - hydrochlorothiazide (HCTZ) 12.5 mg, as well as its effect on the plasma concentration of B-type natriuretic peptide (BNP, a prognostic marker for cardiovascular events), in patients with hypertension uncontrolled by ≥3 months of ARB-based therapy. The present subanalysis used data from patients who received LOS-based therapy before switching to LOS-HCTZ. Efficacy, safety, and changes in blood biochemical variables including BNP were evaluated. After excluding 4 patients with protocol violations, data from 35 patients (aged 36-79 years, mean 63 years; 66% male) were used in the safety analysis. The efficacy analysis used data from the 30 patients who were followed up for 12 months. Systolic/diastolic BP decreased from 156±12/87±11 mmHg at baseline to 125±11/73±10 mmHg at 12 months (p<0.001). After 12 months, half of the patients achieved their target BP as defined by the Japanese Society of Hypertension Guidelines for the Management of Hypertension 2004. In 12 patients with baseline plasma BNP concentration ≥20 pg/mL, BNP decreased from 78.3±18.8 pg/mL to 57.3±17.7 pg/mL (p<0.01). 3 patients experienced adverse events, one of which was cardiovascular. LOS-HCTZ is efficacious, has a good safety profile, and decreases plasma BNP concentration.

Genetic differences and phenotypic plasticity in body size between high- and low-altitude populations of the ground beetle Carabus tosanus.

The body size of a univoltine carabid beetle Carabus tosanus on Shikoku Island, Japan, was clearly smaller in higher-altitude populations (subspecies), which possibly represents incipient speciation. To explore the determinants of altitudinal differences in body size in this species, we studied the degree of phenotypic plasticity by conducting rearing experiments at two constant temperatures and examined genetic differences through interpopulation crosses. At 15 °C, C. tosanus had a longer developmental period and a shorter adult body than at 20 °C. Nevertheless, variation in body size due to temperature effects (phenotypic plasticity) was small compared to the interpopulation differences, which suggests substantial genetic differences between populations (subspecies) at different altitudes. In F(1) offspring from crosses between a low-altitude (subspecies tosanus) and a high-altitude population (subspecies ishizuchianus), adult body length was affected by the genotypes of both parents, with an interaction effect of parental genotype and offspring sex. Further analyses revealed that adult body length was affected by sex-linked factors in addition to autosomal factors. These genetic differences in body size may have resulted from adaptations to different altitudes and may be important for the process of incipient speciation because body size differences could contribute to premating reproductive isolation.