A novel integrin-linked kinase-binding protein, affixin, is involved in the early stage of cell-substrate interaction.

Focal adhesions (FAs) are essential structures for cell adhesion, migration, and morphogenesis. Integrin-linked kinase (ILK), which is capable of interacting with the cytoplasmic domain of beta1 integrin, seems to be a key component of FAs, but its exact role in cell-substrate interaction remains to be clarified. Here, we identified a novel ILK-binding protein, affixin, that consists of two tandem calponin homology domains. In CHOcells, affixin and ILK colocalize at FAs and at the tip of the leading edge, whereas in skeletal muscle cells they colocalize at the sarcolemma where cells attach to the basal lamina, showing a striped pattern corresponding to cytoplasmic Z-band striation. When CHO cells are replated on fibronectin, affixin and ILK but not FA kinase and vinculin concentrate at the cell surface in blebs during the early stages of cell spreading, which will grow into membrane ruffles on lamellipodia. Overexpression of the COOH-terminal region of affixin, which is phosphorylated by ILK in vitro, blocks cell spreading at the initial stage, presumably by interfering with the formation of FAs and stress fibers. The coexpression of ILK enhances this effect. These results provide evidence suggesting that affixin is involved in integrin-ILK signaling required for the establishment of cell-substrate adhesion.

Differences and relationships between residual volumes measured on land and in water calculated from estimate equations.

AIM: Residual volume error influences percent body fat estimated by hydrostatic. The aim of this study was to examine the differences and relationships between the residual volumes measured on land and in water and calculated from estimate equations developed in previous studies. PARTICIPANTS: 20 males and 20 females, aged 18-25 years, participated in this study. SETTING: the residual volumes on land and in water without submerging their head were measured twice in each setting. In addition, the residual volume was calculated from 6 estimate equations developed in previous studies. RESULTS: Residual volumes measured on land and in water have very good trial-to-trial reliabilities (intraclass correlation coefficients: <0.98), and high relationships, and did not show a significant difference. It is inferred that their difference is approximately 500 mL, being larger than trial-to-trial error. If we attach great importance to practicability rather than the above error, the residual volume on land can be used. There were no significant differences between measured volumes and those estimated by equation 5 in males and all equations except equation 6 in females. The relationships between measured and estimated residual volumes were poor in males except for equation 4, but were fair in females. Trial-to-trial reliability of residual volumes measured on land and in water is very good, and they have insignificant differences and high relationships. CONCLUSION: Of 6 estimate equations, equation 4 calculated from vital capacity has high accuracy in both sexes.

Comparison of force-time parameters and EMG in static explosive gripping by various exertion conditions: muscle fatigue state and submaximal exertion.

AIM: The purpose of this study was to compare the exertion and electromyography (EMG) properties during the developmental phase (DFmax) in static explosive grip (SEG), rapid submaximal exertion grip, namely fake SEG exertion (FAKE), and SEG in a muscle fatigue state. METHODS: Thirty healthy males and females performed the SEG and FAKE exertions (50% and 75% of peak value as a target value). Then, they performed sustained repeated rhythmic grip for 6 min (30 times x min(-1)), and SEG after 1-min, 4-min, and 7-min (SEG after the exertion). EMG was measured concurrently to compare with the muscle activation property during each grip exertion. Eight force-time parameters evaluating the DFmax in addition to the peak value were selected. RESULTS: The peak value significantly decreased, and the mean power spectrum density shifted to the low-wave in SEG after the exertion as compared with before. Therefore, SEG after the exertion was judged to be a muscle fatigue state. In addition, because the frequency properties in each exertion differed, the muscle activation properties during their DFmaxs were considered to differ. From the comparison between SEG before and after the exertion and FAKE, it is suggested that the time of reaching the peak value and the relative muscle strength when reaching an inflection point are not useful as parameters to evaluate the explosive muscle function during SEG. CONCLUSIONS: The maximal increasing volume during the DFmax and integrated area until 0.25 and 0.5 s could discriminate a difference of the DFmaxs according to each exertion and they are useful parameters.

The characteristics of simple muscle power by gripping: gender differences and reliability of parameters using various loads.

AIM: There are few studies on muscle power during local muscle contractions with a small range of motion such as in gripping. The purposes of this study were to clarify the properties of the developmental phase based on time series of muscle power output, the reliability of the parameters, their relationships and the load intensity derived peak power by gender differences, and to examine the possibility of evaluating muscle power using gripping. METHODS: Fifteen young males and 15 females participated in this study. Based on a crossover experimental design, each subject carried out 2 explosive grips at 20%, 30%, 40% and 50% loads of maximal using a voluntary grip contraction (MVC). The grip contraction velocities, sampled at 100 Hz, were measured accurately using a power instrument with an accelerometer. Muscle power curves were drawn from the product of the velocity and the set-up load. RESULTS: The cross-correlation coefficients between the trials for the average curve of the time-series moving distance, the velocity, and the power in any load were very high (over 0.95) in both genders. The reliability of each parameter was mostly good in both genders (intraclass correlation coefficient, ICC>0.75). The peak power curve differed between genders, and the curve around the peak value in females was irregular. CONCLUSIONS: A gender difference was found in the maximal power and the properties of the power curve. The maximal muscle power appeared at 30-50% MVC in males, and at 20-40% MVC in females. The peak power during the whole contraction, and the time to peak may reflect the conditions throughout the whole of the contraction. The new device used in this study to evaluate local regional muscle power (grip) is a very reliable and useful tool.

Zinc regulates the function and expression of the iron transporters DMT1 and IREG1 in human intestinal Caco-2 cells.

Trace metals influence the absorption of each other from the diet and it has been suggested that the divalent metal transporter (DMT1) represents a common uptake pathway for these important micronutrients. However, compelling evidence from our laboratory suggests that DMT1 is predominantly an iron transporter, with lower affinity for other metals. Several studies have shown that increasing dietary iron downregulates DMT1. Interestingly, our current data indicate that zinc upregulates DMT1 protein and mRNA expression and also pH-dependent iron uptake. Transepithelial flux of iron was also increased and was associated with a rise in IREG1 mRNA expression.

Regional cerebral blood flow difference between dementia with Lewy bodies and AD.

The authors studied 14 patients with dementia with Lewy bodies (DLB), 14 patients with AD, and 14 healthy control subjects with N-isopropyl-p-[123I]iodoamphetamine SPECT. Comparison with the statistical parametric mappings revealed that relative cerebral blood flow was lower in the occipital lobes and higher in the right medial temporal lobe in the DLB group than in the AD group. Decreased occipital perfusion and relatively well preserved medial temporal perfusion are features that distinguish DLB from AD.

Regional cerebral glucose metabolism in dementia with Lewy bodies and Alzheimer's disease.

OBJECTIVE: To delineate the features of regional cerebral metabolic rate of glucose (CMRglc) in dementia with Lewy bodies (DLB). METHODS: We compared absolute CMRglc in 12 patients with a clinical diagnosis of DLB, 12 patients with a clinical diagnosis of Alzheimer's disease (AD), and 12 normal volunteers (NC), using 18F-fluorodeoxyglucose (FDG) and PET. The three groups were matched for age and sex, and there were no differences in disease duration or severity of cognitive disturbances between the DLB and AD groups. RESULTS: CMRglc was significantly lower in patients with DLB than in that of NC in most parts of the brain, except the sensorimotor cortices, basal ganglia, thalamus, and pons. Between the DLB and AD groups, there were significant regional CMRglc differences in the medial and lateral occipital lobes. In DLB and AD, the CMRglc reduction patterns were similar, though the global metabolic reduction was larger in DLB, and the occipital CMRglc reduction in DLB could differentiate DLB from AD. The relative occipital CMRglc (normalized to the sensorimotor CMRglc) was a useful measure for the differential diagnosis of DLB from AD. The sensitivity and the specificity were 92% when using the minimal value of the normalized occipital CMRglc in the NC group as the cut-off point. CONCLUSION: These different regional CMRglc reductions substantiate the pathologic, neurochemical, and clinical differences between DLB and AD.

Reduction of cerebellar glucose metabolism in advanced Alzheimer's disease.

UNLABELLED: Although regional cerebral metabolism and blood flow in Alzheimer's disease (AD) have been studied extensively with PET and SPECT, few reports have been concerned with cerebellar metabolism or perfusion in Alzheimer's disease. To evaluate cerebellar glucose metabolism in Alzheimer's disease patients, we studied the cerebellar and cerebral metabolic rate for glucose (CMRglc) using 2[18F]fluoro-2-deoxy-D-glucose (18F-FDG) and PET. METHODS: Sixty-eight patients with Alzheimer's disease and 13 age-matched normal control subjects were examined. According to scores obtained on the Mini-Mental State Examination (MMSE), Alzheimer's disease patients were classified into three groups: severe (n = 9), moderate (n = 33) and mild (n = 26). RESULTS: The cerebellar glucose metabolism in the severe Alzheimer's disease group was significantly lower (cerebellar glucose metabolism: 5.71 +/- 0.62 mg/100 g/min) than that of the control group (6.85 +/- 0.66 mg/100 g/min), while temporal and parietal CMRglc were much more decreased. The cerebellar glucose metabolism in the mild and moderate Alzheimer's disease groups also showed lower levels than that of the control group, but the differences did not reach significant levels. Like other cortical CMRglc, the cerebellar glucose metabolism correlated with cognitive impairments. CONCLUSION: In severe Alzheimer's disease, cerebellar glucose metabolism is significantly reduced. The method of analysis using normalization of regional metabolic data to cerebellar values may be liable to err in severe Alzheimer's disease patients.

Changes in cerebral blood flow and oxygen metabolism related to magnetic resonance imaging white matter hyperintensities in Alzheimer's disease.

UNLABELLED: We studied changes in cerebral perfusion and oxygen metabolism to elucidate the pathophysiological nature and clinical significance of white matter hyperintensities in Alzheimer's disease (AD). METHODS: Sixteen AD patients (age 71.6 +/- 3.1 yr) whose T2-weighted MR images showed white matter hyperintensities, and 16 age-matched AD patients (age 71.0 +/- 4.3 yr) without white matter hyperintensities were compared. Regional cerebral blood flow (CBF), oxygen metabolism (CMRO2) and oxygen extraction fraction (OEF) were measured by using (15)O steady-state method and PET. RESULTS: There was no significant difference in cognitive impairment between the two groups. Compared to the patients without white matter hyperintensities, those with them had significantly low CBF values and significantly high OEF values in all cortical and white matter regions. However, there were no significant differences in CMRO2 values between the two groups. Severity of white matter hyperintensities correlated with the mean cortical and mean white matter OEF. CONCLUSION: In AD patients, white matter hyperintensities on T2-weighted MR images represent ischemic changes in which oxygen metabolism and function are fairly compensated. These changes are not disease-specific but are age-associated coincidences, as in normal aging with or without vascular risk factors.

Regional difference in cerebral blood flow and oxidative metabolism in human cortex.

UNLABELLED: We sought to determine if there are regional differences in cerebral blood flow (CBF) and cerebral metabolic ratio for oxygen (CMRO2) in normal subjects during the resting state. METHODS: Regional CBF, CMRO2 and oxygen extraction fraction (OEF) in 15 normal volunteers (mean age 58.8 +/- 8.2 yr) were measured during rest using PET and a 15O-gas steady-state technique. RESULTS: CBF and CMRO2 in the visual cortex were significantly higher than those in other cortices. Additionally, OEF in the sensorimotor cortex was significantly lower than that in other cortical regions. CONCLUSION: CBF and CMRO2 in the visual cortex are always high, and low OEF in the sensorimotor cortex exists even in resting state in normal subjects. We hypothesize that these regional functional differences would result in different resistances to degeneration.

Paradoxical hippocampus perfusion in mild-to-moderate Alzheimer's disease.

UNLABELLED: The purpose of this study was to clarify the changes in hippocampal perfusion in mild-to-moderate Alzheimer's disease using PET and (15)O-labeled water. METHODS: Sixteen patients with probable mild-to-moderate Alzheimer's disease (age: 68.1+/-11.3 yr; MMSE: 21.1+/-4.5) and 10 normal volunteers (age: 65.1+/-8.2 yr) were studied. Regional cerebral blood flow (CBF) and cerebral blood volume (CBV) were measured using (15)O-labeled water autoradiographic method, C(15)O-gas inhalation technique and PET. RESULTS: Although the mean CBF in the parietotemporal region was significantly lower in the patient group than in the control group, the mean CBF in the hippocampus did not show significant reduction between the two groups, both in absolute and relative values. There was no significant regional CBV difference between the two groups. Parietotemporal perfusion correlated well with cognitive scores, both in absolute and relative values, in Alzheimer's disease, but hippocampal perfusion did not correlate well. CONCLUSION: Hippocampal perfusion was preserved in mild-to-moderate Alzheimer's disease.

Cerebral glucose metabolism in patients with frontotemporal dementia.

UNLABELLED: Frontotemporal dementia (FTD) is a dementia syndrome characterized by peculiar behavioral changes arising from frontotemporal involvement and distinct from Alzheimer's disease (AD). The purpose of this study was to elucidate the specific patterns in cerebral glucose metabolism in patients with FTD and to compare them with the patterns in patients with AD and normal elderly subjects using fluorodeoxyglucose (FDG) and PET. METHODS: Twenty-one patients with a clinical diagnosis of FTD [mean age 67.0 +/- 7.0 yr, Mini Mental State Examination (MMSE) score 18.7 +/- 5.7], 21 age-, sex- and dementia-severity-matched patients with probable AD (mean age 66.9 +/- 7.1 yr, MMSE score 20.2 +/- 5.5) and 21 age- and sex-matched normal control subjects (mean age 66.8 +/- 5.7 yr) were studied. The cerebral metabolic rate for glucose (CMRglc) was measured with FDG and PET. Absolute measures of regional CMRglc were compared among the three groups. One-way ANOVA and the posthoc Tukey HSD test were used for statistical analyses. RESULTS: In the FTD group, CMRglc was preserved only in the left cerebellum, right sensorimotor area and occipital lobes. The CMRglc was significantly lower in the FTD group as opposed to the AD group in the hippocampi, orbital gyri, anterior temporal lobes, anterior cingulate gyri, basal ganglia, thalami, middle and superior frontal gyri and left inferior frontal gyrus. CONCLUSION: Although metabolic abnormality in FTD is predominant in the frontal and anterior temporal lobes and the subcortical structures, it is more widespread than has been previously stressed. These findings document an FTD-specific cerebral involvement and facilitate differential diagnosis of degenerative dementias.

Subcutaneous extramedullary hematopoiesis in a patient with secondary myelofibrosis following polycythemia vera.

We describe the case of a 73-year-old woman with secondary myelofibrosis who developed subcutaneous extramedullary hematopoiesis. Although extramedullary hematopoiesis has been generally observed in primary myelofibrosis, in this case it was seen in myelofibrosis secondary to polycythemia vera. Histological examination of the subcutaneous nodule revealed that the lesion included cells from the myeloid and megakaryocytic series. The skin lesion almost disappeared after treatment with hydroxyurea. We report here this rare manifestation in secondary myelofibrosis including a review of literature.

Diastereoselectivity controlled by electrostatic repulsion between the negative charge on a trifluoromethyl group and that on aromatic rings.

Intramolecular electrostatic repulsions between the local negative charge on a trifluoromethyl group and that on the ortho position of an aryl moiety of a nucleophile was found to be a controlling factor of the diastereoselectivity in a cyclopropanation reaction, in which the electrostatic repulsion was evaluated quantitatively.

Regional cerebral glucose metabolism in dementia with Lewy bodies and Alzheimer's disease: a comparative study using positron emission tomography.

Regional cerebral metabolic rate of glucose (rCMRglc) was studied in 19 patients with a clinical diagnosis of dementia with Lewy bodies (DLB) and 19 patients with a clinical diagnosis of Alzheimer's disease (AD), using [18F]fluorodeoxyglucose ([18F]FDG) and positron emission tomography (PET). The two groups were matched with age, gender, disease duration and severity of cognitive disturbances. In 'dementia with Lewy bodies' (DLB) patients, when compared with AD patients, significant rCMRglc decreases were distributed in the temporo-parieto-occipital association cortices and the cerebellar hemispheres. In contrast, the medial temporal and cingulate rCMRglc were significantly lower in AD patients than those in DLB patients. These different regional emphases of glucose hypometabolism are consistent with the pathological and neurochemical differences between DLB and AD and explain the different clinical features of the two diseases.

Effects of food intake and age on the pharmacokinetics of AS-924, a novel ester-type cephem antibiotic. Comparison with cefpodoxime proxetil.

The effects of food intake and age on intestinal absorption of AS-924, a novel prodrug-type cephem antibiotic, were examined in 16 healthy adult volunteers (eight young volunteers and eight elderly volunteers) by the cross-over method, using cefpodoxime proxetil (CPOD-PR) as the control drug. The gastrointestinal absorption of AS-924 and CPOD-PR was increased slightly by food intake and the extent of increase was slightly greater after administration of CPOD-PR. The absorption of AS-924 was not affected by age, whereas intestinal absorption of CPOD-PR increased with age. In conclusion, these results confirmed that AS-924 has the unique characteristics as a novel prodrug and that its absorption is less likely to be affected by food intake and age.

Effects of the quantity of water and milk ingested concomitantly with AS-924, a novel ester-type cephem antibiotic, on its pharmacokinetics.

The effect of the quantity of water ingested concomitantly with drugs, on the absorption of AS-924, a novel prodrug-type cephem antibiotic, was studied in five healthy adult volunteers by a cross-over method, using cefteram-pivoxil (CTER-PI) as the control drug. In addition, the effect of milk on the absorption of AS-924 was also investigated. The absorption of CTER-PI was significantly reduced when administered together with 30 ml of water compared with its absorption when administered together with 150 ml of water, whereas no such reduction was found in the case of AS-924. Ingestion of milk did not significantly affect the absorption of AS-924. These results confirm that absorption of AS-924 after oral administration is not likely to be affected by the quantity of water taken concomitantly with the drug, nor by milk.

Effect of antacid pretreatment on the pharmacokinetics of AS-924, a novel ester-type cephem antibiotic--comparison with cefteram-pivoxil.

The effect of pretreatment with ranitidine, an antacid, on the absorption of AS-924, a novel prodrug-type cephem antibiotic derived from ceftizoxime (CTIZ), was examined in eight healthy adult male volunteers by the cross-over method, using cefteram-pivoxil (CTER-PI) as the control drug. The C(max) and area under the concentration (AUC) values and cumulative urinary excretion rate (0-24 h) of cefteram (CTER) after administration of CTER-PI decreased by 32, 38 and 37%, respectively, in the ranitidine pretreatment group whereas those of AS-924 were not affected by the antacid. The urinary levels of pivaloyl-carnitine determined to evaluate the solubility of these antibiotics in the gastrointestinal tract suggested that this was not affected by ranitidine. These results indicate that the absorption of CTER-PI was affected by pretreatment with ranitidine largely due to inactivation of this antibiotic in the gastrointestinal tract at high pH rather than to a decrease in solubility. In contrast, isomerization of AS-924 was hardly induced by the elevation of pH, thus demonstrating that AS-924 was less likely to be affected by pretreatment with antacids.

Effects of gastrointestinal stimulant and suppressant pretreatment on the pharmacokinetics of AS-924, a novel ester-type cephem antibiotic.

The effects of pretreatment with the gastrointestinal stimulant domperidone and the suppressant scopolamine butylbromide on the absorption of AS-924, a novel prodrug-type cephem antibiotic, were investigated in six healthy adult male volunteers by a cross-over method. The T(max) of ceftizoxime (CTIZ), the active moiety of AS-924, was slightly prolonged by scopolamine butylbromide (T(max)=1.8 vs. 1.5 h for the group without pretreatment). However, there were no significant differences in pharmacokinetic parameters including T(max), cumulative urinary excretion rates of CTIZ and cumulative urinary excretion rates of pivaloylcarnitine for 12 h after the dosing between the pretreated and control groups. Domperidone did not affect the absorption of AS-924.

CSF spaces in idiopathic normal pressure hydrocephalus: morphology and volumetry.

PURPOSE: Idiopathic normal pressure hydrocephalus (NPH) is an important cause of dementia in the elderly; however, idiopathic NPH is often difficult to differentiate from normal aging and vascular dementias in which brain atrophy with ventricular dilatation (hydrocephalus ex vacuo or central atrophy) is present. To elucidate the distinctive features of the distribution of CSF in idiopathic NPH, we used MR imaging to investigate the morphologic features and volume of the CSF space in patients with idiopathic NPH compared with those with other dementias. METHODS: We assessed the size of four CSF compartments (the ventricle, basal cistern, sylvian space, and suprasylvian subarachnoid space) in 11 shunt-responsive patients with idiopathic NPH by semiquantitative and volumetric analyses of coronal T1-weighted MR images. The results were compared with those in 11 age- and sex-matched patients with Alzheimer disease and in 11 patients with vascular dementia. RESULTS: In patients with idiopathic NPH, the CSF volume was significantly increased in the ventricles and decreased in the superior convexity and medial subarachnoid spaces as compared with patients with other dementias. The sylvian CSF volume in patients with idiopathic NPH was significantly greater than in patients with Alzheimer disease. The volume of the basal cistern was comparable among the three groups. In several patients with idiopathic NPH, focally dilated sulci were observed over the convexity or medial surface of the hemisphere. CONCLUSION: Our results indicate that findings of enlarged basal cisterns and sylvian fissures and of focally dilated sulci support, rather than exclude, the diagnosis of shunt-responsive idiopathic NPH and suggest that this condition is caused by a suprasylvian subarachnoid block.