Upper cervical spine movement during intubation: fluoroscopic comparison of the AirWay Scope, McCoy laryngoscope, and Macintosh laryngoscope.

BACKGROUND: The AirWay Scope (AWS) is a new fibreoptic intubation device, which allows visualization of the glottic structures without alignment of the oral, pharyngeal, and tracheal axes, and thus may be useful in patients with limited cervical spine (C-spine) movement. We fluoroscopically evaluated upper C-spine movement during intubation with the AWS or Macintosh or McCoy laryngoscope. METHODS: Forty-five patients, with normal C-spine, scheduled for elective surgery were randomly assigned to one of the three intubation devices. Movement of the upper C-spine was examined by measuring angles formed by adjacent vertebrae during intubation. Time to intubation was also recorded. RESULTS: Median cumulative upper C-spine movement was 22.3 degrees, 32.3 degrees, and 36.5 degrees with the AWS, Macintosh laryngoscope, and McCoy laryngoscope, respectively (P<0.001, AWS vs, Macintosh and McCoy). The AWS reduced maximum movement of the C-spine at C1/C2 in comparison with the Macintosh or McCoy laryngoscope (P=0.012), and at C3/C4 in comparison with the McCoy laryngoscope (P=0.019). Intubation time was significantly longer in the AWS group than in the Macintosh group (P=0.03). CONCLUSIONS: Compared with the Macintosh or McCoy laryngoscope, the AWS produced less movement of upper C-spine for intubation in patients with a normal C-spine.

A long-term follow-up study of radiographically evident degenerative changes in the temporomandibular joint with different conditions of disk displacement.

The purpose of this retrospective study is to assess the relationship between an initial and persisting condition of disk displacement (DD) and the long-term course of radiographically evident degenerative changes of the temporomandibular joint (TMJ). Nineteen patients agreed to a radiographic follow-up examination of 29 joints and were included in this study. The joints were radiographically assessed at the first visit and at least 46 months after the first visit (mean 89.3 months). At the time of the follow-up, all subjects had a good clinical course after a favorable response to the treatments. There were significant relationships between the initial diagnosis of DD and the interval change in the morphology of the articular eminence. The articular eminence became flattened or deformed only in the joints with persistent DD without reduction. And there was a tendency that the condyle became smaller in the joints initially with permanent DD and in the joints which show a progression in the disk-condylar relationship. The results of this study suggested that, in the joints with persisting non-reducing disk displacement, flattening and deformation of the articular eminence and regression of the condylar size were likely to happen even after symptoms and signs of TMJ disorders were resolved or reduced.

Polymorphism of the lipoprotein lipase gene and risk of atherothrombotic cerebral infarction in the Japanese.

BACKGROUND AND PURPOSE: Lipid and lipoprotein abnormalities have been implicated in the pathogenesis of ischemic cerebrovascular disease and atherosclerosis. Lipoprotein lipase (LPL) plays an important role in plasma lipoprotein metabolism. Several studies have recently reported the presence of a relationship between Ser447Stop mutation of LPL and coronary artery disease. Other polymorphisms (HindIII and PvuII) of the LPL gene have already been shown to correlate significantly with dyslipidemia. We investigated whether these polymorphisms are associated with increased risk of ischemic cerebrovascular disease (CVD). METHODS: We recruited 177 CVD patients (atherothrombotic infarction, n=71; cardioembolic infarction, n=30; lacunar infarction, n=76) and 177 healthy control subjects. Subjects were genotyped for the Ser447Stop mutation and for HindIII/PvuII restriction fragment length polymorphisms of the LPL gene, and the findings were investigated for associations with the clinical subtypes of CVD and with lipid levels. RESULTS: The Ser447Stop mutation correlated significantly with CVD (0.107 versus 0.158; P=0.035). For the CG+GG versus CC genotype, the odds ratio between control subjects and CVD patients with atherothrombotic infarction was 0.42 (95% CI, 0.18 to 0.99) (P=0.046). Serum HDL cholesterol and triglyceride levels did not correlate significantly with the Ser447Stop genotype. HindIII polymorphism correlated significantly with CVD (0.234 versus 0.169; P=0.031), but the frequency of PvuII polymorphism was not significantly different between groups. CONCLUSIONS: Our results suggest that the Ser447Stop mutation of the LPL gene is a novel genetic marker for low risk of atherothrombotic cerebral infarction.

Solution structure of Grb2 reveals extensive flexibility necessary for target recognition.

Grb2 is an adaptor protein composed of a single SH2 domain flanked by two SH3 domains. Grb2 functions as an important evolutionary conserved link between a variety of cell membrane receptors and the Ras/MAP kinase-signaling cascade. Here, we describe the solution structure of Grb2 as revealed by NMR and small angle X-ray scattering measurements. We demonstrate that Grb2 is a flexible protein in which the C-terminal SH3 domain is connected to the SH2 domain via a flexible linker. This is in contrast to the previously described Grb2 crystal structure, which showed a compact structure with intramolecular contact between two SH3 domains. Binding experiments on Grb2 and peptides containing two different proline-rich sequences indicate that Grb2 adapts the relative position and orientation of the two SH3 domains to bind bivalently to the target peptide sequences.

PARKIN as a pathogenic gene for autosomal recessive juvenile parkinsonism.

Parkinson's disease is a common neurodegenerative disease with complex clinical features. Recently, we idenfied a novel gene named Parkin to be responsible for the pathogenesis of autosomal recessive juvenile parkinsonism (AR-JP). Various mutations were found in AR-JP patients of Japanese and other ethnic origins, providing a definitive evidence for the Parkin to be a causative gene for AR-JP. The predicted structure of Parkin protein and its mutation provide important clues for studying the functional role of the Parkin protein in leading to selective degeneration of nigral neurons in the brains of AR-JP patients.

Development of the nosological analysis of juvenile parkinsonism.

In the nosological viewpoint concerning diseases with a pathophysiological dysfunction of the nigro-striatal dopaminergic system, juvenile parkinsonism (JP) is discussed in this paper in relation to hereditary progressive dystonia (HPD) and Parkinson's disease (PD). Most cases of JP have dystonia with parkinsonism, which is the main symptom of HPD. In the symptomatological analysis of complication with dystonia, an interesting observation arose as regards on the anatomical and functional development of the basal ganglia through patients with childhood onset HPD and JP. Genetic analysis revealed the disease entity of HPD to be an abnormality of the GTP-CH I gene. Consequently, it has been clarified that clinical differences between HPD and JP were not merely derived from differences in developmental processes. Furthermore, the autosomal recessive type of JP (AR-JP) was confirmed to be a disease entity by the detection of an abnormality of the 'parkin' gene. The nosological controversy about JP and PD in the clinical standpoint has been clarified. However, as more than half of patients with JP do not carry a mutation in the 'parkin' gene, more investigations concerning nosological entities should be carried out. The absence of Lewy bodies in most patients with AR-JP has been confirmed to be a characteristic neorupathological finding as compared with those with typical PD pathology. In this paper, we discuss the above findings.

Molecular genetic analysis of a novel Parkin gene in Japanese families with autosomal recessive juvenile parkinsonism: evidence for variable homozygous deletions in the Parkin gene in affected individuals.

Autosomal recessive juvenile parkinsonism (AR-JP) is a distinct clinical and genetic entity characterized by selective degeneration of nigral dopaminergic neurons and young-onset parkinsonism with remarkable response to levodopa. Recently, we mapped the gene locus for AR-JP to chromosome 6q25.2-q27 by linkage analysis and we identified a novel large gene, Parkin, consisting of 12 exons from this region; mutations of this gene were found to be the cause of AR-JP in two families. Now we report results of extensive molecular analysis on 34 affected individuals from 18 unrelated families with AR-JP. We found four different homozygous intragenic deletional mutations, involving exons 3 to 4, exon 3, exon 4, and exon 5 in 10 families (17 affected individuals). In addition to the exonic deletions, we identified a novel one-base deletion involving exon 5 in two families (2 affected individuals). All mutations so far found were deletional types in which large exonic deletion accounted for 50% (17 of 34) and the one-base deletion accounted for 6% (2/34); in the remaining, no homozygous mutations were found in the coding regions. Our findings indicate that loss of function of the Parkin protein results in the clinical phenotype of AR-JP and that subregions between introns 2 and 5 of the Parkin gene are mutational hot spots.

Pathologic and biochemical studies of juvenile parkinsonism linked to chromosome 6q.

We report the results of pathologic and biochemical studies in a patient with 6q-linked autosomal recessive juvenile parkinsonism (AR-JP). Neuronal loss and gliosis were restricted to the substantia nigra and the locus ceruleus. No Lewy bodies were found, but neurofibrillary tangles and argyrophilic astrocytes were seen in the cerebral cortex and brainstem nuclei. The later findings, which have not been reported previously in AR-JP, suggest the pathologic heterogeneity of 6q-linked AR-JP.

Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism.

Parkinson's disease is a common neurodegenerative disease with complex clinical features. Autosomal recessive juvenile parkinsonism (AR-JP) maps to the long arm of chromosome 6 (6q25.2-q27) and is linked strongly to the markers D6S305 and D6S253; the former is deleted in one Japanese AR-JP patient. By positional cloning within this microdeletion, we have now isolated a complementary DNA done of 2,960 base pairs with a 1,395-base-pair open reading frame, encoding a protein of 465 amino acids with moderate similarity to ubiquitin at the amino terminus and a RING-finger motif at the carboxy terminus. The gene spans more than 500 kilobases and has 12 exons, five of which (exons 3-7) are deleted in the patient. Four other AR-JP patients from three unrelated families have a deletion affecting exon 4 alone. A 4.5-kilobase transcript that is expressed in many human tissues but is abundant in the brain, including the substantia nigra, is shorter in brain tissue from one of the groups of exon-4-deleted patients. Mutations in the newly identified gene appear to be responsible for the pathogenesis of AR-JP, and we have therefore named the protein product 'Parkin'.

Levodopa effective parkinsonism associated with aqueductal stenosis: a case report and review of the literature.

A case of aqueductal stenosis (AS) associated with marked parkinsonism is described. A ventriculoperitoneal (V-P) shunt was performed in an 18-year-old female because of hydrocephalus associated with non-neoplastic aqueductal stenosis. The patient developed acute parkinsonism with Parinaud's sign after the shunt revision. She had a marked response to levodopa and the parkinsonism improved. Subsequently, levodopa therapy was gradually discontinued without any manifestation of parkinsonism. The pathophysiology of this type of parkinsonism probably involved presynaptic dopaminergic dysfunction. However, the etiology of this complication has not been confirmed.

[Slowly progressive dressing and constructional apraxia: symptomatological study, especially for dressing apraxia].

In 1982, Mesulam drew attention to a clinical picture characterized by slowly progressive aphasia without dementia, and since then, there have been many such reports. Recently, there have been 30 reports of slowly progressive apraxia. However, the nature of this apraxia is not uniform. We now report a patient with slowly progressive dressing and constructional apraxia. The patient is a 60-year-old right-handed woman with a 2-year history of a slowly progressive praxic disturbance. On admission, she was alert and aware of this difficulty. A neurological examination disclosed mild rigidity and myoclonus in her left hand. A neuropsychological assessment disclosed severe dressing apraxia, which was unlikely to be caused by dementia and moderate constructional apraxia. Her dressing apraxia was manifested in upper limbs, neck, trunk and lower limbs. However, she could express verbally the action of dressing. She also showed mild limb-kinetic apraxia, but neither ideational apraxia nor ideomotor apraxia was present. Aphasia and agnosia were also absent. On an MRI, the bilateral cerebral hemispheres were atrophic (right > left). A 99m-Tc ECD SPECT revealed decreased uptake in the right cerebral hemisphere and left frontal lobe, and an EEG showed slow waves over the right cerebral hemisphere. There have been 30 reports of slowly progressive apraxia. Most of these cases presented with slowly progressive clumsiness in one or both hands as an initial symptom, followed by constructional, ideomotor or dressing apraxia. Our patient differed from these cases in that dressing and constructional apraxia progressed slowly without any other apraxia except only mild limb-kinetic apraxia. There was a similarity between dressing apraxia of our patient and that of Marie's and Brain's original cases.

Localization of a gene for an autosomal recessive form of juvenile Parkinsonism to chromosome 6q25.2-27.

An autosomal recessive form of juvenile Parkinsonism (AR-JP) (MIM 600116) is a levodopa-responsive Parkinsonism whose pathological finding is a highly selective degeneration of dopaminergic neurons in the zona compacta of the substantia nigra. By linkage analysis of diallelic polymorphism of the Mn-superoxide dismutase gene (SOD2), we found a family with AR-JP showing perfect segregation of the disease with the SOD2 locus. By extending the linkage analysis to 13 families with AR-JP, we discovered strong evidence for the localization of the AR-JP gene at chromosome 6q25.2-27, including the SOD2 locus, with the maximal cumulative pairwise LOD scores of 7.26 and 7.71 at D6S305 (theta = .03) and D6S253 (theta = .02), respectively. Observation of obligate recombination events, as well as multipoint linkage analysis, placed the AR-JP gene in a 17-cM interval between D6S437 and D6S264. Delineation of the AR-JP gene will be an important step toward our understanding of the molecular mechanism underlying selective degeneration of the nigral neurons.

Effects of tolcapone, a catechol-O-methyltransferase inhibitor, on motor symptoms and pharmacokinetics of levodopa in patients with Parkinson's disease.

The effects of tolcapone, a catechol-O-methyltransferase inhibitor, on the bioavailability and efficacy of levodopa were evaluated in 12 patients with Parkinson's disease (PD), 8 of whom showed signs of daily motor fluctuations (wearing-off phenomenon). Motor disabilities were assessed in 12 patients at 7 time points before and after the chronic administration of tolcapone using the Unified Parkinson's Disease Rating Scale (UPDRS). The UPDRS score was improved at all points of determination. Eight patients with wearing-off phenomenon on levodopa showed symptomatic improvement on the combination. The area under the curve (AUC) for levodopa increased by 34% (p = 0.0059) after the administration of tolcapone. The elimination half-life (T1/2) of levodopa was significantly prolonged by 81% (p = 0.0001) after the treatment. The AUC of 3-O-methyldopa, a metabolite of levodopa, was decreased by 79% (p = 0.0001) and the Cmax (maximum concentration) was also decreased by 80%d after the administration (p = 0.0001) of tolcapone. The combination of tolcapone and levodopa was well tolerated. Our findings suggest that tolcapone improves the pharmacokinetics of levodopa in plasma and motor symptoms of fluctuating PD patients. It is suggested that tolcapone may be useful drug adjunct to levodopa in treating patients with PD with wearing-off phenomena.

[Definition and nosological concept of juvenile parkinsonism].

Clinicopathological identification of juvenile parkinsonism(JP) was described in reference to Dopa-responsive syndrome or to dopamine-dependent disorders. Recently, hereditary progressive dystonia(HPD), a dopamine-dependent disorder, was identified as a nosological entity from JP and Parkinson's disease(PD) by discovery of mutations of the gene. JP includes young onset Parkinson's disease(YOPD) and idiopathic JP with much younger-onset cases. YOPD belongs to PD-nosology based on clinical and pathological findings of our own autopsied cases. However, the idiopathic JP' might involve independent pathophysiological changes. Namely, cases of the JP are associated with atypical pathological findings with lack of Lewy body or hypoplasia of the substantia nigra and specific clinical manifestations of autosomal recessive trait and of dystonic feature and diurnal fluctuation of the symptoms.

Familial juvenile parkinsonism.

Some cases of parkinsonism without Lewy bodies were detected, although the presence of Lewy bodies is a diagnostic criterion for PD. Thereafter, similar cases were repeatedly encountered by researchers at Juntendo University, Tokyo. Groups in Niigata and Hiroshima also reported cases of parkinsonism without Lewy bodies, which suggests that such cases occur frequently in Japan. Clinically, most of these are cases of typical juvenile parkinsonism (JP) and have sufficient response to levodopa therapy. Diurnal motor fluctuations were mentioned in some reports. The clinical findings vary slightly from case to case but the primary pathological finding is restricted to the substantia nigra. Therefore, JP almost certainly results from a dopamine deficiency in the nigrostriatal system. However, the absence of Lewy bodies raises the possibility of differences in the degenerative process from a general pathology of the substantia nigra with the Lewy bodies. Many cases without Lewy bodies are familial cases with autosomal recessive (AR) inheritance. Both factors may be integrated in a single disease although this is still uncertain. Families in which JP appeared to be inherited in an autosomal dominant (AD) manner as well as those in which it appeared to be inherited in an AR manner were identified. The onset ages of the probands were slightly higher in the former than in the latter families. The age of onset in AD inheritance family cases may coincide with an age of onset of typical JP due to anticipation of the disease. The sporadic cases, which account for half of the JP cases, require further analysis.

Injection of a GABA antagonist into the mesopontine reticular formation abolishes haloperidol-induced catalepsy in rats.

THE pedunculopontine nucleus and its adjacent structure of the mesopontine reticular formation are known as a mesencephalic locomotor region, since either electrical or chemical stimulation of these regions induces locomotion in decerebrate animals. In parkinsonism, it is presumed that the pedunculopontine nucleus is under GABAergic overinhibition from the basal ganglia. To reveal the behavioural effects of GABAergic disinhibition of the mesopontine reticular formation in parkinsonism, picrotoxin, a GABAA antagonist, (5 or 10 ng/ 0.25 microliter) or vehicle was injected unilaterally into the mesopontine reticular formation of rats via implanted cannulae after induction of catalepsy using haloperidol (1.5 mg kg-1, i.p.). Injection of the larger dose of picrotoxin, but not the smaller dose nor the vehicle, abolished the catalepsy with or without spontaneous locomotor activity. The present result suggests that the disinhibition of the brainstem output structures contributes to the recovery of mobility in the cataleptic state induced by blocking the dopaminergic transmission of the basal ganglia.

[A 43-year-old woman with 18 years history of parkinsonism].

We report a 43-year-old woman who died after 18 years history of parkinsonism. She was well until 25 years of the age (1976) when she noted a difficulty in stepping her feet. In the next year, she started to drag her feet. She was treated with levodopa with good response, however, she developed dyskinesia when she was 33 years of the age. She was evaluated in another hospital in 1984. She showed normal intelligence, normal ocular movement, masked face, small voice, small step gait, stooped posture, freezing of the gait, retropulsion, and cogwheel rigidity in limbs. No tremor or ataxia was noted. She received left ventrolateral thalamotomy at that time. Rigidity on the right side markedly reduced, however, she continued to show bradykinesia and motor fluctuations. On August 1 of 1994, she developed fever of 40 degrees C and dyspnea. On the next day, she expired from acute respiratory distress. She was able to walk unsupported until just before her last admission. The patient was discussed in a neurological CPC. The chief discussant arrived at the conclusion that this patient had Lewy body-positive young onset Parkinson's disease. Opinions were divided into two groups, i.e., young onset Lewy-body positive Parkinson's disease and Lewy-body negative young onset parkinsonism. Post-mortem examination revealed moderate loss of pigmented neurons in the substantia nigra more in the ventro-lateral part. Lewy bodies were found in the remaining neurons. Lewy bodies were more frequently seen in the locus coeruleus, although neuronal loss was less prominent in the locus coeruleus. The dorsal vagal motor nucleus showed moderate loss of neurons. Otherwise, the central nervous system was unremarkable. To our knowledge, this patient had the second youngest age of the onset so far reported in the literature for Lewy-body positive typical Parkinson's disease.