Spectrum of clinical and genetic features of patients with inherited platelet disorder with suspected predisposition to hematological malignancies: a nationwide survey in Japan.

BACKGROUND: Inherited thrombocytopenia (IT) contains several forms of familial thrombocytopenia and some of them have propensity to hematological malignancies. The etiological and genetic features of this heterogeneous syndrome have not yet been elucidated. PATIENTS AND METHODS: We conducted a nationwide survey to collect clinical information and samples from patients with familial thrombocytopenia and/or hematological malignancies in order to obtain a comprehensive understanding of IT. RESULTS: Among the 43 pedigrees with clinical samples, RUNX1 mutations were identified in 8 pedigrees (18.6%). While MYH9 and ANKRD26 mutations were identified in 2 and 1 pedigrees, respectively, no gene mutations were detected in the remaining 32 pedigrees from a panel of previously reported pathogenetic mutations. Clinical data were comparable between FPD/AML and non-FPD/AML probands. CONCLUSIONS: Our study clarified that it is unexpectedly difficult to diagnose FPD/AML based on clinical information alone, and thus, genetic testing is strongly recommended. Our survey also identified some pedigrees with a strong family history of myelodysplastic syndromes of unknown origin. Additionally, there were 14 pedigrees in which three or more members were affected by immune thrombocytopenia (ITP), and a computer-aided simulation suggested that such a distribution almost never happens by coincidence, which implicates a genetic predisposition to ITP.

Impact of body mass index on postoperative complications and long-term survival in patients with esophageal squamous cell cancer.

Undernutrition and cachexia have been suggested to be risk factors for postoperative complications and survival in cancer patients. The aim of this study was to investigate whether body mass index (BMI) is related to the short-term and long-term outcomes in patients who undergo an esophagectomy for the resection of esophageal squamous cell cancer (ESCC). Three hundred forty patients who underwent an esophagectomy for the resection of ESCC between 2003 and 2008 were retrospectively reviewed. The patients were divided into two groups: an L-BMI group characterized by a BMI < 18.5 kg/m(2) and an N-BMI group characterized by a BMI ≥ 18.5 kg/m(2). Clinical and pathological outcome were compared between groups. The study included 40 patients in the L-BMI group and 300 patients in the N-BMI group. A clinicopathological assessment showed that nodal involvement was seen more frequently in the L-BMI group (P = 0.016). Pulmonary complications seemed to occur more frequently in the L-BMI group (P = 0.006). The 5-year overall survival rate was higher in the N-BMI group (63.6%) than in the L-BMI group (32.3%) (P < 0.001). The 5-year disease-free survival rate was also higher in the N-BMI group (58.0%) than in the L-BMI group (33.6%) (P = 0.001). In multivariate analysis, the BMI (hazard ratio, 2.154; 95% CI, 1.349-3.440, P = 0.001) was found to be an independent prognostic factor for overall survival. Our data suggested that a lower BMI not only increased pulmonary complications but also impaired overall and disease-free survival after an esophagectomy for the resection of ESCC.

Function of insulin in snail brain in associative learning.

Insulin is well known as a hormone regulating glucose homeostasis across phyla. Although there are insulin-independent mechanisms for glucose uptake in the mammalian brain, which had contributed to a perception of the brain as an insulin-insensitive organ for decades, the finding of insulin and its receptors in the brain revolutionized the concept of insulin signaling in the brain. However, insulin's role in brain functions, such as cognition, attention, and memory, remains unknown. Studies using invertebrates with their open blood-vascular system have the promise of promoting a better understanding of the role played by insulin in mediating/modulating cognitive functions. In this review, the relationship between insulin and its impact on long-term memory (LTM) is discussed particularly in snails. The pond snail Lymnaea stagnalis has the ability to undergo conditioned taste aversion (CTA), that is, it associatively learns and forms LTM not to respond with a feeding response to a food that normally elicits a robust feeding response. We show that molluscan insulin-related peptides are up-regulated in snails exhibiting CTA-LTM and play a key role in the causal neural basis of CTA-LTM. We also survey the relevant literature of the roles played by insulin in learning and memory in other phyla.

Can Spirulina maxima reduce the mutagenic potential of sibutramine?

The worldwide obesity pandemic requires the use of anti-obesity drugs. Sibutramine is an anti-obesity drug that has been used worldwide but is indiscriminately consumed in Brazil. Several studies have demonstrated that sibutramine promotes weight loss and weight maintenance, but several side effects have been associated with its systematic consumption. For this reason, sibutramine was withdrawn from the European and American markets, but still remains legal for use in Brazil. Studies have shown that a 5-10% reduction in body weight results in outstanding health benefits for obese patients. However, in order to promote significant weight loss, it is necessary to use sibutramine for at least 2 years. This long-term exposure has carcinogenic potential, as sibutramine causes DNA damage. Thus, this study evaluated the in vivo mutagenic potential of sibutramine alone (5, 7, 10, 15, and 20 mg/kg) and in association with Spirulina maxima (150 and 300 mg/kg), a cyanobacterium with antioxidant potential, using the polychromatic erythrocyte micronucleus test. Our results reinforced the mutagenic potential of sibutramine alone, which showed a time-dependent action. Combinatory treatments with S. maxima were not able to reduce the genotoxicity of sibutramine. These results were confirmed in vitro with the cytokinesis-blocked micronucleus test. In conclusion, our data showed that new alternative anti-obesity treatments are needed since the consumption of sibutramine can increase the risk of cancer in overweight patients.

Radiation therapy for extramammary Paget's disease: treatment outcomes and prognostic factors.

BACKGROUND: Extramammary Paget's disease (EMPD) is a relatively rare malignancy, and there are few reports related to radiation therapy. In the present study, we investigated the outcome of radiation therapy for EMPD. PATIENTS AND METHODS: Forty-one patients with EMPD in the genitalia underwent radiation therapy with curative intent. Fifteen patients had regional lymph node metastases before radiation therapy, but none had distant metastasis. Total doses of 45-80.2 Gy (median, 60 Gy) were delivered to tumor sites in 23-43 fractions (median, 33 fractions). RESULTS: At a median follow-up period of 41 months, 16 patients had developed recurrences, including 5 with local progression within the radiation field and 12 with lymph node or/and distant metastases outside the radiation field. The local progression-free and disease-free rates were 88% and 55% at 3 years, and 82% and 46% at 5 years, respectively. Nine patients died at 6-73 months after irradiation; the causes of death were tumor progression in five patients, infectious pneumonia in two, renal failure in one and old age in one. The overall and cause-specific survival rates were 93% and 96% at 3 years, and 68% and 84% at 5 years, respectively. Tumor invasion into the dermis and regional lymph node metastasis were significant prognostic factors for both distant metastasis and survival. No therapy-related toxicities of grade ≥3 were observed. CONCLUSIONS: Radiation therapy is safe and effective for patients with EMPD. It appeared to contribute to prolonged survival owing to good tumor control, and to be a promising curative treatment option.

Clinicopathological significance of laminin-5γ2 chain expression in superficial esophageal cancer.

The glycoprotein laminin 5γ2 chain (LN-5γ2) has recently become a focus of increased interest and investigation as a marker of invasion in gastrointestinal malignancies. We investigated the significance of LN-5γ2 expression as a prognostic factor in superficial esophageal cancer. The study population consisted of 87 patients who had undergone a transthoracic esophagectomy and three-field lymphadenectomy for the treatment of superficial esophageal cancer at Tokai University Hospital. Formalin-fixed, paraffin-embedded sections of the resected specimens were examined using immunohistochemical staining and hematoxylin and eosin staining to assess the correlations between the LN-5γ2 expression pattern and the clinicopathological factors (age, sex, T-factor, N-factor, ly-factor, v-factor, degree of differentiation, infiltrative growth pattern, tumor node metastasis classification of malignant tumors [TNM] stage, etc.) and the patient outcome. The expression pattern of LN-5γ2 was classified into an extracellular type (E type), characterized by the staining of extracellular matrix such as the basement membrane and the stroma (31 cases, 35.6%), and a cytoplasmic type (C type), characterized by the staining of the cytoplasm in the cancer cells (56 cases, 64.6%). The expression pattern was not correlated with any of the clinicopathological factors that were assessed. However, univariate analyses of the survival analysis data showed that the N-factor (P = 0.011), TNM stage (P = 0.011), and LN-5γ2 C type (P = 0.017) were prognostic factors. A multivariate analysis revealed that the N-factor (P = 0.049) and LN-5γ2 C type (P = 0.048) were prognostic factors. In the survival analysis, a univariate analysis of the 75 T1b cases also showed that the N-factor (P = 0.048), TNM stage (P = 0.048), and LN-5γ2 C type (P = 0.029) were prognostic factors, while a multivariate analysis showed that the LN-5γ2 C type (P = 0.035) was a prognostic factor. The C type expression of LN-5γ2, i.e. confined to the cytoplasm, was correlated with an unfavorable outcome among the patients with superficial esophageal cancer in the present series. Observation of the LN-5γ2 expression pattern may be useful for the diagnosis of highly malignant tumors.

Mutagenic potential of Cordia ecalyculata alone and in association with Spirulina maxima for their evaluation as candidate anti-obesity drugs.

Obesity is one of the most important nutritional disorders, and can be currently considered as an epidemic. Although there are few weight reduction drugs available on the market, some new drug candidates have been proposed, including Cordia ecalyculata, a Brazilian plant with anorectic properties, and Spirulina maxima, a cyanobacterium with antioxidant and anti-genotoxic activity. In this study, we evaluated the mutagenic potential of C. ecalyculata at doses of 150, 300, and 500 mg/kg alone and in association with S. maxima at doses of 75, 150, and 250 mg/kg, respectively, through an in vivo micronucleus test, using mice of both sexes, and an in vitro micronucleus test and comet assay, using human peripheral blood. For all tests, cyclophosphamide was used as a positive control. The results showed that treatment of 300 mg/kg C. ecalyculata and the combination treatment of 500 mg/kg C. ecalyculata with 250 mg/kg S. maxima resulted in anorectic effects. The mutagenic tests did not reveal any clastogenic or genotoxic activity for any treatment, indicating that these candidates could be marketed as weight-reduction drugs. Moreover, the drugs contain chemo-preventive substances that can protect against tumorigenesis, which has been associated with obesity.

Spatiotemporal and seasonal transmission dynamics of Schistosoma haematobium and snail infectivity in Ase River catchment, Delta State, Nigeria.

Bulinus are intermediate snail hosts of Schistosoma haematobium. Despite their vectorial role, the transmission dynamics and infectivity of these intermediate snail hosts remain understudied in the Ase River. This longitudinal study evaluated the geospatial and seasonal transmission patterns and infectivity of three S. haematobium vectors between November 2020 and October 2022 in the Ase River catchment, Delta State, Nigeria. Eleven (11) geospatial water contact coordinates were mapped for monthly spatiotemporal collection of Bulinus species along the Ase River and its catchment, for two years. Snail sampling was performed for 45 min at each study site using scooping/hand-picking techniques and subsequently counted, identified and recorded. Snails of the Bulinus genus were individually placed in a beaker containing distilled water and exposed to light to shed cercariae which were identified to be human schistosome type. The number of infected snails for each month and season was also documented to analyze the spatiotemporal and seasonal transmission dynamics of infectivity. Out of the 2345 Bulinus snails collected, a total of 41.45% were found to be infected with S. haematobium. The monthly infectivity of Bulinus snails varied significantly (P < 0.05) throughout the study period (P = < 0.0001; F = 23.11; df = 11). Further analysis showed a strong significant association (χ2 = 23.57; df = 11; p = 0.015) between the study years. The Principal Component Analysis (PCA) results suggest that Bulinus infectivity within the Ase River catchment area was primarily associated with the months of February and January. B. truncatus consistently had the highest transmission potential, followed by B. globosus and B. senegalensis. ANOVA confirms that the monthly/study site infectivity and transmission potential in B. truncates, B. globosus and S. senegalensis were statistically, significant (P < 0.05). These results demonstrated a clear distinction in the patterns and relationships between the different months in terms of snail infectivity and seasonal transmission potential. This understanding will help in the continuous monitoring and targeted interventions to control schistosomiasis transmission in Ase River.

GABAergic effects on the slow oscillatory neural activities in the procerebrum of Limax valentianus. Short communication.

We examined GABAergic modulation on "slow" oscillation (<1.0 Hz) of the procerebrum in the terrestrial mollusk, Limax valentianus. Short application of GABA-receptor agonists slightly increased the frequency of a periodic oscillation in the procerebrum, whereas persistent application decreased it. GABA-receptor antagonists decreased the oscillatory frequency. The GABA-like immunoreactivities were found in the neuropil and the cell body layers of the procerebrum. Because GABAergic inhibition is known to be essential for the generation of "fast" synchronous neuronal oscillation in the CNSs in othre many animals, our present findings are first evidence suggesting that GABA modulates 'slow' oscillation in the CNS.

Analysis of DNA endoreplication in the brain neurons in the terrestrial slug, Limax valentianus.

DNA endoreplication is the DNA synthesis without cell division, resulting in the generation of a nucleus containing a larger amount of genomic DNA compared to a normal diploid genome. There are many such giant neurons in the molluscan brain that are generated as a result of repeated endoreplication. However, it has been controversial whether the endoreplication is the whole genome replication (polyploidy) or the local amplification of the genes that are necessary for the neuron's function (polyteny/polysomy). Here in this study, we investigated these two possibilities by (1) immunohistochemical analysis of the distribution of 5'-bromodeoxyuridine incorporated into the nuclei of the brain neurons, and by (2) quantitative genomic PCR directed to two different genes expressed in specific brain regions. Our data supported the view that the DNA endoreplication is the whole genome replication rather than the local amplification of a specific genomic region.

Mathematical analysis of the honeybee waggle dance.

A honeybee informs her nestmates of the location of a flower by doing a waggle dance. The waggle dance encodes both the direction of and distance to the flower from the hive. To reveal how the waggle dance benefits the colony, we created a Markov model of bee foraging behavior and performed simulation experiments by incorporating the biological parameters that we obtained from our own observations of real bees as well as from the literature. When two feeders were each placed 400 m away from the hive in different directions, a virtual colony in which honeybees danced and correctly transferred information (a normal, real bee colony) made significantly greater numbers of successful visits to the feeders compared to a colony with inaccurate information transfer. Howerer, when five feeders were each located 400 m from the hive, the inaccurate information transfer colony performed better than the normal colony. These results suggest that dancing's ability to communicate accurate information depends on the number of feeders. Furthermore, because non-dancing colonies always made significantly fewer visits than those two colonies, we concluded that dancing behavior is beneficial for hives' ability to visit food sources.

Insulin and memory in Lymnaea.

The pond snail, Lymnaea stagnalis, is capable of learning conditioned taste aversion (CTA) and consolidating this CTA into long-term memory (LTM). The DNA microarray experiments showed that some of molluscan insulin-related peptides (MIPs) were up-regulated in snails exhibiting CTA-LTM. On the other hand, the electrophysiological experiments showed that application of secretions from the MIPs-containing cells evoked long-term potentiation (LTP) at the synapses between the cerebral giant cell (a key interneuron for CTA) and the B1 motoneuron (a buccal motoneuron). We thus hypothesized that MIPs and MIP receptors play an important role at the synapses, probably underlying the CTA-LTM consolidation process. To examine this hypothesis, we applied the antibody, which recognizes the binding site of mammalian insulin receptors and is thought to cross-react MIP receptors, to the Lymnaea CNS. Our present data showed that an application of the antibody for insulin receptors to the isolated CNS blocked LTP, and that an injection of the antibody into the Lymnaea abdominal cavity inhibited LTM consolidation, but not CTA formation.

High-pressure synthesis of the cubic perovskite BaRuO3 and evolution of ferromagnetism in ARuO3 (A = Ca, Sr, Ba) ruthenates.

The cubic perovskite BaRuO(3) has been synthesized under 18 GPa at 1,000 degrees C. Rietveld refinement indicates that the new compound has a stretched Ru-O bond. The cubic perovskite BaRuO(3) remains metallic to 4 K and exhibits a ferromagnetic transition at T(c) = 60 K, which is significantly lower than the T(c) approximately = 160 K for SrRuO(3). The availability of cubic perovskite BaRuO(3) not only makes it possible to map out the evolution of magnetism in the whole series of ARuO(3) (A = Ca, Sr, Ba) as a function of the ionic size of the A-site r(A,) but also completes the polytypes of BaRuO(3). Extension of the plot of T(c) versus r(A) in perovskites ARuO(3) (A = Ca, Sr, Ba) shows that T(c) does not increase as the cubic structure is approached, but has a maximum for orthorhombic SrRuO(3). Suppressing T(c) by Ca and Ba doping in SrRuO(3) is distinguished by sharply different magnetic susceptibilities chi(T) of the paramagnetic phase. This distinction has been interpreted in the context of a Griffiths' phase on the (Ca Sr)RuO(3) side and bandwidth broadening on the (Sr,Ba)RuO(3) side.

Retinoic acid-inducible gene-I (RIG-I) is induced by IFN-{gamma} in human mesangial cells in culture: possible involvement of RIG-I in the inflammation in lupus nephritis.

Interferon-gamma is a potent Th1-type cytokine and a key molecule in the pathogenesis of autoimmune diseases including lupus nephritis. Retinoic acid-inducible gene-I is a putative RNA helicase that plays an important role in immune and inflammatory reactions. We previously demonstrated the increased expression of the retinoic acid-inducible gene-I protein in the kidney tissue of patients with lupus nephritis, and the presence of a significant amount of retinoic acid-inducible gene-I mRNA in the urinary sediment of patients with this inflammatory renal disease. In the present study, interferon-gamma was found to induce the expression of retinoic acid-inducible gene-I in human mesangial cells in culture. Knockdown of retinoic acid-inducible gene-I inhibited the interferon-gamma-induced upregulation of interferon regulatory factor 7, a transcriptional factor involved in immune and inflammatory reactions. These findings suggest that retinoic acid-inducible gene-I produced by mesangial cells may be involved in the pathogenesis of lupus nephritis.

CD24 gene exon 2 dimorphism does not affect disease susceptibility in Japanese sarcoidosis patients.

BACKGROUND: CD24 proteins are expressed on several inflammatory cells, and play an important role for the T-cell activation. OBJECTIVES: The aim of this study is to investigate the relationship of a CD24 gene polymorphism to disease susceptibility or clinical findings including bronchoalveolar lavage (BAL) cell profiles in Japanese sarcoidosis patients. METHODS: A previously reported functional single nucleotide polymorphism (SNP) of CD24 gene exon 2 was examined in 186 Japanese sarcoidosis patients and 146 sex and age-matched healthy controls using restriction fragment length polymorphism method. The distribution of genotypes was compared between the two groups. The association between genotypes or alleles and clinical features or BAL cell profiles was also examined. RESULTS: There were no significant differences in the distribution of genotypes or allele frequencies between sarcoidosis and controls. There were also no significant differences in clinical features or BAL cell profiles among patients with different genotypes of CD24. CONCLUSIONS: There was no relationship between a CD24 exon 2 SNP and disease susceptibility or clinical findings in Japanese sarcoidosis patients.

Synchrotron Infrared Absorbance Measurements of Hydrogen in MgSiO3 Perovskite.

Micro-infrared spectroscopic measurements on single crystals of MgSiO(3) perovskite document two pleochroic hydroxyl absorbance peaks at 3483 and 3423 centimeter(-1). These measurements were obtained with the use of a synchrotron infrared source for spectroscopy. These data are consistent with a trace hydrogen content of 700 +/- 170 hydrogen atoms per 10(6) silicon atoms in the nominally anhydrous MgSiO(3) perovskite. When integrated over the volume of the lower mantle, this concentration is comparable to 12 percent of the mass of hydrogen in the Earth's hydrosphere.

Negative Pressure-Temperature Slopes for Reactions Formign MgSiO3 Perovskite from Calorimetry.

A new and sensitive differential drop solution calorimetric technique was developed for very small samples. A single experiment using one 5.18-milligram sample of perovskite, synthesized at 25 gigapascals and 1873 Kelvin, gave 110.1 +/- 4.1 kilojoules per mole for the enthalpy of the ilmenite-pervoskite transition in MgSiO(3). The thermodynamics of the reaction of MgSiO(3) (ilmenite) to MgSiO(3) (perovskite) and of Mg(2)SiO(4) (spinel) to MgSiO(3) (pervoskite) and MgO (periclase) were assessed. Despite uncertainties in heat capacity and molar volume at high pressure and temperature, both reactions clearly have negative pressure-temperature slopes, -0.005 +/- 0.002 and -0.004 +/- 0.002 gigapascals per Kelvin, respectively. The latter may be insufficiently negative to preclude whole-mantle convection.

Elasticity of MgSiO3 in the Perovskite Structure.

The single-crystal elastic moduli of MgSiO(3) in the perovskite structure, the high-pressure polymorph of MgSiO(3) pyroxene, have been determined. The data indicate that a mantle with either pyrolite or pyroxene stoichiometry is compatible with the seismic models appropriate to the earth's lower mantle, provided that the shear modulus of MgSiO(3) perovskite exhibits a strong negative temperature derivative. Such a temperature derivative falls outside of the range expected for a well-behaved refractory ceramic and could result if the pressure-temperature regime of the earth's lower mantle is near that required for a ferroelastic phase transformation of the perovskite phase.

Soluble beta-amyloid induction of Alzheimer's phenotype for human fibroblast K+ channels.

Although beta-amyloid is the main constituent of neurite plaques and may play a role in the pathophysiology of Alzheimer's disease, mechanisms by which soluble beta-amyloid might produce early symptoms such as memory loss before diffuse plaque deposition have not been implicated. Treatment of fibroblasts with beta-amyloid (10 nM) induced the same potassium channel dysfunction previously shown to occur specifically in fibroblasts from patients with Alzheimer's disease--namely, the absence of a 113-picosiemen potassium channel. A tetraethylammonium-induced increase of intracellular concentrations of calcium, [Ca2+]i, a response that depends on functional 113-picosiemen potassium channels, was also eliminated or markedly reduced by 10 nM beta-amyloid. Increased [Ca2+]i induced by high concentrations of extracellular potassium and 166-picosiemen potassium channels were unaffected by 10 nM beta-amyloid. In Alzheimer's disease, then, beta-amyloid might alter potassium channels and thus impair neuronal function to produce symptoms such as memory loss by a means other than plaque formation.