Biomedical subjects

S Minoshima

Publications and source records attributed to S Minoshima.

At least 73 records · Page 4Linked to original sources

PubMed2000

Normalized spleen/liver ratios on 111In-labelled platelet scintigraphy to predict the outcome of partial splenic embolization in patients with idiopathic thrombocytopenic purpura.

In this study, we examined the use of 111In-labelled platelet imaging to predict the outcome of partial splenic embolization (PSE) in patients with idiopathic thrombocytopenic purpura (ITP). Thirty-eight patients with a clinical diagnosis of ITP underwent 111In-labelled platelet scintigraphy. Twenty-four patients with intractable ITP underwent PSE after 111In-labelled platelet scintigraphy. The conventional spleen/liver ratio at 1 h and 192 h and the normalized spleen/liver ratio [(spleen uptake at 192 h/liver uptake at 192 h)/(spleen uptake at 1 h/liver uptake at 1 h)] were compared between responders and non-responders to PSE. Patients with ITP showed a significant reduction in platelet counts, increased platelet associated IgG, decreased platelet survival, and an increased conventional spleen/liver ratio at 192 h. No significant difference was found between patients who had and who had not undergone previous medical treatment. A significant difference was observed in the mean conventional spleen/liver ratio at 192 h between responders and non-responders, but there was substantial overlap among individuals. The mean normalized spleen/liver ratio was significantly higher in responders than non-responders; there was less overlap between the two groups with the normalized spleen/liver ratio than the conventional spleen/liver ratio. The therapeutic outcome of PSE is predicted more accurately using a normalized spleen/liver uptake ratio of 111In-labelled platelets in patients with idiopathic thrombocytopenic purpura than a conventional splenic/hepatic uptake ratio on delayed images.

Adult↗

PubMed2000

Pathobiology of visceral pain: molecular mechanisms and therapeutic implications V. Central nervous system processing of somatic and visceral sensory signals.

Somatic and visceral sensation, including pain perception, can be studied noninvasively in humans with functional brain imaging techniques. Positron emission tomography and functional magnetic resonance imaging have identified a series of cerebral regions involved in the processing of somatic pain, including the anterior cingulate, insular, prefrontal, inferior parietal, primary and secondary somatosensory, and primary motor and premotor cortices, the thalamus, hypothalamus, brain stem, and cerebellum. Experimental evidence supports possible specific roles for individual structures in processing the various dimensions of pain, such as encoding of affect in the anterior cingulate cortex. Visceral sensation has been examined in the setting of myocardial ischemia, distension of hollow viscera, and esophageal acidification. Although knowledge regarding somatic sensation is more extensive than the information available for visceral sensation, important similarities have emerged between cerebral representations of somatic and visceral pain.

Brain↗

PubMed2000

Selective opiate modulation of nociceptive processing in the human brain.

Fentanyl, a mu-opioid receptor agonist, produces analgesia while leaving vibrotactile sensation intact. We used positron emission tomography (PET) to study the mechanisms mediating this specific effect in healthy, right-handed human males (ages 18-28 yr). Subjects received either painful cold (n = 11) or painless vibratory (n = 9) stimulation before and after the intravenous injection of fentanyl (1.5 microgram/kg) or placebo (saline). Compared with cool water (29 degrees C), immersion of the hand in ice water (1 degrees C) is painful and produces highly significant increases in regional cerebral blood flow (rCBF) within the contralateral second somatosensory (S2) and insular cortex, bilaterally in the thalamus and cerebellum, and medially in the cerebellar vermis. Responses just below the statistical threshold (3.5 < Z < 4.0) are seen in the contralateral anterior cingulate, ipsilateral insular cortex, and dorsal medial midbrain. The contralateral primary sensory cortex (S1) shows a trend of activation. Except for slight changes in intensity, this pattern is unchanged following a saline placebo injection. Fentanyl reduces the average visual analogue scale ratings of perceived pain intensity (47%) and unpleasantness (50%), reduces pain-related cardioacceleration, and has positive hedonic effects. After fentanyl, but not placebo, all cortical and subcortical responses to noxious cold are greatly reduced. Subtraction analysis [(innocuous water + fentanyl) - (innocuous water + no injection)] shows that fentanyl alone increases rCBF in the anterior cingulate cortex, particularly in the perigenual region. Vibration (compared with mock vibration) evokes highly significant rCBF responses in the contralateral S1 cortex in the baseline (no injection) and placebo conditions; borderline responses (3.5 < Z < 4. 0) are detected also in the contralateral thalamus. Fentanyl has no effect on the perceived intensity or unpleasantness of vibratory stimulation, which continues to activate contralateral S1. Fentanyl alone [(mock vibration + fentanyl) - (mock vibration + no injection)] again produces highly significant activation of the perigenual and mid-anterior cingulate cortex. A specific comparison of volumes of interest, developed from activation peaks in the baseline condition (no injection), shows that fentanyl strongly attenuates both the contralateral thalamic and S1 cortical responses to noxious cold stimulation (P < 0.048 and 0.007, respectively) but fails to affect significantly these responses to vibrotactile stimulation (P > 0.26 and 0.91, respectively). In addition, fentanyl, compared with placebo, produces a unique activation of the mid-anterior cingulate cortex during fentanyl analgesia, suggesting that this region of the cingulate cortex participates actively in mediating opioid analgesia. The results are consistent with a selective, fentanyl-mediated suppression of nociceptive spinothalamic transmission to the forebrain. This effect could be implemented directly at the spinal level, indirectly through cingulate corticofugal pathways, or by a combination of both mechanisms.

Adolescent↗

PubMed2000

The myocilin (MYOC) gene expression in the human trabecular meshwork.

PURPOSE: We previously reported a novel cytoskeletal protein with a myosin-like domain which is localized in the ciliary rootlet and basal body of connecting cilium of photoreceptor and hence we named it 'myocilin'. It was soon realized that myocilin is identical to a protein called TIGR (trabecular meshwork inducible glucocorticoid response protein) which was found to be responsible for the pathogenesis of juvenile open angle glaucoma. In this study, we employed in situ RNA hybridization to examine the myocilin (MYOC)/ TIGR gene expression in the trabecular meshworks of glaucomatous and nonglaucomatous eyes. METHODS: The glaucomatous specimens were obtained by trabeculectomy from the patients with primary open angle glaucoma (POAG), chronic angle closure glaucoma (CACG) and steroid glaucoma, respectively, and the nonglaucomatous specimens were obtained from a victim of traffic accident at autopsy and from a patient with maxillary sinus carcinoma at enucleation for the operation. The in situ RNA hybridization was carried out with digoxigenin-labeled sense and antisense RNA probes. RESULTS: In all cases, hybridization signals were detected primarily in the trabecular meshwork cells and secondarily in the fibroblast-like cells of corneoscleral wall. CONCLUSIONS: Myocilin gene is expressed clearly in the trabecular meshwork cells of both glaucomatous and nonglaucomatous eyes.

Aged↗

PubMed2000

[Computer databases on cancer-related genes].

A database of mutations in various cancer-related genes has been constructed and named as KMcancerDB (Keio Mutation DataBase for cancer-related genes). This KMcancerDB utilizes a database software called MutationView which we designed to compile various mutation data and to provide graphical presentation of data analysis through the network using ordinary internet browser softwares such as Netscape. Currently, the KMcancerDB accommodates 1261 mutation data of different genes for cancers in 9 different organs/tissues (breast, stomach, uterus, liver, prostate, colon, ovary, thymus and retinoblastoma). KMcancerDB is accessible through http:¿mutview.dmb.med.keio.ac.jp. OMIM is an important document database for human Mendelian traits and hereditary diseases. The information from OMIM is also used in MutationView/KMcancerDB. Some display windows of OMIM and KMcancerDB are presented.

Computer Communication Networks↗

PubMed2000

Limited donepezil inhibition of acetylcholinesterase measured with positron emission tomography in living Alzheimer cerebral cortex.

Based on surrogate assays of peripheral red blood cells, reports state that widely prescribed doses of donepezil hydrochloride provide nearly complete inhibition of cerebral cortical acetylcholinesterase activity in the treatment of Alzheimer's disease (AD). To test this, direct positron emission tomography measures of cerebral acetylcholinesterase activity were made in AD patients before and after treatment with donepezil (5 and 10 mg/day) for at least 5 weeks and compared with similar measures in normal controls who were untreated or after acute administration of another AChE inhibitor, physostigmine salicylate (1.5 mg/hr). After physostigmine, acetylcholinesterase inhibition averaged 52% in normal cerebral cortex. After donepezil, cerebral cortical inhibition in AD brain averaged only 27%. Clinical trials of this donepezil dose schedule are not testing the effect of nearly complete cerebral cortical inhibition.

Acetylcholinesterase↗

PubMed2000

Three-dimensional stereotactic surface projection analysis of macaque brain PET: development and initial applications.

UNLABELLED: To characterize better the local brain functions of conscious rhesus macaques, we developed automated image analysis techniques for monkey PET images, examined the cerebral glucose metabolism of monkeys, and compared it with that of humans. METHODS: Glucose metabolic PET images from 11 monkeys were obtained using a high-resolution animal PET scanner after intravenous administration of FDG. T1-weighted MR images were obtained from 6 of the monkeys. Referencing a bicommissural stereotactic macaque brain atlas, we created a PET brain template using coregistered MR images. Each individual PET image set was transformed to the PET template through an automated affine transformation, followed by nonlinear warping along the directions of the major neuronal fiber bundles in the brain. For minimization of residual anatomic variability, metabolic activities were extracted using 3-dimensional stereotactic surface projections. The effects of anatomic standardization were evaluated using MR images. Patterns of cerebral glucose metabolism of young versus aged monkeys were examined. The metabolic activities of aged monkeys were compared with those of elderly healthy human volunteers that had been analyzed similarly. RESULTS: Anatomic standardization reduced individuals' anatomic variability as evidenced by a reduction in the number of MR pixels with higher SDs calculated across monkeys. Coefficient-of-variation maps of conscious monkeys revealed that the greatest metabolic variances were near the central sulci and occipital cortices. Age-associated glucose metabolic reductions were most pronounced in the occipital lobe, caudate nucleus, and temporal lobe. Compared with human brains, the monkey frontal lobe and posterior cingulate gyrus had significantly less metabolic activity and the supramarginal gyrus and vermis had significantly more metabolic activity. CONCLUSION: The proposed method permits pixel-by-pixel characterization of the metabolic activities of rhesus macaque brains in the stereotactic coordinate system. Greater metabolic variances in the central sulcus region and occipital lobe suggest potential difficulties in controlling sensory input and motor output or planning in conscious monkey experiments. The analyses revealed age-related metabolic reductions in monkeys and marked differences in metabolic patterns between aged monkey brains and aged human brains. The proposed brain-mapping technique enables reproducible and observer-independent analyses and will serve as an important investigative tool for primate brain imaging research.

Aging↗

PubMed1999

Identification of a putative regulatory subunit of a calcium-activated potassium channel in the dup(3q) syndrome region and a related sequence on 22q11.2.

Duplication of a segment of the long arm of human chromosome 3 (3q26.3-q27) results in a syndrome characterized by multiple congenital abnormalities and neurological anomalies in some patients. We have identified a novel gene (KCNMB3) that maps to this region. KCNMB3 has significant sequence similarity to the regulatory subunit of the large-conductance calcium-activated potassium channel. Due to the significance of potassium channels in neuronal functions, the overexpression of this gene may play a role in the abnormal neurological functions seen in some of these patients. A related sequence corresponding to the second and third exons of this gene resides in the pericentromeric region of 22q11, where a number of other unprocessed pseudogenes are known to map.

Abnormalities, Multiple↗

PubMed1999

Striatal presynaptic monoaminergic vesicles are not increased in Tourette's syndrome.

BACKGROUND: Abnormal function of striatal dopaminergic synapses is suggested to underlie Tourette's syndrome (TS). OBJECTIVE: To determine dorsal striatal dopaminergic innervation in TS. Prior in vitro and in vivo studies of dopamine reuptake transporter binding sites suggest increased striatal dopaminergic innervation in TS. METHODS: We used in vivo measures of striatal vesicular monoamine transporter type-2 (VMAT2) binding to quantify striatal dopaminergic innervation in TS. Eight TS patients (mean age 30+/-9 years) and 22 age-comparable normal controls (age 34+/-8 years) underwent PET imaging with the VMAT2 ligand (+)-alpha-[11C]dihydrotetrabenazine (DTBZ). Compartmental modeling was used to quantify blood-to-brain ligand transport and VMAT2 binding site density from the tissue-to-plasma distribution volume (DV) during continuous (+)-alpha-[11C]DTBZ infusion. DTBZ DV in dorsal striatal regions was expressed relative to the occipital cortex to estimate relative specific VMAT2 binding (binding potential). RESULTS: We found no significant differences in VMAT2 binding potential between patients and controls in the caudate nucleus, anterior putamen, or posterior putamen. There were no significant differences in striatal VMAT2 binding between patients with (n = 5) or without (n = 3) features of obsessive-compulsive disorder. CONCLUSIONS: There is no evidence for increased binding to the VMAT2 in TS striatum and that dorsal striatal dopaminergic innervation density is normal in TS. The previously reported changes in dopamine transporter binding sites may reflect medication effect and/or altered synaptic activity or regulation of dopamine transporter expression in nigrostriatal neurons.

Adult↗

PubMed1999

A 1.5-Mb contig within the cat eye syndrome critical region at human chromosome 22q11.2.

We have constructed a 1.5-Mb contig spanning the distal half of the critical region for cat eye syndrome on human chromosome 22 from D22S543 to D22S181. The contig consists of 20 P1 artificial chromosome (PAC) clones and 11 bacterial artificial chromosome (BAC) clones screened from 2 BAC and 2 PAC libraries. Continuous overlap between the clones was confirmed using vectorette PCR and riboprobes. Despite the instability of this region in a previous YAC contig, only 1 BAC showed a minor instability and then in only one isolation. This contig is now providing the basis for genomic sequencing and gene identification in the cat eye syndrome critical region.

Abnormalities, Multiple↗

PubMed1999

Brain activation in PTSD in response to trauma-related stimuli.

BACKGROUND: Repetitive recall of traumatic memories and chronic intermittent hyperarousal are characteristic of posttraumatic stress disorder (PTSD). Hyperarousal and memory dysfunction implicates "limbic" brain regions, including the amygdaloid complex, hippocampal formation, and limbic cortex, such as the orbitofrontal and anterior cingulate areas. To investigate the neurobiologic role of these brain regions in PTSD, we measured regional cerebral blood flow in PTSD with single photon emission computerized tomography (SPECT) during a symptom provocation paradigm. METHODS: Fourteen Vietnam veterans with PTSD, 11 combat control subjects, and 14 normal control subjects were studied with [99mTc]HMPAO in two sessions 48 hours apart: one session after exposure to white noise and the other following exposure to combat sounds. Skin conductance, heart rate, and subjective experience were recorded at the time of the studies. RESULTS: Activation for all three groups occurred in the anterior cingulate/middle prefrontal gyrus. Activation in the region of the left amygdala/nucleus accumbens was found in PTSD patients only. Deactivation was found in all three groups in the left retrosplenial region. CONCLUSIONS: These findings implicate regions of the "limbic" brain, which may mediate the response to aversive stimuli in healthy individuals and in patients suffering from PTSD.

Arousal↗

PubMed1999

Organization of the gene for gelatin-binding protein (GBP28).

GBP28 is a novel human plasma gelatin-binding protein that is encoded by apM1 mRNA, expressed specifically in adipose tissue. Three overlapping clones (two lambda clones and one BAC clone) containing the human plasma gelatin-binding protein (GBP28) gene were isolated and characterized. The GBP28 gene spans 16kb and is composed of three exons from 18bp to 4277bp in size with consensus splice sites. The sizes of the two introns were 0.8 and 12kb, respectively. The gene's regulatory sequences contain putative promoter elements, but no typical TATA box. The third exon of this gene contains a long 3'-untranslated sequence containing three Alu repeats. The exon-intron organization of this gene was very similar to that of obese gene, encoding leptin. We also report the chromosome mapping of this gene by fluorescence in situ hybridization (FISH) using a genomic DNA fragment as a probe. The GBP28 gene was located on human chromosome 3q27. The nucleotide sequence data reported in this paper will appear in the DDBJ/EMBL/GenBank nucleotide sequence databases with the accession numbers ABO12163, ABO12164 or ABO12165.

Adiponectin↗

PubMed1999

In vivo mapping of cerebral acetylcholinesterase activity in aging and Alzheimer's disease.

OBJECTIVE: To validate an in vivo method for mapping acetylcholinesterase (AChE) activity in human brain, preparatory to monitoring inhibitor therapy in AD. BACKGROUND: AChE activity is decreased in postmortem AD brain. Lacking a reliable in vivo measure, little is known about central activity in early AD, when the disease is commonly targeted by AChE inhibitor drug therapy. METHODS: Intravenous N-[11C]methylpiperidin-4-yl propionate ([11C]PMP) served as an in vivo AChE substrate. AChE activity was defined using cerebral PET for tracer kinetic estimates of the local rate of [11C]PMP hydrolysis in 26 normal controls and 14 patients with AD. Eleven AD patients also had concomitant in vivo cerebral measures of vesicular acetylcholine transporter (cholinergic terminal) density and glucose metabolism. RESULTS: Cerebral AChE activity measures 1) were independent of changes in tracer delivery to cerebral cortex; 2) agreed with reported postmortem data concerning normal relative cerebral distributions, absence of large age-effect in normal aging, and deficits in AD; 3) correlated in AD cerebral cortex with concomitant in vivo measures of cholinergic terminal deficits, but not with metabolic deficits; and 4) agreed quantitatively with predicted level of cerebral AChE inhibition induced by physostimine. CONCLUSIONS: This in vivo PET method provided valid measures of central AChE activity in normal subjects and AD patients. Applied in early AD, it should facilitate inhibitor treatment by confirming central inhibition, optimizing drug dosage, identifying likely responders, and testing surrogate markers of therapeutic response.

Acetylcholinesterase↗

PubMed1999

Identification and mutation analysis of DOC-1R, a DOC-1 growth suppressor-related gene.

The tumor suppressor gene MEN1 and several oncogenes including CCND1/cyclin D1/PRAD1 map to chromosome 11q13. However, molecular and cytogenetic analysis suggests the presence of a second tumor suppressor locus at this chromosome region. We have identified a novel gene from chromosome 11q13, which encodes a protein of 126 amino acids sharing an overall 57% identity with the p12(DOC-1) protein encoded by the DOC-1 gene, the human homolog of hamster putative tumor suppressor doc-1 (deleted in oral cancer-1). We therefore designated the novel gene as DOC-1R for DOC-1-related. The cytogenetic location was confirmed by chromosome fluorescent in situ hybridization. Northern blot analysis indicated that it was expressed in all the tissues examined. DOC-1R protein showed heterogeneous subcellular localization. RT-PCR-SSCP analysis failed to detect deleterious mutations of the DOC-1R transcript in four premalignant oral keratinocyte lines and 20 different cancer cell lines from tumor types which frequently harbor LOH at chromosome 11q13.

Amino Acid Sequence↗

PubMed1999

Keio Mutation Database for eye disease genes (KMeyeDB).

A database of mutations in human eye disease genes has been constructed. This KMeyeDB employs a database software MutationView which provides graphical data presentation and analysis as a smooth user-interface. Currently, the KMeyeDB contains mutation data of 16 different genes for 18 eye diseases. The KMeyeDB is accessible through http://mutview.dmb.med.keio.ac.jp with advanced internet browsers.

Age of Onset↗

PubMed1999

Polymorphism in the parkin gene in sporadic Parkinson's disease.

We report polymorphism of the parkin gene in 160 sporadic Parkinson's disease (PD) patients and controls. Three polymorphisms were found: a G-to-A transition in exon 4 (S/N167), a C-to-T transition in exon 10 (R/W366), and a G-to-C transition in exon 10 (V/L380). Genotype distributions and allele frequencies of S/N167 and V/L380 did not differ significantly between the two groups. The R/W366 allele frequency was significantly lower in PD patients (1.2 vs 4.4%). The level of protection from PD provided by this allele was 3.60 (95% CI; range, 0.45-6.50), suggesting that it may be a protective factor against PD.

Aged↗

PubMed1999

Immunohistochemical and subcellular localization of Parkin protein: absence of protein in autosomal recessive juvenile parkinsonism patients.

Autosomal recessive juvenile parkinsonism (AR-JP) is a distinct clinical entity characterized by a selective degeneration of nigral neurons. Recently, the parkin gene responsible for AR-JP has been identified. Now, we report the subcellular localization of Parkin protein in patients with AR-JP or Parkinson's disease (PD) and in controls by immunoblotting and immunohistochemistry using antibodies raised against the Parkin molecule. Parkin protein was absent in all regions of the brains of patients with AR-JP. Parkin protein was not decreased in the brains of sporadic PD patients. Immunoreactivity was detected in a few Lewy bodies. Parkin protein was located in both the Golgi complex and cytosol.

Brain↗

PubMed1999

Arterial/venous plasma nicotine concentrations following nicotine nasal spray.

BACKGROUND AND OBJECTIVES: Arterial (A) and venous (V) plasma nicotine and cotinine concentrations were measured after nasal nicotine spray in tobacco smokers of both genders. The hypothesis for this research was that a greater A/V difference in plasma nicotine would be present in males than females because males have greater skeletal muscle mass to bind nicotine. SUBJECTS AND METHODS: Nine male and nine female healthy adult smokers were studied. They all abstained from use of tobacco overnight for 10 h or more prior to the study. Nicotine nasal spray was given in doses of 1-2.5 mg total, with half in each nostril while the subject was supine. Both A and V blood samples were obtained prior to and 3, 6, 10, 15, 20, and 30 min post-nasal nicotine spray. RESULTS AND CONCLUSIONS: Nasal nicotine administration produced greater A than V plasma levels. There were no gender differences in A/V nicotine concentrations, disproving the above hypothesis, suggesting that other physiochemical factors besides skeletal muscle mass must be involved. Heart rate increases correlated well with arterial plasma nicotine levels (r = 0.77). Males had less variance than females in the expected increase in arterial plasma nicotine concentrations with increased number of nasal sprays. Although there was considerable overlap, mean A cotinine concentrations were consistently slightly larger than V concentrations.

Administration, Intranasal↗