Molecular chaperone-mediated tau protein metabolism counteracts the formation of granular tau oligomers in human brain.

Intracellular accumulation of filamentous tau proteins is a defining feature of neurodegenerative diseases termed tauopathies. The pathogenesis of tauopathies remains largely unknown. Molecular chaperones such as heat shock proteins (HSPs), however, have been implicated in tauopathies as well as in other neurodegenerative diseases characterized by the accumulation of insoluble protein aggregates. To search for in vivo evidence of chaperone-related tau protein metabolism, we analyzed human brains with varying degrees of neurofibrillary tangle (NFT) pathology, as defined by Braak NFT staging. Quantitative analysis of soluble protein levels revealed significant positive correlations between tau and Hsp90, Hsp40, Hsp27, alpha-crystallin, and CHIP. An inverse correlation was observed between the levels of HSPs in each specimen and the levels of granular tau oligomers, the latter of which were isolated from brain as intermediates of tau filaments. We speculate that HSPs function as regulators of soluble tau protein levels, and, once the capacity of this chaperone system is saturated, granular tau oligomers form virtually unabated. This is expressed pathologically as an early sign of NFT formation. The molecular basis of chaperone-mediated protection against neurodegeneration might lead to the development of therapeutics for tauopathies. (c) 2007 Wiley-Liss, Inc.

Magnetic resonance analysis of abnormal diaphragmatic motion in patients with emphysema.

The purpose of this study was to quantitatively evaluate paradoxical diaphragmatic motion using magnetic resonance (MR) imaging. A total of 27 subjects were examined, including 12 normal young adults, six control individuals, and nine patients with emphysema. With subjects in the supine position, 30 sequential sagittal MR images of the entire right lung were obtained during tidal and deep slow breathing. Diaphragmatic movement between sequential images was estimated as the displacement area and the total diaphragmatic movement in a respiratory cycle was calculated. The paradoxical motion of the diaphragm, representing the inverted movement to increase or decrease lung area, since paradoxical movement ratio (Mpr=(total paradoxical diaphragmatic movement/total diaphragmatic movement)x100), was evaluated. In patients with emphysema, paradoxical diaphragmatic motion was observed on MR images during deep breathing. The mean Mpr in emphysematous patients during deep breathing was 10+/-4%, which was significantly higher than 0.5+/-0.2% in young adults (p<0.05), and 1.2+/-0.6% in aged-matched controls (p<0.05). The present results indicate that magnetic resonance images could be used to detect paradoxical diaphragmatic motion in patients with emphysema.

Formation of filamentous tau aggregations in transgenic mice expressing V337M human tau.

Formation of neurofibrillary tangles (NFTs) is the most common feature in several neurodegenerative diseases, including Alzheimer's disease (AD). Here we report the formation of filamentous tau aggregations having a beta-sheet structure in transgenic mice expressing mutant human tau. These mice contain a tau gene with a mutation of the frontotemporal dementia parkinsonism (FTDP-17) type, in which valine is substituted with methionine residue 337. The aggregation of tau in these transgenic mice satisfies all histological criteria used to identify NFTs common to human neurodegenerative diseases. These mice, therefore, provide a preclinical model for the testing of therapeutic drugs for the treatment of neurodegenerative disorders that exhibit NFTs.

New insights on how metals disrupt amyloid beta-aggregation and their effects on amyloid-beta cytotoxicity.

Amyloid-beta protein (A beta) aggregates in the brain to form senile plaques. By using thioflavin T, a dye that specifically binds to fibrillar structures, we found that metals such as Zn(II) and Cu(II) normally inhibit amyloid beta-aggregation. Another method for detecting A beta, which does not distinguish the types of aggregates, showed that these metals induce a non-beta-sheeted aggregation, as reported previously. Secondary structural analysis and microscopic studies revealed that metals induced A beta to make non-fibrillar aggregates by disrupting beta-sheet formation. These non-fibrillar A beta aggregates displayed much weaker Congo Red birefringence, and in separate cell culture experiments, were less toxic than self beta-aggregates, as demonstrated by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. The toxicity of soluble A beta was enhanced in the presence of Cu(II), which suggests the previously hypothesized role of A beta in generating oxidative stress. Finally, under an acidic condition, similar to that in the inflammation associated with senile plaques, beta-aggregation was robustly facilitated at one specific concentration of Zn(II) in the presence of heparin. However, because a higher concentration of Zn(II) virtually abolished this abnormal phenomenon, and at normal pH any concentrations strongly inhibit beta-aggregation and its associated cytotoxicity, including its anti-oxidative nature we suggest that Zn(II) has an overall protective effect against beta-amyloid toxicity.

The appeal cycle in three cultures: an exploratory comparison of child development.

Mother-child behaviors were studied in three cultural groups: Caucasian American (CA), overseas Japanese (JPN), and Chinese Vietnamese (CVN) immigrants. The children were sixteen to twenty-five months old, and the appeal cycle, with its descriptive analytic method, was the research paradigm. Group differences were found in appeal cycle occurrence and phase frequencies. CA mothers promoted independence through encouragement of decision making and toddler-initiated play, and through nonintrusive interactions. Neither JPN nor CVN mothers encouraged independence. JPN mothers were subtly directive; CVN mothers overtly so. Generally, CA toddlers played independently, evincing a beginning capacity for self-regulation. JPN and CVN toddlers reacted to separation by staying close to their mothers, and fewer were observed to play independently than in the CA group. CVN toddlers played independently more frequently than JPN toddlers, but less frequently than CA toddlers. Quantitative measures of dyadic behaviors generally support the descriptive findings, though methodological constraints did not permit comparison of phase sequencing. The findings reflect cultural differences in child development thought to influence psychic structure formation.

Paradoxical motion of the hemidiaphragm in patients with emphysema.

The authors evaluate paradoxical diaphragmatic motion using magnetic resonance (MR) imaging in patients with emphysema. The subjects were 12 healthy volunteers and 10 male patients with moderate to severe air flow obstruction. With subjects in the supine position, 30 sequential sagittal images of the bilateral lungs were obtained during quiet and forced breathing using a 1.5T MR unit with a body coil. The sequence was single shot fast spin echo (SSFSE) with half Fourier transformation. Subtraction images were made from the original images (by subtracting a given image from the preceding image), which visualized the chest wall motion as white or black bands on the edge of the lung fields. The authors evaluated both the original and subtraction images. MR imaging showed abnormal hemidiaphragmatic motion during forced breathing: the ventral portion of the hemidiaphragm moved downward while the dorsal part moved upward like a seesaw in 6 patients. MR images also revealed abnormal ribcage motion; the ventral ribcage moved anteriorly when the hemidiaphragm moved upward in 7 patients. No abnormal motion was observed in healthy volunteers. MR is a noninvasive and useful tool for evaluating the asynchronous respiratory motion in patients with emphysema.

Insufficient effectiveness of 5-hydroxytryptamine-3 receptor antagonists due to oral morphine administration in patients with cisplatin-induced emesis.

PURPOSE: To compare the effect of 5-hydroxytryptamine-3 (5HT(3)) receptor antagonists in cancer patients receiving chemotherapy including cisplatin (CDDP), with or without sustained-release oral morphine (MS Contin; Shionogi Co, Osaka, Japan). PATIENTS AND METHODS: We retrospectively studied 58 lung cancer patients given chemotherapy including at least 50 mg/m(2) CDDP with 5-HT(3) receptor antagonists between January 1996 and December 1997. Number of vomiting episodes, average proportions of hospital-supplied meals consumed (0 to 100%, as an index of appetite), and nausea severity scores (0 to 2 points, subjective patient judgment) were compared between oral morphine-administered (+) and morphine-free (-) groups. RESULTS: Sixteen morphine(+) and 42 morphine(-) cases were used. In cases of acute emesis (within 24 hours after CDDP injection), morphine(+) and morphine(-) groups were significantly different in number of vomiting episodes (1.25 and 0.14, respectively; P <.0001), appetite (58.13% and 90.24%; P <.0001), and nausea severity scores (1.63 and 0.62; P <.0001). In delayed-emesis cases (24 to 120 hours after CDDP), these groups differed significantly in number of vomiting episodes (1.94 and 0.43, respectively; P =.0001), appetite (23.13% and 52.08%; P <.0001), and nausea severity (1.38 and 0.91; P =.009). There were no significant differences in sex, age, anticancer drugs concurrent with CDDP, CDDP dose, corticosteroid administration, clinical stage, or type of 5-HT(3) antagonist. CONCLUSIONS: These data suggest that morphine can markedly reduce the effectiveness of 5-HT(3) receptor antagonists in patients receiving chemotherapy that includes CDDP. These results require confirmation by reinvestigation of clinical data on the efficacy of 5-HT(3) receptor antagonists and by extensive prospective analyses.

[Usefulness of bronchoscopy for the diagnosis of atypical pulmonary mycobacteriosis].

In 14 subjects whose chest radiographs showed abnormal shadows during the two years from January 1995 until December 1996, no definite diagnosis could be obtained because sputum, smears and cultures all gave negative results for mycobacteria. Bronchoscopy was therefore performed, revealing atypical mycobacteria in cultures of the bronchial washing fluid for mycobacteria, and the significance of bronchoscopic examinations in cases diagnosed an atypical pulmonary mycobacteriosis was investigated. Most of the subjects (9) were women. Nine subjects had been informed that they had abnormal chest shadows; five had subjective symptoms; bloody sputum, 3 and cough, 2. The characteristics of the shadows were as follows: in the plain radiographs, the main shadows had a mottled or granular appearance in the majority of the patients (9) and there were infiltrative shadows in 3 patients and nodular shadows in another 3. In computed tomograms, the shadows in the vicinity of the pleura appeared as micronodular conglomerates in 12 patients, in 11 of whom bronchiectasis was also present near the shadows. Alveolar infiltrative shadows were present in four cases, and a cavity was seen in only one. Smears of the bronchial washing fluid for mycobacteria were positive in 7 patients, and cultures of this fluid yielded at least 100 colonies in 8 of the 14 subjects for whom the results were positive. By culture, Mycobacterium avium complex (MAC) was identified in 13 patients, but eleven of these in whom the bronchial washing fluid was concurrently tested for MAC by the polymerase chain reaction, only four were MAC-positive. Transbronchial lung biopsies were performed in 11 cases, in which the histological findings of mycobacterial infections showed granuloma in four, and caseation in three. Bronchoscopy is making possible initial-stage diagnosis, which are normally difficult, among the recently growing number of cases of the bronchial form of atypical pulmonary mycobacteriosis and is also useful for reaching definite diagnosis in the early stage.

Normal in-plane respiratory motion of the bilateral hemidiaphragms evaluated by sequentially subtracted fast magnetic resonance images.

The purpose of this study was to demonstrate hemidiaphragmatic motion using magnetic resonance imaging. The subjects were 13 healthy, nonsmoking volunteers. The sequence consisted of a fast gradient-recalled echo for coronal images and a single-shot fast spin echo with half Fourier transformation for sagittal images. The coronal and sagittal acquisition times were 0.83 msec and 0.58 msec per image, respectively. Thirty sequential images were obtained during quiet, deep respiration. Two series of subtraction images were made from these original sequential images (a given image was subtracted from the preceding or the next image in the original series). Hemidiaphragmatic motion was visualized as white or black bands on subtraction images. In the coronal plane through the left ventricle, there was a difference in motion between the right and left hemidiaphragms in 10 subjects during tidal respiration and in 12 subjects during deep respiration. On the sagittal images, the dorsal part of the hemidiaphragm moved more rapidly during quiet, deep respiration, especially on the left side.

Effects of fenoterol on ventilatory response to hypercapnia and hypoxia in patients with chronic obstructive pulmonary disease.

BACKGROUND: It has previously been shown that fenoterol, a beta 2 adrenergic agonist, increases the ventilatory response to hypoxia (HVR) and hypercapnia (HCVR) in normal subjects. The effects of beta 2 adrenergic agonists on chemoreceptors in patients with chronic obstructive pulmonary disease (COPD) remain controversial. This study was designed to examine whether fenoterol increases the HVR and HCVR in patients with COPD. METHODS: The HCVR was tested in 20 patients using a rebreathing method and the HVR was examined using a progressive isocapnic hypoxic method. The HCVR and HVR were assessed by calculating the slopes of plots of occlusion pressure (P0.1) and ventilation (VE) against end tidal carbon dioxide pressure (PETCO2) and arterial oxygen saturation (SaO2), respectively. Spirometric values, lung volumes, and respiratory muscle strength were also measured. The HCVR and HVR were examined after the oral administration of fenoterol (15 mg/day) or placebo for seven days. RESULTS: Fenoterol treatment increased the forced expiratory volume in one second (FEV1) and inspiratory muscle strength. In the HCVR the slope of P0.1 versus PETCO2 was increased by fenoterol from 0.35 (0.23) to 0.43 (0.24) (p < 0.01). Moreover, the P0.1 at PETCO2 of 8 kPa was higher on fenoterol than on placebo (p < 0.05) and the VE was also greater (p < 0.01). In the HVR fenoterol treatment increased the P0.1 at 80% SaO2 from 0.90 (0.72) to 0.97 (0.55) kPa (p < 0.05) while the slopes of the response of P0.1 and VE were not changed. CONCLUSIONS: Fenoterol increases the ventilatory response to hypercapnia in patients with COPD, presumably by stimulation of the central chemoreceptor. The hypoxic ventilatory response is only slightly affected by fenoterol.

Effects of fenoterol on ventilatory responses to hypoxia and hypercapnia in normal subjects.

BACKGROUND: The effects of beta 2 adrenergic agonists on chemoreceptors remain controversial. This study was designed to examine whether fenoterol, a beta 2 adrenergic agonist, increases the ventilatory responses to hypercapnia (HCVR) and hypoxia (HVR) in normal subjects. METHODS: HCVR was tested with a rebreathing method and HVR was examined with a progressive isocapnic hypoxic method in 11 normal subjects. Both HCVR and HVR were assessed by the slope of occlusion pressure (P0.1) or ventilation (VE) plotted against end tidal carbon dioxide pressure and arterial oxygen saturation, respectively. Respiratory muscle strength, spirometric values and lung volume were measured. After a single oral administration of 5 mg fenoterol or placebo HCVR and HVR were evaluated. RESULTS: Fenoterol treatment did not change the specific airway conductance or forced expiratory volume in one second. Respiratory muscle strength did not change. Fenoterol increased the slope of the HCVR of both P0.1 (from 0.251 (0.116) to 0.386 (0.206) kPa/kPa, average increase 71%) and VE (from 10.7 (3.4) to 15.1 (4.2) l/min/kPa, average increase 52%), and shifted the response curves to higher values. For the HVR fenoterol increased the slopes of both P0.1 and VE (from -4.06 (2.00) x 10(-3) to -7.99 (4.29) x 10(-3) kPa/%, an average increase of 83%, and from -0.221 (0.070) to -0.313 (0.112) l/min/%, a 44.5% increase, respectively), and shifted the response curves to higher values. CONCLUSION: Acute administration of fenoterol increases the ventilatory responses to both hypercapnia and hypoxia in normal subjects.

Inspiratory muscle training and respiratory sensation during treadmill exercise.

We studied whether inspiratory muscle training (IMT) changed respiratory sensation during exercise in 12 healthy women; IMT was performed twice daily, for 15 minutes, using a pressure threshold device and continued for 4 weeks. The inspiratory threshold was set to 30 percent of each individual's maximal inspiratory pressure (Pimax). Breathing effort was evaluated during a progressive exercise test using Borg scale. After IMT, both Pimax and maximal transdiaphragmatic pressure increased by 30 percent in the training group (p < 0.05) but did not change in the control group. Prior to IMT, the Borg score increased in proportion to exercise grade. The difference in the sensory score-exercise stage curves before and after IMT in the training group was not significant. No significant difference was noted in the relationship of the Borg score to minute ventilation before and after 4 weeks in either group. We concluded that IMT may not affect respiratory sensation during exercise in normal subjects, although IMT increases diaphragmatic strength.

[A case of polymyositis associated with unusual CPK isoenzyme pattern and myocardial imaging].

A case of polymyositis (PM) associated with abnormal creatinine phosphokinase (CPK) isoenzyme pattern and Thallium-201 (Tl-201) myocardial imaging was reported. No such case has ever been reported in Japan. A 44-year-old female was admitted for evaluation of muscular weakness of proximal limbs and polyarthralgia. On laboratory examinations, the serum levels of CPK, aldolase and transaminase were markedly elevated. The electromyograms revealed a typical myogenic pattern. On the pathological findings, the principal changes in muscle tissue consisted of inflammatory cell infiltration. Based on those findings, she was diagnosed as having polymyositis. In our patient, there were three characteristics as following; (1) CPK-MB of CPK isoenzyme showed persistent high levels, (2) macro CPK in Electrophoresis of CPK was observed, (3) Tl-201 myocardial imaging revealed multifocal perfusion defects and localized defect in left ventricular inferior wall. She was started on therapy with prednisolone (30 mg/day). The clinical and laboratory manifestations were improved. Abnormal CPK isoenzyme pattern and myocardial imaging were also improved parallel with disease activity of PM. Thus, this case indicated the relation of the damage of skeletal muscle and cardial involvement in PM to unusual CPK isoenzyme pattern. Then wer reported this case.

Effects and mechanism of fenoterol on fatigued canine diaphragm.

We have studied the effects and mechanism of fenoterol (a beta 2-agonist) on contractility of the fatigued canine diaphragm. Transdiaphragmatic pressure (Pdi) was measured by a pair of balloons, and diaphragmatic contractility was assessed from changes in tetanic contraction, produced by supramaximal electrical stimulation of the phrenic nerves. Diaphragmatic fatigue was developed by applying an inspiratory resistive load to a spontaneously breathing dog for approximately 30 min. Fenoterol improved the Pdi of the fatigued canine diaphragm at all stimulation frequencies, and the increases in Pdi at low frequencies were greater. The potentiation of Pdi by fenoterol occurred in a dose-dependent manner with doses of 2.5 to 10 micrograms/kg and was equal to that of aminophylline. Dibutyryl cyclic AMP did not have significant effect on the Pdi at all stimulation frequencies. The augmentation of Pdi in the fatigued diaphragm by fenoterol was abolished by administration of a calcium antagonist, verapamil, and fenoterol did not change the diaphragmatic contractility in nonfatigued dogs. We thus have concluded that fenoterol improves contractility in the fatigued canine diaphragm and the effect might be brought about by an increased influx of calcium to the muscle cell.

A case of ACTH-producing pheochromocytoma.

A woman with sustained hypertension, facial roundness, hirsutism, marked sweating, and generalized tremor was found to have a right adrenal pheochromocytoma. Elevated levels of serum cortisol, plasma ACTH, and serum catecholamines returned to normal after the tumor was removed. It was confirmed that enzymatically dispersed tumor cells produced ACTH and catecholamines concomitantly during in vitro incubation.