Cortical functional abnormality assessed by auditory-evoked magnetic fields and therapeutic approach in patients with chronic dizziness

A long-lasting dizzy sensation is a common complaint in elderly subjects. The pathogenesis and effective treatment of such chronic dizziness (CD), however, have not yet been fully elucidated because of lack of methods for evaluating this sensation. On the basis of assumption that CD may be attributable partly to cortical functional abnormality, we attempted to estimate the function of auditory cortex by measurements of auditory-evoked magnetic fields (AEFs). Magnetic field signals in the parieto-temporal cortex were evoked by 1000-Hz tone-burst with 90-dB normal hearing level sounds, and the highest-amplitude magnetic waveforms at approximately 100-ms (N100m) were analyzed as electrical current arrows in normal subjects (n=11), patients with CD (n=27) and patients with cerebral infarction but no dizzy sensation (n=9). In the normal subjects, the current arrows pointed to a nearly straight line with small directional distortion as indicated by a rotation-degree parameter, dI(rot) of 1.59+/-0.46. In 17 of 27 CD patients, the directions of current arrows were markedly distorted showing abnormally high dI(rot) values greater than 2.50 (the mean plus two standard deviations of normal values) and disclosed a clockwise or counter-clockwise rotation in either side or both sides of parieto-temporal cortex. In all the patients with cerebral infarction, the current arrows exhibited the similar pattern as the normal subjects. None of them exhibited abnormally high dI(rot) values. We hypothesized that the rotational abnormality may be caused by abnormal neuronal excitation, since non-evoked magnetic fields in temporal lobe epilepsy demonstrated the similar current rotational abnormality as reported previously. Seven CD patients were treated with anticonvulsants, and four showed remarkable amelioration of dizzy sensation. In all the four patients with symptomatic amelioration, the disappearance of rotational abnormality in AEFs or the tendency towards disappearance was observed following symptomatic amelioration. The results of the present study suggest that the auditory center may contribute to the maintenance of equilibrium, and its dysfunction may lead to the development of CD. AEFs measurements may make it possible to evaluate the functional abnormality of auditory center and may be useful for studying the pathophysiology and treatment of CD.     

Dystypia: isolated typing impairment without aphasia, apraxia or visuospatial impairment

We report a 60-year-old right-handed Japanese man who showed an isolated persistent typing impairment without aphasia, agraphia, apraxia or any other neuropsychological deficit. We coined the term 'dystypia' for this peculiar neuropsychological manifestation. The symptom was caused by an infarction in the left frontal lobe involving the foot of the second frontal convolution and the frontal operculum. The patient's typing impairment was not attributable to a disturbance of the linguistic process, since he had no aphasia or agraphia. The impairment was not attributable to the impairment of the motor execution process either, since he had no apraxia. Thus, his typing impairment was deduced to be based on a disturbance of the intermediate process where the linguistic phonological information is converted into the corresponding performance. We hypothesized that there is a specific process for typing which branches from the motor programming process presented in neurolinguistic models. The foot of the left second frontal convolution and the operculum may play an important role in the manifestation of 'dystypia'.     

Abnormalities of rate-corrected QT intervals in Parkinson's disease-a comparison with multiple system atrophy and progressive supranuclear palsy

A number of patients with Parkinson's disease (PD) and multiple system atrophy (MSA), in whom sudden death does occur occasionally, have QT or rate-corrected QT (QTc) interval prolongation on electrocardiogram (ECG). Although these QT or QTc interval abnormalities are likely related to autonomic dysfunction, the pathophysiology remains unknown. The aim of this study was to compare the degree of QTc interval prolongation among akinetic-rigid syndromes, namely PD and related disorders, and to evaluate the relationship between QTc prolongation and severity of autonomic dysfunction. Thirty-four patients with PD, 22 with MSA, 11 with progressive supranuclear palsy (PSP) and 30 healthy controls underwent standard autonomic function tests, and electrocardiography variables (RR, QT and QTc intervals) were measured by an ECG recorder with an automated analyzer. The relationship between QTc interval and cardiovascular reflex tests were also analyzed. Orthostatic hypotension and decreased heart rate in response to respiratory stimuli were prominent in MSA, while these were relatively mild in PD. Unlike the RR and QT intervals, the QTc interval significantly differed among all groups (p<0.01). The QTc interval was significantly prolonged in PD (409+/-17 ms; p<0.001) and MSA (404+/-14 ms; p<0.05) compared with healthy controls (394+/-19 ms). Neither autonomic dysfunction nor QTc interval prolongation was evident in PSP. QTc intervals and cardiovascular reflexes did not correlate, except for Valsalva ratio. The QTc interval was obviously prolonged in PD patients to an extent that could not be accounted for simply by autonomic dysfunction levels. MSA patients showed slightly prolonged QTc intervals in spite of marked cardiovascular autonomic dysfunction. Abnormalities of the QTc may reflect the degeneration of cardioselective sympathetic and parasympathetic neurons that cannot be fully captured by cardiovascular autonomic function tests.     

Monoclonal antibody to stage-specific fetal brain 68-kDa glycoprotein (FGP68) revealed increased FGP68 expression in human primary brain tumors

We have produced a novel rat IgG(2a) monoclonal antibody against a stage-specific fetal brain glycoprotein of 68 kDa (FGP68), and succeeded in applying it to staining paraffin sections. To gain some insight into the pathobiological significance of this FGP68, this monoclonal antibody was used in immunohistochemical studies to compare the expression of FGP68 and Ki-67 antigen (MIB-1) in 235 primary brain tumors. Approximately half of the glioblastomas multiforme (GBMs) (44/75) and anaplastic astrocytomas (9/17) as well as some astrocytomas (5/30), medulloblastomas (2/14) and primitive neuroectodermal tumors (2/10) had tumor cells that expressed FGP68; however, pilocytic astrocytomas (0/7), oligodendrogliomas (0/15), ependymomas (0/6), schwannomas (0/21), meningiomas (0/22) and pituitary adenomas (0/18) did not express FGP68. The values of the MIB-1 labeling index were statistically higher in GBMs (0.005< P<0.01, Wilcoxon rank-sum test) and anaplastic astrocytomas (0.025< P<0.05) that expressed FGP68 than in those that did not. Normal brain tissue from 20 individuals aged 3-75 years was negative for FGP68 and MIB-1. We conclude that primary brain tumors express FGP68, one of the oncofetal proteins derived from fetal brain, and that FGP68 expression in certain brain tumor cells may depend, in part, on proliferation potential. Based on the possibility that the stage-specific FGP68 plays an important role in brain embryogenesis, some of FGP68-expressing tumor cells might phylogenetically revert to more primitive cells.     

A pectin glucuronyltransferase gene is essential for intercellular attachment in the plant meristem

Intercellular attachment is an essential process in the morphogenesis of multicellular organisms. A unique mutant, nolac-H18 (nonorganogenic callus with loosely attached cells), generated by T-DNA transformation using leaf-disk cultures of haploid Nicotiana plumbaginifolia, lost the ability to form tight intercellular attachments and adventitious shoots. The gene tagged with T-DNA, named NpGUT1 (glucuronyltransferase 1), was similar to the gene for the catalytic domains of animal glucuronyltransferases and was expressed predominantly in shoot and root apical meristems. The transformation of NpGUT1 complemented the nolac-H18 mutation, and the expression of antisense NpGUT1 RNA produced crumbled shoots. The mutation caused defects in the glucuronic acid of rhamnogalacturonan II of pectin, which drastically reduced the formation of borate cross-linking of rhamnogalacturonan II. NpGUT1, which encodes a unique glucuronyltransferase, is a glycosyltransferase gene identified in pectin biosynthesis and is essential for intercellular attachment in plant meristems and tissues.     

Platelet reactivity in spontaneously diabetic rats is independent from blood glucose and insulin levels

Diabetes is associated with thrombotic disorders. Chemically induced and spontaneously induced diabetic animals and various in vitro tests have been used to reveal the prothrombotic state of diabetic patients. However, the results are not consistent. In the present study, platelet reactivity of spontaneously diabetic Goto-Kakizaki rats in vivo and in vitro was evaluated by laser-induced and shear-induced thrombosis models, which are physiologically relevant to thrombosis. Both results showed platelet hyperreactivity.     

Synergistic induction of apoptosis by acyclic retinoid and interferon-beta in human hepatocellular carcinoma cells

Acyclic retinoid, a synthetic retinoid analog, as well as interferon alfa (IFN-alpha) and IFN-beta induce apoptosis in hepatocellular carcinoma (HCC) cells and are used clinically in the prevention of HCC. Here, we show that acyclic retinoid acts synergistically with IFNs in suppressing the growth and inducing apoptosis (as characterized by DNA fragmentation and chromatin condensation) in 5 human HCC cell lines (JHH7, HuH7, PLC/PRF/5, HLE, and HLF). This synergism was only observed when cells were pretreated with the acyclic retinoid, whereas natural retinoic acids (all-trans and 9-cis retinoic acid) were ineffective. This promotion may be due to up-regulation of type 1 IFN receptor (IFNR) expression by the retinoid. Accordingly, incubation with antitype 1 IFNR antibody abolished the synergy. Enhanced IFNR expression was accompanied by increased expression and DNA-binding activity of STAT1, an intracellular signal transducing molecule of IFNR, and increased induction of 2', 5'-oligoadenyl-5'-triphosphate synthetase, which is a target gene of STAT1. Acyclic retinoid did not have any effects on the growth of normal human hepatocytes (Hc) probably because of a lack of IFNR and STAT1 up-regulation. In conclusion, these results provide a rationale for combined biochemoprevention of HCC using acyclic retinoid and IFN-beta.     

Coexpression of microsomal prostaglandin E synthase with cyclooxygenase-2 in human rheumatoid synovial cells

OBJECTIVE: Recently, microsomal prostaglandin (PG) E synthase (mPGES) was cloned as a terminal enzyme catalyzing PGH2 to PGE2. We investigated mPGES as well as cyclooxygenase (COX)-2, catalyzing arachidonic acid to PGH2, in synovial cells from patients with rheumatoid arthritis (RA). The effect of dexamethasone on mPGES expression was also studied. METHODS: Synovial cells were treated with interleukin 1beta (IL-1beta) and dexamethasone under various conditions, and expression of mPGES mRNA and protein was analyzed by Northern blot and Western blot, respectively. Conversions of arachidonic acid or PGH2 to PGE2 were measured by ELISA. Subcellular localization of mPGES and COX-2 was determined by immunofluorescent microscopic analysis. RESULTS: mPGES mRNA and protein expression were significantly upregulated by IL-1beta in synovial cells. COX-2 mRNA and protein were also upregulated by IL-1beta, but with a different time course from that of mPGES. Conversion of PGH2 to PGE2 increased by IL-1beta and was correlated with mPGES expression. Increased conversion of arachidonic acid to PGE2 was maintained when mPGES and COX-2 were coexpressed. Subcellular localization of mPGES and COX-2 overlapped in the perinuclear region in IL-1beta stimulated synovial cells. Dexamethasone inhibited mRNA and protein expression for mPGES and increased conversion of arachidonic acid to PGE2, but inhibition of mPGES was weaker compared with that of COX-2 in IL-1beta stimulated cells. CONCLUSION: The results suggest that abundant PGE2 production at inflammation sites such as rheumatoid synovia is caused by the coordinated upregulation of mPGES and COX-2. Thus mPGES might be a potential new target for therapeutic strategies to control PGE2 synthesis specifically in patients with RA and other inflammatory diseases.     

Meta-analyses of therapies for postmenopausal osteoporosis. VI. Meta-analysis of calcitonin for the treatment of postmenopausal osteoporosis

OBJECTIVE: To review the effect of calcitonin on bone density and fractures in postmenopausal women. DATA SOURCE: We searched MEDLINE and EMBASE from 1966 to 2000 and examined citations of relevant articles and the proceedings of international osteoporosis meetings. We contacted osteoporosis investigators to identify additional studies and primary authors for unpublished data. STUDY SELECTION: We included 30 studies that randomized women to calcitonin or an alternative (placebo or calcium and/or vitamin D) and measured bone density or fracture incidence for at least 1 yr. DATA EXTRACTION: For each trial, three independent reviewers assessed the methodological quality and abstracted data. DATA SYNTHESIS: Calcitonin reduced the incidence of vertebral fractures, with a pooled relative risk (RR) of 0.46 [95% confidence interval (CI) 0.25-0.87, P = 0.02, n = 1404, 4 trials]. However, the RR from the one relatively large randomized controlled trial (RCT) was 0.79 (95% CI 0.62-1.00, P = 0.05, n = 1108). For nonvertebral fractures, the pooled RR was 0.52 (95% CI 0.22-1.23, P = 0.14, n = 1481, 3 trials). Once again, the single large trial showed a less impressive effect than the smaller trials (RR 0.80, 95% CI 0.59-1.09, P = 0.16, n = 1245). For bone density of the lumbar spine, the pooled weekly dose of 250 to 2800 IU per week resulted in significant increase in the weighted mean difference (WMD) of 3.74 (2.04-5.43, P < 0.01, n = 2260, 24 trials). The combined forearm showed a similar effect, with a WMD of 3.02 (95% CI 0.98-5.07, P < 0.01, n = 468, 9 trials). At the femoral neck, the pooled weighted mean difference showed a nonsignificant trend toward benefit, WMD 3.80 (95% CI -0.32-7.91, P = 0.07, 9 trials, n = 513). Methodologically weaker studies tended to show greater effects on bone density, and the lumbar spine results suggested the possibility of publication bias. CONCLUSIONS: Calcitonin likely increases bone density in postmenopausal women predominantly at the lumbar spine and forearm for weekly doses of greater than 250 IU, although the true effect may be smaller than the pooled estimate would suggest. Calcitonin likely reduces the risk of vertebral fracture; its effect on nonvertebral fracture remains uncertain.