Influence of ABCB1 and ABCG2 polymorphisms on the antiemetic efficacy in patients with cancer receiving cisplatin-based chemotherapy: a TRIPLE pharmacogenomics study.

Resistance to antiemetic treatment with 5-hydroxytryptamine-3 receptor antagonist is an issue. This study evaluated the potential roles of ABCB1 and ABCG2 polymorphisms in antiemetic treatment resistance in patients with cancer previously enrolled in a randomized controlled trial. A total of 156 patients were evaluated for their responses to antiemetic therapy and then subdivided into granisetron or palonosetron groups. The genotypes were evaluated for their association with antiemetic efficacy in each treatment groups. Additional risk factors associated with complete response (CR) were examined using a multivariate regression analysis. No significant associations were identified for genetic polymorphisms in the palonosetron group. In the granisetron group, patients with ABCB1 2677TT and 3435TT genotypes had higher proportion of CR. In addition to ABCB1 polymorphisms, gender and cisplatin dose were associated with granisetron response by univariate analysis. Multivariate logistic regression analysis revealed that the ABCB1 3435C>T polymorphism and cisplatin dose were significant predictors of CR.

Signatures of Quantum-Tunneling Diffusion of Hydrogen Atoms on Water Ice at 10 K.

Reported here is the first observation of the tunneling surface diffusion of a hydrogen (H) atom on water ice. Photostimulated desorption and resonance-enhanced multiphoton ionization methods were used to determine the diffusion rates at 10 K on amorphous solid water and polycrystalline ice. H-atom diffusion on polycrystalline ice was 2 orders of magnitude faster than that of deuterium atoms, indicating the occurrence of tunneling diffusion. Whether diffusion is by tunneling or thermal hopping also depends on the diffusion length of the atoms and the morphology of the surface. Our findings contribute to a better understanding of elementary physicochemical processes of hydrogen on cosmic ice dust.

Nanodiamond finding in the hyblean shallow mantle xenoliths.

Most of Earth's diamonds are connected with deep-seated mantle rocks; however, in recent years, µm-sized diamonds have been found in shallower metamorphic rocks, and the process of shallow-seated diamond formation has become a hotly debated topic. Nanodiamonds occur mainly in chondrite meteorites associated with organic matter and water. They can be synthesized in the stability field of graphite from organic compounds under hydrothermal conditions. Similar physicochemical conditions occur in serpentinite-hosted hydrothermal systems. Herein, we report the first finding of nanodiamonds, primarily of 6 and 10 nm, in Hyblean asphaltene-bearing serpentinite xenoliths (Sicily, Italy). The discovery was made by electron microscopy observations coupled with Raman spectroscopy analyses. The finding reveals new aspects of carbon speciation and diamond formation in shallow crustal settings. Nanodiamonds can grow during the hydrothermal alteration of ultramafic rocks, as well as during the lithogenesis of sediments bearing organic matter.

Nitrogen and phosphorus effluent loads from a paddy-field district adopting collective crop rotation.

Japanese paddy rice systems commonly adopt the rotation of vegetables, wheat and soybeans with paddy rice. Crop rotation may, however, increase the nutrient load in effluent discharged from the district because more fertilizer is applied to the rotation crops than is applied to paddy crops. We investigated a paddy-field district subject to collective crop rotation and quantified the annual nutrient load of effluent from the district in three consecutive years. The total annual exports of nitrogen and phosphorus over the investigation period ranged from 30.3 to 40.6 kg N ha(-1) and 2.62 to 3.13 kg P ha(-1). The results suggest that rotation cropping increases the effluent nutrient load because applied fertilizer is converted to nitrate, and surface runoff is increased due to the absence of shuttering boards at the field outlets.

Mucosal eosinophilia and recurrence of nasal polyps - new classification of chronic rhinosinusitis.

BACKGROUND: Eosinophils and nasal polyps are believed to affect the surgical outcome of chronic rhinosinusitis (CRS). CRS is classified based on the presence of nasal polyps in western countries. The majority of patients with CRS with nasal polyps (CRS with NP) are characterized by predominantly eosinophilic inflammation. However, Asian patients with CRS with NP show characteristics indicative of neutrophilic inflammation. Therefore, are eosinophils or nasal polyps more important for the classification of CRS? METHODS: A prospective cohort study conducted from April 2007 to March 2008 classified patients with CRS based on the presence of nasal polyps and mucosal eosinophilia. The recurrence rate of nasal polyps was compared between the groups. Recurrence rate was analysed as a time-dependent variable by the Kaplan-Meier method. RESULTS: Eosinophilic inflammation was found in 59.6% of patients with CRS with NP. Patients with mucosal eosinophilia had higher polyp recurrence rate than patients without mucosal eosinophilia, whereas patients with nasal polyps did not have higher polyp recurrence rate than patients without nasal polyps. CONCLUSIONS: Presence of mucosal eosinophilia is a more important factor than nasal polyps for classifying CRS in terms of the surgical outcome.

Pupillary autonomic dysfunction in multiple system atrophy and Parkinson's disease: an assessment by eye-drop tests.

PURPOSE: To compare pupillary autonomic dysfunction in multiple system atrophy (MSA) and Parkinson's disease (PD). METHODS: We administered eye-drop tests to 40 MSA patients, 40 PD patients with similar disease duration, and 20 age-matched healthy controls. Pupillary supersensitivity to a parasympathomimetic agent (0.05% pilocarpine hydrochloride) and to a sympathomimetic agent (0.02% dipivefrine hydrochloride) was examined by assessing changes in pupil diameter. RESULTS: Pupillary supersensitivity to a parasympathomimetic agent (0.05% pilocarpine hydrochloride) and to a sympathomimetic agent (0.02% dipivefrine hydrochloride) was examined by assessing changes in pupil diameter. Pupillary supersensitivity to 0.05% pilocarpine was greatest among the PD patients (PD -23.1 +/- 14.4%, MSA -12.4 +/- 11.5%, control -9.5 +/- 8.2%, p < 0.05) but was not correlated with disease duration. Pupillary sensitivity to 0.02% dipivefrine was significantly greater in the PD and MSA patients versus controls (PD 10.5 +/- 12.0%, MSA 11.8 +/- 11.0%, control 3.1 +/- 5.8%, p < 0.05). MSA patients had pupillary sympathetic dysfunction from an early stage, whereas in PD patients it tended to gradually accelerate as the disease advanced. In MSA patients, pupillary sympathetic sensitivity to 0.02% dipivefrine was correlated with the severity of orthostatic hypotension during a head-up tilt test and with the elevation of systolic blood pressure during a noradrenaline infusion test. In PD patients, pupillary sympathetic sensitivity to 0.02% dipivefrine was correlated with a reduction of the heart-to-mediastinum (H/M) ratio using delayed-phase iodine-123 meta-iodobenzylguanidine ((123)I-MIBG) myocardial scintigraphy. CONCLUSION: These data indicate that eye-drop tests can reveal differences in the progression of pupillary autonomic dysfunction in patients with MSA and PD.

An electroluminescence device for printable electronics using coprecipitated ZnS:Mn nanocrystal ink.

Electroluminescence (EL) devices for printable electronics using coprecipitated ZnS:Mn nanocrystal (NC) ink are demonstrated. The EL properties of these devices were investigated along with the structural and optical properties of ZnS:Mn NCs with an emphasis on their dependence on crystal size. Transmission electron microscopy and x-ray diffraction studies revealed that the NCs, with a crystal size of 3-4 nm, are nearly monodisperse; the crystal size can be controlled by the Zn(2+) concentration in the starting solution for coprecipitation. The results of optical studies indicate the presence of quantum confinement effects; in addition, the NC surfaces are well passivated, regardless of the crystal size. Finally, an increase in the luminance of EL devices with a decrease in crystal size is observed, which suggests the excitation mechanism of ZnS:Mn NC EL devices.

Preoperative evaluation of the extrahepatic bile duct structure for laparoscopic cholecystectomy.

BACKGROUND: The incidence of aberrant bile duct injury associated with laparoscopic cholecystectomy (LC) has not yet been adequately examined. This study aimed to clarify the types of normal cystic ducts and the incidence of aberrant extrahepatic bile ducts, and to search for a method of avoiding injuries during LC. METHODS: Aberrant hepatic ducts were retrospectively categorized into five types according to the pattern of the cystic ducts and the accessory hepatic ducts by preoperative endoscopic retrograde cholangiography or multidetector three-dimensional computed tomography using drip infusion cholangiography. The aberrant bile ducts were classified as type A (merging at the right side of the common bile duct), type B (merging at the anterior side), or type C (merging at the posterior left side). RESULTS: The intrahepatic bile ducts and cystic duct were clearly shown for 1,044 of the 1,278 patients who underwent LC. Secondary branches of aberrant cystic ducts were observed in 37 cases (3.5%), and accessory hepatic ducts were observed in 30 cases (2.9%). A comparison of the difficulties encountered with LC for each type based on the merging patterns of cystic ducts showed that type C needed a much longer operation time for LC than the other types. CONCLUSIONS: A preoperative evaluation of the bile duct tract and the accessory hepatic duct before LC is important. Patients with a cystic duct merging normally into the posterior left side of the common hepatic duct (type C) experienced difficulty when undergoing LC. The authors have safely performed LC with the use of an endoscopic nasobiliary drainage tube in type D cases (cystic duct merging with the right hepatic duct), in type IV cases (cystic duct merging with an accessory hepatic duct).

Gender differences in postoperative pain after laparoscopic cholecystectomy.

BACKGROUND: Some evidence suggests that females have a lower pain threshold and a lower tolerance to painful stimuli. This study investigated gender differences in postoperative pain after laparoscopic cholecystectomy (LC) on the basis of visual analog pain scale (VAS) scores and the clinical course. METHODS: The 100 patients in this study (46 males and 54 females) underwent LC for cholecystolithiasis or gallbladder polyps without intraoperative complications. An 8-mm Penrose drain was retained for 42 h below the liver bed. All the patients were hospitalized for 4 days after LC, and the pain reported by patients, the time course of changes in the highest body temperature, the leukocyte count, and the C-reactive protein level were studied comparatively for the male and female patients. RESULTS: The VAS scores were significantly higher for the female patients than for the male patients at 24 h (62.7 +/- 24.6 vs 47.0 +/- 23.3; p = 0.0015) and at 48 h (39.2 +/- 24.3 vs 28.3 +/- 19.1; p = 0.0137) after LC. The female patients used analgesics more frequently and had significantly higher body temperatures than the male patients on day 1 (37.2 +/- 0.6 vs 36.9 +/- 0.4; p = 0.0037) and day 2 (36.9 +/- 0.6 vs 36.6 +/- 0.4; p = 0.0037) after surgery. CONCLUSIONS: Early postoperative pain after LC was more severe in female patients, and patients with high VAS scores tended to use analgesics more frequently.

Identification and molecular cloning of a novel brain-specific receptor protein that binds to brain injury-derived neurotrophic peptide. Possible role for neuronal survival.

Brain injury-derived neurotrophic peptide (BINP) is a synthetic 13-mer peptide that supports neuronal survival and protects hippocampal neurons in primary cultures from cell death caused by glutamate. We have developed a monoclonal antibody named mAb 6A22 against the 40-kDa BINP-binding protein, p40BBP. mAb 6A22 inhibits binding between BINP and rat brain synaptosomes and abolishes the protective effect of BINP. The antigen of mAb 6A22 should be the BINP-binding protein that mediates the neuroprotective action of BINP. Using an expression cloning approach with mAb 6A22, we isolated a cDNA encoding a novel receptor protein that shows binding activity of BINP. COS7 cells transfected with the cloned cDNA show binding of BINP and cell surfaces that are stained by 6A22. The mRNA for p40BBP is specific for the rat brain and is increased after birth. From immunohistochemical studies using mAb 6A22, p40BBP increased after kainic acid treatment in rat hippocampal neurons.

Flavonoid glucuronides from Helicteres isora.

Five flavonoid glucuronides were obtained from the fruit of Helicteres isora, three of which were previously unknown compounds: isoscutellarein 4'-methyl ether 8-O-beta-D-glucuronide 6"-n-butyl ester. isoscutellarein 4'-methyl ether 8-O-beta-D-glucuronide 2", 4"-disulfate and isoscutellarein 8-O-beta-D-glucuronide 2",4"-disulfate. The structures were determined on the basis of spectroscopy and hydrolysis experiments.

Development of an antibody against a 40,000 mol. wt brain injury-derived neurotrophic peptide-binding protein and identification of a 40,000 mol. wt brain injury-derived neurotrophic peptide-binding protein in hippocampal neurons.

Brain injury-derived neurotrophic peptide is a 13-amino acid peptide derived from a 15,000 mol. wt neurotrophic factor released from sites of mechanical injury in neonatal rat brain. This peptide promotes survival of septal cholinergic neurons and mesencephalic dopaminergic neurons, and protects hippocampal neurons from glutamate-induced neurotoxicity. In this study, we have developed a monoclonal antibody against a brain injury-derived neurotrophic peptide-binding protein by immunizing mice with septal synaptosomes from five-week-old rat brain. Monoclonal antibodies were screened for inhibition of the binding of a 125I-labeled analogue of brain injury-derived neurotrophic peptide to rat brain synaptosomes. The monoclonal antibody 6A22 suppressed the biological activity of brain injury-derived neurotrophic peptide and abolished the protective effect of the neurotrophic peptide against glutamate-induced neurotoxicity. This monoclonal antibody recognized a 40,000 mol. wt brain injury-derived neurotrophic peptide-binding protein, which was also identified by cross-linking experiments. Immunohistochemical studies showed that the 6A22 antibody bound to the cell surfaces of a subpopulation (about 60%) of hippocampal neurons in culture. These results are consistent with the possibility that the 40,000 mol. wt protein belongs to brain injury-derived neurotrophic peptide receptors.

Exposure to Japanese cedar pollen in early life and subsequent sensitization to Japanese cedar pollen.

The effect of exposure to Japanese cedar pollen (JCP) in early life on subsequent sensitization to it was evaluated. Specific IgE antibody to JCP was examined in 440-504 school children in a rural town each year during 1995-98. The amount of dispersed pollen measured by a Durham sampler widely ranged from 165 to 5941 grains/cm2/year during this period. The amount had been measured during the period of 1982-91 in which these children were born, and it also widely ranged from 148 to 8566 grains/cm2/year. Children born during November to January, who were exposed to JCP within 6 months of age, increased at the risk of sensitization to JCP, especially severe sensitization, relative to those born in the other months. Age-adjusted prevalence rate ratio (RR) of having a JCP-IgE > or = 15 U/ml (control; < 0.35 U/ml) for children born in December to February relative to children born in the other months was 1.74 (95% confidence interval; 1.06-2.87, examined in 1998), and for those born in November to January was 1.57 (95% CI; 1.00-2.46, examined in 1997). The risk of sensitization to JCP was low for those born in May to July (RR = 0.42, 95% CI; 0.19-0.93, examined in 1998). There was also a strong correlation between the amount of the dispersed pollen during the period of 2-6 months after birth and the prevalence of sensitization to JCP.

[Simple evaluation of CT findings in the paranasal sinuses for chronic sinusitis].

The CT scores and scoring for improvement based on them, which we proposed previously, is a simple and highly reproducible method of evaluation of sinus units before and after an operation for chronic sinusitis. We compared this evaluation method with the results of quantitative assay and showed its advantages and disadvantages. The subjects were 258 sinuses in patients who underwent endonasal sinus surgery (ESS) in the department of otolaryngology, Kyoto Prefectural University of Medicine Hospital from April 1996 to April 1997. The subjects were evaluated according to the following 4 grades negligible shadow in the paranasal sinus CT scored 0, less than 50% shadow scored 1, more than 50% of shadow scored 2, and mostly filled with shadow scored 3. Furthermore, the preoperative and postoperative CT scores were compared and the rate of improvement was rated in the following 3 grades: score 0 for unchanged or aggravated subjects, score 1 for subjects showing improved CT score by 1 grade, and score 2 for those showing improved CT score by 2 grades or a postoperative CT score of 0. Quantitative image analysis was input into a personal computer and the ratio occupied by the shadow was calculated, as the shadow ratio. While some discrepancies were seen in parts in the comparison of the quantitative image analysis and CT scores as the former captures minute shadows, a positive correlation was obtained overall. Attention is needed to accurately evaluate small paranasal sinuses such as the frontal sinus, and small amounts of shadow, which are areas where errors may occur. A satisfactory correlation was obtained between the score for the improvement rate and the difference in the shadow ratios before and after surgery. The CT scores and the scores for the improvement rate showed no difference from the results of other evaluation methods reported in the past, and evaluation of similar precision was possible. It was thought that this simple evaluation method of CT findings in the paranasal sinuses, which we examined in the present study, was quite useful as a simple stage-classification method that could be utilized in everyday practice considering its facility, reproducibility and satisfactory precision.

Different recognition by peroxisome proliferator structures in rat peroxisomal induction: application of sandwich ELISA using monoclonal antibody against rat peroxisomes.

A novel assay for a peroxisomal beta-oxidation enzyme by sandwich ELISA using a monoclonal antibody (RPX-5) against purified rat liver peroxisomes was developed. Immunoblot analysis revealed that RPX-5 recognized a 78 Kd protein, which is a peroxisomal bifunctional enzyme (PBE) in the beta-oxidation pathway. Immunoprecipitation by RPX-5 and the resulting reduction of PBE activity were dependent on RPX-5 concentrations. Sandwich ELISA using RPX-5 could be used to assay PBE in the range of 30 to 2000 ng protein/ml. In rat hepatocyte cultures, the PBE amount by this assay correlated well with PBE activity, with correlation coefficients of 0.965. Studying the mechanisms of peroxisomal induction, patterns of peroxisomal induction were examined by co-treatment of rat hepatocytes with various peroxisome proliferators (PxPs). Treatment with clofibrate and bezafibrate resulted in neither an additive nor synergistic effect on PBE level. On the other hand, co-treatment with either bezafibrate-Wy-14,643 or clofibrate-MEHP(mono(2-ethylhexyl)phthalate) both resulted in an additive effect. From these results, it is suggested that PxPs of the fibrate group may exert their functions via a common process, and non-fibrate PxPs via a different process in hepatocytes. The cognition site for peroxisome proliferators, therefore, might not involve a single site for inducing peroxisomal enzymes.

Characteristics of brain injury-derived neurotrophic peptide-binding sites on rat brain synaptosomes and neurons in culture.

Brain injury-derived neurotrophic peptide is the fragmental 13-mer peptide of the novel neurotrophic factor which was extracted and purified from Sponge Gelform made of gelatin implanted at the mechanically-induced injury site in neonatal rat brains. Brain injury-derived neurotrophic peptide supports survival of septal cholinergic and mesencephalic dopaminergic neurons in culture, and rescues hippocampal neurons in culture from glutamate neurotoxicity. Here we studied the binding characteristics of brain injury-derived neurotrophic peptide to synaptosomes from normal adult rat brains and neurons in culture from neonatal rat brains. [125I]Asp-[Tyr11]-brain injury-derived neurotrophic peptide binding to rat brain synaptosomes was specific and saturable. Equilibrium binding studies revealed that [125I]Asp-[Tyr11]-brain injury-derived neurotrophic peptide bound to 1.1 pmol/mg protein with a Kd (dissociation constant) of 0.17 microM in hippocampal synaptosomes and to 2.0 pmol/mg protein with a Kd of 0.38 microM in septal synaptosomes. [125I]Asp-[Tyr11]-brain injury-derived neurotrophic peptide could bind to a subpopulation of hippocampal neurons in culture from embryonic rat brains. Affinity cross-linking with the carboxyl-reactive cross-linking reagent 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide-HCl and [125I]Asp-[Tyr11]-brain injury-derived neurotrophic peptide produced radiolabeled bands corresponding to 100,000, 50,000 and 40,000 mol. wt molecules on hippocampal neurons in culture. These results suggest that the 13-mer sequence of brain injury-derived neurotrophic peptide plays a crucial role in expressing the neurotrophic properties of the factor.

Real time in situ confocal imaging of calcium wave in the perfused whole heart of the rat.

To understand the calcium handling in whole heart having automaticity of the sinus node, we have developed a system of in situ imaging the intracellular calcium ion concentration in the perfused whole heart of the rat. The system consists of a stage-fixed upright microscope equipped with a real-time confocal laser scanning device of a multipinhole type with a water-immersion objective lens for observation. This in situ imaging system rendered observations and analyses of the rapidly changing images of intracellular calcium dynamics possible in the whole rat heart loaded with fluo-3. The scanning was conducted at a video rate of 30 frames per second, and the confocal effects included both X and Y planes. Calcium waves were frequently interrupted by calcium transients from either external electro-stimulation pulses or spontaneous sinus rhythm. Our findings suggest that abnormal calcium waves in minute areas cannot disturb the excitation-contraction coupling in the whole heart if the myocardial cells have orderly end-on-end intercellular electric paths.

Synthesis and antinociceptive activity of [D-Ala2]Leu-enkephalin derivatives conjugated with the adamantane moiety.

Based on the physicochemical and pharmacological properties of drugs having an adamantane skeleton, an adamantane-based moiety was evaluated as a drug carrier for poorly absorbed compounds, including peptides, active towards the central nervous system (CNS). Seven [D-Ala2]Leu-enkephalin derivatives conjugated with an adamantane-based moiety at the C-terminus or N-terminus were prepared by the solution-phase method and their biological activities were examined. The compounds derivatized at the C-terminus through an ester or amide linkage were much more lipophilic than the parent peptide and exhibited moderate in vitro opioid activity (guinea-pig ileum assay). Among them, four derivatives (1, 2, 4, 5), exhibited significant antinociceptive effects in an in vivo assay (mouse tail-pressure test) after subcutaneous administration. This result suggests that the introduction of the lipophilic adamantane moiety into [D-Ala2]Leu-enkephalin would improve the permeation of the poorly absorbed parent peptide through the blood-brain-barrier (BBB) without loss of antinociceptive effect.

Evolutionary consideration on 5-aminolevulinate synthase in nature.

5-Aminolevulinic acid (ALA), a universal precursor of tetrapyrrole compounds can be synthesized by two pathways: the C5 (glutamate) pathway and ALA synthase. From the phylogenetic distribution it is shown that distribution of ALA synthase is restricted to the alpha subclass of purple bacteria in prokaryotes, and further distributed to mitochondria of eukaryotes. The monophyletic origin of bacterial and eukaryotic ALA synthase is shown by sequence analysis of the enzyme. Evolution of ALA synthase in the alpha subclass of purple bacteria is discussed in relation to the energy-generating and biosynthetic devices in subclasses of this bacteria.