Association of the GNAS1 gene variant with hypertension is dependent on alcohol consumption.

The beta-adrenoceptor (beta-AR)-stimulatory guanine nucleotide-binding (Gs) protein system has been shown to play important roles in the cardiovascular system. The gene encoding the alpha-subunit of Gs proteins (GNAS1) is a candidate genetic determinant for hypertension. Because alcohol consumption is known to affect blood pressure partly through the beta-AR-Gs protein system, we examined the possible interaction between GNAS1 T393C polymorphism and drinking status in the association with hypertension in the present study. As a result, a non-significant but reasonable trend supporting the presence of an interaction was shown (p = 0.076). In line with this trend, the T393C polymorphism significantly interacted with drinking status in the association with systolic blood pressure (p = 0.028). Moreover, supporting the presence of an interaction, T allele carriers consistently had a higher probability of hypertension, higher systolic blood pressure, and higher diastolic blood pressure than CC homozygotes in non-drinkers and light drinkers. In contrast, CC homozygotes consistently had a higher probability of hypertension, higher systolic blood pressure, and higher diastolic blood pressure than T allele carriers in moderate to heavy drinkers. The present study also showed a significant interaction between the T393C polymorphism and drinking status in the association with pulse pressure (p = 0.026), reflected by a significant association between the T393C polymorphism and pulse pressure in moderate to heavy drinkers (p = 0.026). These findings may be helpful in conducting further molecular and biological studies on the relationship among the effects of alcohol, the beta-AR-Gs protein system, and hypertension.     

Migraine is associated with enhanced arterial stiffness.

Migraine is a common subtype of headache. Epidemiological studies have revealed that migraine could be an independent risk factor for ischemic stroke even in elderly subjects. Arterial stiffness is one of the major pathophysiological bases of stroke. In the present study, we cross-sectionally investigated the possible relationship between migraine and arterial stiffness in community-dwelling subjects. The study subjects were independently recruited from two sources (Group A, n=134, 68+/-5 years; Group B, n=138, 68+/-7 years). Augmentation index (AI), the ratio of augmented pressure by the reflection pressure wave to the pulse pressure, was obtained from the radial arterial waveform as an index of arterial stiffness. Brachial blood pressure was also measured simultaneously. Migraine was diagnosed using a previously validated questionnaire. The prevalence of migraine was 5.2% (Group A) and 16.7% (Group B). Subjects with migraine had higher radial AI in both Group A (migraine, 101+/-15%; other headache, 88+/-12%; no headache, 86+/-12%, p=0.003) and Group B (95+/-11%, 90+/-11%, 91+/-14%, p=0.058). Multiple linear regression analysis revealed that migraine was an independent determinant of AI (beta=0.154, p=0.002) after adjustment for other confounding factors: age (beta=-0.024, p=0.654); sex (beta=0.141, p=0.069); body height (beta=-0.215, p=0.005); systolic blood pressure (beta=0.174, p=0.001); medication for hypertension, hyperlipidemia, and diabetes mellitus (beta=-0.014, p=0.787); and heart rate (beta=-0.539, p<0.001). In a separate analysis by sex, migraine was also a significant determinant for AI (male, beta=0.246, p=0.019; female, beta=0.159, p=0.008). Migraine in the elderly could be a clinical manifestation of enhanced arterial stiffness.     

Phenotypic and Genotypic Lineage Switch of a Lymphoma with Shared Chromosome Translocation and T-Cell Receptor γ Gene Rearrangement

A case of non-Hodgkin's lymphoma showed a phenotypic and genotypic cell lineage switch twice during nine years of his clinical history; first, T-cell type, pleomorphic small cell lymphoma developed, followed by B-cell type, diffuse centroblastic/centrocytic lymphoma, and finally T-zone lymphoma without follicles again developed, from which AST-1 cultured cell line was established. Karyotype analysis demonstrated a shared abnormal chromosome, der(1)t(1;?)(p36;?), among the first relapsed B-cell tumor, the second relapsed T-cell tumor and AST-1 cell line. Furthermore, T-cell receptor (TCR) γ gene rearrangement bands of the same size were observed in the first relapsed B-cell tumor and the second relapsed T-cell tumor as well as AST-1 cell line. These results suggested that both relapsed tumors of different cell lineages are derived from a common malignant clone, presumably a committed lymphoid stem cell. A unique translocation, t(2;14)(q37;q11.2), which may involve TCR δ/α gene complex, was observed in the second relapsed tumor and AST-1 cells. To attempt to isolate the breakpoint of this translocation, the configuration of TCR δ/α gene complex was studied. The result showed that two rearrangements of TCR α gene detected with J_α probes were the products of the normal TCR rearrangement process, and were not involved in the translocation at this region. This patient, together with the AST-1 cell line, provided us a unique opportunity to study the development and clonal evolution of malignant lymphoma.     

Experience with cefuzonam in the field of obstetrics and gynecology

Cefuzonam (CZON, L-105) was studied clinically in the field of obstetrics and gynecology, and the results obtained are summarized below: 1. The concentration of the drug in blood decreased rapidly after drip infusion was completed, and the concentration diminished after 1 hour to one tenth of the level detected at 5-9 minutes, and to an almost undetectable level after 3 hours. The rapid decrease of blood concentrations appears to indicate that the excretion of CZON was much faster than other antibiotics. No conclusive data were obtained on changes of concentrations with time in tissues due to the small number of cases analyzed and scattering of the data obtained. 2. The concentration in the pelvic dead space exudate reached a peak of 18.5 micrograms/ml at 30 minutes after the end of infusion and decreased to 0.092 microgram/ml after 10 hours. 3. CZON was administered to 5 cases of obstetric and gynecological infections. The efficacy was good in 4 cases and poor in 1 case. No side effects or laboratory test abnormalities were observed.     

Activity-dependent survival and enhanced turnover of calcium in cultured rat cerebellar granule neurons

Neurons survive when their activity is maintained. An influential hypothesis on the cellular mechanism underlying this phenomenon is that there is an appropriate range of intracellular Ca²⁺ concentration ([Ca²⁺]i) for survival. The rat cerebellar granule neuron in culture serves as the most often used model system for the analysis of activity-dependent survival, since it does not survive unless an excitant (KCl or glutamate) is added to the culture medium. Against the above-mentioned hypothesis, we found in our previous examination no difference between steady-state [Ca²⁺]i in granule neurons cultured under high KCl (i.e., survival) and low KCl (i.e., death) conditions. In this report, we present the quantitative background of unchanged [Ca²⁺]i between the two culture conditions. Influx of Ca²⁺ due predominantly to L-type voltage-dependent calcium channels was higher in high KCl cultures than in low KCl cultures. At the same time, efflux of Ca²⁺ due to the activity of Ca²⁺/Na⁺ antiport was also higher in high KCl cultures. Additionally, we found that the endocytotic activity was greater in high KCl cultures than in low KCl cultures, as monitored by the rate of uptake of horseradish peroxidase added to medium. Since the uptake was blocked by an internal Ca²⁺ chelator, the increased endocytotic activity in high KCl cultures might be a consequence of the enhanced Ca²⁺ turnover.     

Transcriptome analysis of hagfish leukocytes: a framework for understanding the immune system of jawless fishes

Jawless fishes occupy a critical phylogenetic position in understanding the origin of the adaptive immune system. Here, we performed large-scale expressed sequence tag analysis of leukocytes isolated from the inshore hagfish Eptatretus burgeri. Although we found many immunity-related genes such as those involved in lymphocyte or hematopoietic cell signaling and development as well as cytokine and cytokine receptor genes, MHC molecules or antigen receptors were not identified. We characterized two hagfish cDNAs that closely resembled mammalian proteins with essential roles in adaptive immunity, one encoding a GATA3-like molecule and another encoding a Bruton's tyrosine kinase (Btk)-like molecule. The GATA3-like gene of hagfish was equidistant from GATA3 and GATA2 in jawed vertebrates. Similarly, the hagfish Btk-like molecule was not Btk itself, but qualified as a pre-duplicated form of Btk and Bmx in jawed vertebrates. In total, our work provides circumstantial evidence that adaptive immunity is unique to jawed vertebrates.     

Effects of short-term pulmonary rehabilitation on exercise capacity and quality of life in patients with chronic obstructive pulmonary disease

Although the rehabilitation of patients with chronic obstructive pulmonary disease (COPD) improves both exercise capacity and quality of life, a standard protocol for COPD patients has not been established. To clarify whether physiologic and quality-of-life improvements can be achieved by an inpatient pulmonary rehabilitation program 5 days per week for 3 weeks, 18 patients with COPD were enrolled in a rehabilitation program. The physical exercise training regimen consisted of respiratory muscle stretch gymnastics and cycle ergometer exercise training. Pulmonary function tests, an incremental ergometer exercise test, a 6-min walking test, and a quality of life assessment by the Chronic Respiratory Questionnaire were administered before and after the program. The peak VO2, an indicator of maximal exercise capacity, did not increase, although the 6-min walking distance, an indicator of functional exercise capacity, increased significantly after rehabilitation. There was a significant improvement in the quality of life in terms of dyspnea, fatigue, and emotional state. These findings suggest that even a 3-week program may be beneficial for COPD patients. Increases in functional exercise capacity, even without an increase in maximal exercise capacity, are helpful for reducing dyspnea and improving quality of life parameters in patients with COPD.     

ABC proteins: key molecules for lipid homeostasis

Forty-nine ABC protein genes exist on human chromosomes. Eukaryotic ABC proteins were originally recognized as drug efflux pumps involved in the multidrug resistance of cancer cells. However, it is now realized that one of their major physiological roles is cellular lipid transport and homeostasis, and their dysfunction is often associated with human diseases. ABCA1 and ABCA7 mediate the apolipoprotein-dependent formation of a high-density lipoprotein–cholesterol complex. ABCA3 is indispensable for pulmonary surfactant secretion. ABCG5 and ABCG8 are involved in the secretion of plant sterols and cholesterol into bile. However, the primary substrates and mechanism of action of these ABC proteins have not been precisely defined. In this review article, we first describe the general structure and functions of eukaryotic ABC proteins. The current model of ABCA1 functionality is then explained based on studies on a topological model, subcellular localization, apoA-I dependence of HDL formation, functional defects of Tangier disease mutants, and ATP hydrolysis of purified ABCA1. ABCA1 is supposed to function as a transporter of lipids as well as a receptor for apoA-I. ABCA3 is likely involved in accumulating phospholipids and cholesterol in lamellar bodies and in generating multivesicular structures.     

Caenorhabditis elegans RBX1 is essential for meiosis, mitotic chromosomal condensation and segregation, and cytokinesis

BACKGROUND: The RING-H2 finger protein RBX1 (ROC1/HRT1) is a common subunit of SKP1-CDC53/CUL1-F-box (SCF), other cullins and von Hippel-Lindau (VHL) tumour suppressor E3 ubiquitin ligase complexes. RBX1 protein sequences are highly conserved in various species, including yeasts, Drosophila melanogaster, mice and humans. In Saccharomyces cerevisiae, RBX1 is essential for the G1/S transition. RESULTS: Caenorhabditis elegans RBX1 is strongly expressed in early embryos and in the gonad, including meiotic cells. Depletion of RBX1 by RNA-mediated interference (RNAi) caused pronounced defects in the first meiotic division. Several irregular phenotypes were identified in embryos that escaped from meiotic arrest: defects in mitotic chromosomal condensation and segregation, abnormal chromosome bridges, giant nuclei, abnormal cortical protrusion, multinucleate cells and defects in germ cell proliferation. Moreover, histone H3 phosphorylation at Ser10 and Ser28 was significantly reduced in these embryos. The histone H3 phosphorylation defect of embryos was rescued by the additional depletion of protein phosphatase 1 (GLC7alpha/beta) by RNAi. CONCLUSION: These results indicate that the RBX1 protein participates in diverse functions relevant to chromosome metabolism and cell cycle control.