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Peptide drugs have traditionally suffered from poor pharmacokinetic properties due to their conformational flexibility and the interaction of proteases with backbone amide bonds. "Stapled Peptides" are cyclized using an all-hydrocarbon cross-linking strategy to reinforce their α-helical conformation, yielding improved protease resistance and drug-like properties. Here we demonstrate that hydrogen exchange-mass spectrometry (HX-MS) effectively probes the conformational dynamics of Stapled Peptides derived from the survivin-borealin protein-protein interface and predicts their susceptibility to proteolytic degradation. In Stapled Peptides, amide exchange was reduced by over five orders-of-magnitude versus the native peptide sequence depending on staple placement. Furthermore, deuteration kinetics correlated directly with rates of proteolysis to reveal the optimal staple placement for improved drug properties.

SAR exploration from an initial hit, (S)-N-(2-cyclohexenylethyl)-2-fluoro-6-(2-(1-hydroxy-3-phenylpropan-2-ylamino)-2-oxoethoxy)benzamide (1), identified using our proprietary automated ligand identification system (ALIS),(1) has led to a novel series of selective hepatitis C virus (HCV) NS5B polymerase inhibitors with improved in vitro potency as exemplified by (S)-2-fluoro-6-(2-(1-hydroxy-3-phenylpropan-2-ylamino)-2-oxoethoxy)-N-isopentyl-N-methylbenzamidecarboxamide (41) (IC(50)=0.5 microM). The crystal structure of an analogue (44) was solved and provided rationalization of the SAR of this series, which binds in a distinct manner in the palm domain of NS5B, consistent with biochemical analysis using enzyme mutant variants. These data warrant further lead optimization efforts on this novel series of non-nucleoside inhibitors targeting the HCV polymerase., (2010 Elsevier Ltd. All rights reserved.)

The biotin carboxylase (AccC) is part of the multi-component bacterial acetyl coenzyme-A carboxylase (ACCase) and is essential for pathogen survival. We describe herein the affinity optimization of an initial hit to give 2-(2-chlorobenzylamino)-1-(cyclohexylmethyl)-1H-benzo[d]imidazole-5-carboxamide (1), which was identified using our proprietary Automated Ligand Identification System (ALIS).(1) The X-ray co-crystal structure of 1 was solved and revealed several key interactions and opportunities for further optimization in the ATP site of AccC. Structure Based Drug Design (SBDD) and parallel synthetic approaches resulted in a novel series of AccC inhibitors, exemplified by (R)-2-(2-chlorobenzylamino)-1-(2,3-dihydro-1H-inden-1-yl)-1H-imidazo[4,5-b]pyridine-5-carboxamide (40). This compound is a potent and selective inhibitor of bacterial AccC with an IC(50) of 20 nM and a MIC of 0.8 microg/mL against a sensitized strain of Escherichia coli (HS294 E. coli).

The aim of this study was to develop a three-dimensional method to analyze edentulous ridge shapes. A laser projection method was used to record the shape of edentulous plaster models. Contour of residual ridge on the reconstructed image was then subdivided into small triangles, and a 'normal line' representing the center of gravity of each triangle was determined buccolingually and anteroposteriorly. Angle between the normal line on the residual ridge and the tentative occlusal plane was calculated for each triangle. These angles were then used to analyze the ridge shape. This method was used to analyze the ridges of 20 edentulous patients with excessive bone resorption. The results suggested that this method was useful for analyzing edentulous ridges regardless of ridge shape and degree of resorption.

The design of bone-targeted pyrido[2,3-d]pyrimidin-7-ones as Src tyrosine kinase inhibitors is described. Leveraging SAR from known compounds and using structure-based methods, we were able to rapidly incorporate bone binding components, which maintained, and even increased potency against the target enzyme. Compound 4 displayed a high affinity for hydroxyapatite, a major constituent of bone, and demonstrated antiresoprtive activity in our cell-based assay.

A series of novel nonpeptide inhibitors of the pp60(c-Src) (Src) SH2 domain is described that exploit multifunctional group replacement of the phenylphosphate moiety of phosphotyrosine (pTyr). Relative to an x-ray structure of citrate complexed to the pTyr binding site of the Src SH2 domain, these nonpeptide ligands illustrate the systematic replacement of the phosphate group by multiple nonhydrolyzable, mono- or dianionic functionalities. Specifically, several phenylalanine (Phe) analogs incorporating key 4' and 3' substituents were synthesized and incorporated into a bicyclic benzamide template previously reported (W. C. Shakespeare et al., Proceedings of the National Academy of Science USA, 2000, Vol. 97, pp. 9373-9378). These pTyr mimetics included 4',3'-diphosphono-Phe (Dpp), 4',3'-dicarboxymethyloxy-Phe (Dcp), and 4'-phosphono-3'-carboxymethyloxy-Phe (Cpp). Noteworthy were nonpeptide inhibitors 8-11 that were 5- to 10-fold more potent than the cognate tetrapeptide ligand Ac-pTyr-Glu-Glu-Ile-NH(2) in binding to the Src SH2 domain., (Copyright 2004 Wiley Periodicals, Inc.)

The structural and functional characterization of Src homology-2 (SH2) domains and their relationship to catalytic proteins (e.g., kinases, phosphatases, and lipases) or non-catalytic proteins (e.g., upstream adapters, and downstream transcription factors) has significantly impacted our understanding of signal transduction pathways and the identification of promising therapeutic targets for drug discovery. Such SH2-containing proteins are known to be intimately involved in the regulation of a number of cellular processes, including growth, mitogenesis, motility, metabolism, and gene transcription. Molecular recognition and biochemical selectivity exists for various SH2 domains based on their binding to phosphotyrosine (pTyr) and contiguous C-terminal amino acids of cognate protein 'partners' in a sequence-dependent manner (i.e., -pTyr-AA(1)-AA(2)-AA(3)-) which result in the formation of signal transduction protein complexes in cells. In recent years, drug discovery efforts have advanced peptidomimetic and nonpeptide inhibitors of such protein-protein interactions based on mimicking pTyr-containing peptide ligands as well as SH2 structure-based de novo design of nonpeptide templates that can capture key binding sites on the target protein. Noteworthy are peptidomimetic and nonpeptide inhibitors of Src, Lck, Grb2, PI-3K, and Zap70 from pioneering efforts that led to the first examples of cellularly and in vivo active SH2 inhibitors. This mini-review highlights key achievements in SH2 inhibitor drug discovery with an emphasis on peptidomimetic and nonpeptide lead compounds in terms of structure-based design, key chemical and biological properties, and proof-of-concept studies relative to further defining the role(s) of SH2 domains in signal transduction processes, cellular functions, and in vivo disease models.

This study was conducted to estimate agreement and explain differences between treatment decisions and associated fees recommended by dentists and by a computer-based decision-support program (TxDENT 2.0). The treatment fees associated with forty-eight clinical records of patients attending a dental school clinic provided a measure of correlation and agreement between treatments recommended by TxDENT and by clinical instructors with students. The average difference between the two methods of forecasting fees was $466, and a regression line (y=0.43x+407) with an r-value of 0.54 indicated the strength of the relationship. The differences between methods increased as the cost of treatment increased, due largely to disagreements about the need to restore or replace weak or missing teeth. There is reasonable agreement between TxDENT and the collaborative treatment plans of clinical instructors with their students, which suggests that this computer-based decision-support system for screening patients in a standardized way could be a helpful predictor of treatment provided in a dental school clinic.

The purpose of this study was to develop a diagnostic system with which to determine the adequate area for artificial tooth arrangement on the posterior residual ridge. Edentulous plaster models and occlusion rims were measured by a non-contact type shape measurement system. Three trigonal pyramids and their impressions on the occlusion rims were used as landmarks for the analysis and superimposition of the analysis results for the upper and lower ridges. The data points were obtained at intervals of 0.5 mm in the lateral direction and of 0.25 mm in the anteroposterior direction, and were interpolated by cubic spline curves in the lateral direction. When the ridge contour of the reconstructed image came in contact with the tangent line inclined at 30 degrees to the tentative plane of occlusion at the buccal and lingual sides in the frontal section, the area between their points of contact on both sides was comparatively flat and was regarded as adequate for the artificial posterior tooth arrangement in this study. This diagnostic system seems to be useful in determining the adequate area for the artificial tooth arrangement on the posterior residual ridges of edentulous plaster models and in displaying their horizontal relationship.

Mean cerebral blood flow (mCBF) was measured by SPECT using the 99mTc-ECD-Patlak-Plot method in a selected group of 61 normal non-hospitalized subjects aged 51 to 91 years. The mCBF values showed 48.4 +/- 4.7 ml/100 g/min in aged 50-59 years group, 49.9 +/- 5.9 ml/100 g/min in aged 60-69 years group, 46.4 +/- 6.5 ml/100 g/min in aged 70-79 group, 38.0 +/- 3.7 ml/100 g/min in aged 80-89 years group, 38.9 ml/100 g/min in aged 90-99 years group. There was a statistically significant reduction of mCBF with advancing age (R = -0.41; p = 0.001). Women have significantly higher mCBF values than men up to aged 70 years group. In this study, there was no significant laterality in the mCBF between right and left hemispheres in all decade groups. The history of hypertension, alcohol consumption, and cigarette smoking failed to show significant difference in the mCBF values. The present study shows that normal aging is associated with mCBF reduction.

We present three patients who showed, in addition to signs of callosal interruption, a variety of abnormal motor behaviour of the left hand dissociated from conscious volition, in the absence of pathological grasping phenomena. The abnormal movements of the left hand consisted of (i) antagonistic movements to the right; (ii) non-antagonistic, irrelevant movements to the right; (iii) symmetric movements to the right in which the left hand sometimes preceded the right, and (iv) occasional inability to move at will during a bimanual task. From these observations and a review of previous publications, we propose that, in most right-handed subjects; diagonistic dyspraxia could be defined as abnormal motor behaviour of the left hand activated by voluntary movements of the right hand. Motor phenomena similar to diagonistic dyspraxia but attributable to impulsive groping movements induced by medial frontal lobe pathology should be excluded from diagonistic dyspraxia. Comparison of MRIs of the three patients with those of five patients who developed no diagonistic dyspraxia following an infarction of the corpus callosum, with or without medial hemispheric involvement, revealed that damage to the ventral part of the posterior end of the body of the corpus callosum was crucial for the development of diagonistic dyspraxia. Since the commissural fibres between the superior parietal lobules pass through the caudal part of the body of the corpus callosum, and also since there is accumulating evidence that the human superior parietal lobule is concerned with selection of movement based on the integration of visual and/or somatosensory information, we infer that diagonistic dyspraxia is produced by a disconnection of the right superior parietal lobule from the left which is dominant for volitional control of movement in most right-handed subjects.

The crystal structure of the hydantoin 1-[(S)-1'-aminoethylmalonyl benzyl ester]-(S)-4-methylimidazolidin-2,5-dione (1) derived from the peptide H-Ala-gAla-mGly-OBzl, having the retro-inverso modification of the Ala-Gly bond, has been determined by x-ray diffraction analysis. The crystals are orthorhombic, space group P2(1)2(1)2(1) with a = 6.539, b = 14.721, c = 17.101 A, z = 4. The structure was solved by direct methods and refined with anisotropic thermal factors to a final R value of 0.067 for the 947 observed reflections. Reversal of the Ala-Gly amide bond perturbs the folding tendency of the backbone shown by the parent peptide t-BuCO-Ala-Gly-NHiPr. The gem-diamino residue, gAla, and the malonyl moieties are found in the helical and the extended conformations, respectively. Intramolecular hydrogen bonding is not observed. The molecules in the crystal are held together by the formation of two intermolecular hydrogen bonds of the N-H ... O=C type with N ... O distances of 2.86 and 3.17 A, respectively.

We studied a clinical significance of hypertension and diabetes mellitus between silent brain infarction and symptomatic brain infarction. History of hypertension was present in 50% of silent infarction and in 53.3% of symptomatic infarction. Untreated hypertension was more frequent in symptomatic infarction than silent infarction (28.3% vs 16.7%) and the control of the blood pressure was very poor even if the patients with symptomatic infarction was treated with antihypertensive drugs. 66.7% of silent infarction with hypertension was treated with antihypertensive therapy and the control of the blood pressure was also relatively good. In the population with silent infarction, good control of the blood pressure was important for the prevention of symptomatic infarction. Diabetes mellitus with long history was strongly related to symptomatic infarction as compared with silent infarction. The prevalence of both hypertension and diabetes mellitus was high in the population with symptomatic infarction as compared with silent infarction and control individual.

We report two cases of typical global aphasia without hemiparesis due to cerebral embolism. Case 1 was a 65-year-old right-handed man with a history of old myocardial infarction. No spontaneous speech was noted by his family. Neurological examination upon admission revealed confusional state, global aphasia, conjugate deviation to the left and slight drift of the outstretched right limbs. The right hemiparesis rapidly recovered after admission. CT scan performed on the second hospital day showed discrete low density areas in the left posterior frontal lobe and left temporo-parietal regions. The extent and severity of his global aphasia were unchanged. The second case was an 82-year-old right-handed man with a history of atrial fibrillation. He was admitted to our hospital one hour after he was found unable to speak. Neurological examination upon admission revealed global aphasia, conjugate deviation to the left and suspected right homonymous hemianopia by confrontation. There was no sign of hemiparesis. CT scan showed extensive low density area in the left temporo-parietal regions. In both cases, cerebral angiography failed to demonstrate any occlusion of intra- and extra-cranial blood vessels. IMP-SPECT showed a depression of cerebral blood flow in the left anterior and posterior watershed areas in case 1 and 2. In the literature, there have been 20 cases of global aphasia without hemiparesis including our two cases. In many cases, the initial symptom was inability or difficulty in speaking.(ABSTRACT TRUNCATED AT 250 WORDS)

The medical records and autopsy data of patients over the age of 70 years at death with a diagnosis of cortical artery infarction (CAI) in the Yokufukai Geriatric Hospital were reviewed. Among 690 autopsied cases from 1981 to 1988, there were 45 cases (21 men and 24 women) with CAI available for this study. Fourteen cases (31.1%) suffered CAI while hospitalized for another disorder. Their ages at death ranged from 70 to 102 years with a mean of 82.4 years. From the results of this neurological and psychological analysis, the residuals of senile stroke were classified into six subtypes: 1) cerebrovascular dementia, 2) cerebrovascular Parkinsonism, 3) pseudobulbar palsy, 4) chronic stage of aphasia, 5) slowly-progressive decreased motivation or spontaneity without dementia, 6) the so-called bedridden state (prolonged vegetative or apallic state). Sixty-nine percent had anamnetic hypertension before the stroke. The ages at which they became bedridden ranged from 69 to 102 years with a mean of 81.8 years. Within one year after becoming bedridden, 83.3% of all patients died. The bedridden state in the elderly with residual CAI indicated a poor prognosis within one year after stroke. Causes of death included brain death in 22.3% of all patients, pneumonia in 20.0%, and digestive bleeding in 8.9%.

Thirty-one consecutive cases of intracerebral hemorrhage (ICH) in the elderly (over 70 years at the onset) were reported with special reference to neurological evaluations, prognosis and mortality in the acute phase. There were 11 men and 20 women with ICH, who were admitted to the Yokufukai Geriatric Hospital within 24 hours after the onset of ICH. Their ages at the onset ranged from 71 to 93 years with a mean of 81.1 years. The lesion location showed 5 cases with thalamic hemorrhage, 4 cases with putaminal hemorrhage, 6 cases with subcortical hemorrhage, 7 cases with cerebellar hemorrhage, 8 cases with mixed hemorrhage and 1 case with unclassified hemorrhage. 61.3% of all cases showed the onset during daytime but the remaining awoke in the morning with their symptoms or had the onset from the stage of the bedridden state. The classical prodromal symptoms headache and nausea or vomiting were found in 30% and 54.8%, respectively. Two cases with cerebellar hemorrhage were accompanied by vertigo. Twenty-four patients had consciousness disturbance at admission. There were 18 cases with right or left hemiparetic symptoms, 5 cases with tetraparesis, and 5 cases without motor dysfunction. The remaining already had hemiparesis due to old stroke. Patients with mixed hemorrhage usually exhibited conjugate deviation. In 9 of 31 cases there were mental symptoms such as wandering or night delirium. The 30-day mortality rate was 64.5% and sixty-five percent of them died within 6 days after the onset of ICH. Consciousness at admission was the overwhelming predictive factor.(ABSTRACT TRUNCATED AT 250 WORDS)

The alveolar bone of edentulous ridge is resorbed after the teeth extraction and the subsequent denture insertion. For the periodontal structure, the stress transmitted along the longitudinal axis is favorable, but the horizontal stress is destructive. Under the overdenture application which the retained teeth have the reduced clinical crown, it is possible to prevent the alveolar bone resorption and to improve the involved teeth. However it is difficult for the inclined teeth to get the successful results. In a case, having a few remained teeth contained the embedded root stump and the overdenture being applicated, we obtained the suggestion as follows. 1. Also the embedded root stump is useful to prevent the alveolar bone resorption. 2. The top and direction of longitudinal axes of the inclined abutment teeth can be determined by means of surveying the least teeth movement when the stress was applied to the teeth by the fingers with dental pincette. 3. Also to the inclined abutment teeth, it is possible to transmit the stress along the longitudinal axes, when the overdenture has the contact with the short dome coping at the top and in the inferior area to the longitudinal axes inclined, and is relieved in the superior area to its axes.

The medical records and autopsy data of patients over the age of 70 years at death with a diagnosis of intracerebral hemorrhage (ICH) in the Yokufukai Geriatric Hospital were reviewed. All cases with ICH caused by head injury, rupture aneurysms or arteriovenous malformations were excluded from this study. There were 73 autopsied cases with spontaneous ICH from January 1978 to September 1988. There were 33 men and 40 women. Fourteen percent of the patients had a stroke while hospitalized for another disorder. Their ages at death ranged from 70 to 99 years with a mean of 81.8 years. Of these, 48 cases (66%) were 70 years or older at the time of ICH. In the senile ICH (over 70 years), the following characteristics were observed; (1) the most common location was the thalamus, which accounted for 33.3% of the hemorrhage. (2) subcortical and cerebellar hemorrhage accounted for 16.6% and 14.6% of the total, respectively. (3) there was no pontine hemorrhage. Fifty-seven percent had anamnestic hypertension before the stroke. The ages at which they became bedridden state ranged from 62 to 92 years with a mean of 79.5 years. This study revealed that the non-organic factors such as insidious generalized muscular weakness or decreased spontaneity were important as causes of the deterioration of ADL in the chronic stage of the senile ICH. Within one year after becoming bedridden state, 76.1% of all patients died. The bedridden state in the elderly with the residuals of ICH indicated a poor prognosis. As causes of death, pneumonia occurred in 28.8% of all patients, brain death in 19.2%, and sudden death in 12.3%.

Candidemias were reviewed in 22 elderly patients hospitalized in Yokufukai Geriatric Hospital. Their ages ranged from 62 to 101 years, with a mean age of 81 years. Sixteen patients had either old cerebrovascular disease or senile dementia. In seven patients, synchronous or metachronous bacteremia in the blood culture was associated with the candidemia. Eighty-six percent of total candidemias were related to intravenous hyperalimentation (IVH). The mean duration from the start of IVH to candidemia was 46 days. Eleven patients (50%) developed candidemia within one month after the beginning of IVH. Fourteen patients had the IVH catheters changed one or more times before the time of positive candida in the blood culture. The mean duration from the start of IVH to candidemia was 59 days. Eight patients, on the other hand, had the catheters unchanged and the mean duration was 23 days. Ninety-six percent were receiving broad-spectrum antibiotic therapy at the time of the positive candida in blood culture. Eight patients developed DIC. The overall mortality was 91% (twenty patients) and thirteen (65%) of them died within one month after the onset of candidemia. There was no difference in mortality when all candidemic patients received no anti-mycotic therapy were compared with the patients given any amount of miconazole or 5-FC. The causes of death for candidemic patients included fungemic shock (6 patients), hemorrhagic shock (4 patients), and shock associated with DIC (3 patients). From the results of this study, candidemia in the elderly was produced by various underlying diseases such as central nervous system diseases or pneumonia.(ABSTRACT TRUNCATED AT 250 WORDS)

The records of 1280 patients autopsied at the Yokufukai Geriatric Hospital from October 1, 1973 to August 31, 1987 were reviewed and 75 patients with untreated lung cancer, aged 70 or older, were selected. The mean age and standard deviation was 82.1 +/- 5.4 years. Male consisted of 34 subjects and 41 were female of. Histological study revealed 42 cases of adenocarcinoma, 19 cases of squamous cell carcinoma, 7 cases of small cell carcinoma, 2 cases of large cell carcinoma, 1 case of carcinoid and 4 cases of the other types. The mean survival period of 44 untreated patients diagnosed as lung cancer during life was 21.1 +/- 24.1 months. The mean survival periods for 24 patients with adenocarcinoma and 11 patients with squamous cell carcinoma were 24.0 +/- 29.3 and 12.9 +/- 11.7 months, respectively. There was no statistically significant difference in the mean survival period of adenocarcinoma and squamous cell carcinoma. 9% of 44 untreated lung cancers survived for at least 5 years, although the survival rate was slightly lower than that generally reported in the literature. On the basis of staging of TNM classification at the autopsy, the mean survival period from the diagnosis for 13 patients with stage 1 and 27 patients with stage 4 were 27.5 +/- 33.3 and 18.5 +/- 19.7 months, respectively. The incidence of brain metastasis in 75 cases was 14.7%. In this study, adenocarcinoma was more predominant in the elderly (56.0%). An inverse relationship of age to stage was partially observed.

A 61-year-old right-handed man fell downstairs and was found unconscious. There was no abnormality in the general physical examinations. Neurological examinations revealed a quadrantanopia. Neuropsychological examination revealed an impairment in recent verbal memory, alexia, agraphia, object agnosia, color naming difficulty, prosopagnosia, and visuospatial constructional disability. CT scan demonstrated subcortical hematomas in the temporo-occipital regions of both hemispheres. MRI demonstrated extensive low-intensity lesions in the lingual, fusiform and posterior inferior temporal gyri on both hemispheres. Both inferior longitudinal fasciculi were also affected. His neuropsychological deficits seem best described as a typical form of associative visual agnosia. From the results of neuroradiological findings, the authors emphasize that associative visual agnosia might be produced by an intrahemispheric disconnection between the visual cortices and the temporal lobes which are supposed to be the storage site of the engrams of visual memories. Moreover, the neuropsychological findings suggest that the visuo-constructional ability to convert the two-dimensional input to the three-dimensional construction and the capacity of three-dimensional imagination were severely impaired in our patient. It was considered that these neuropsychological features play an important role in the recognition difficulties of associative visual agnosia.

A 61 year-old right-handed man, a president of a company fell downstairs and was found unconscious on January 1, 1985. He was admitted to a hospital and he had been unresponsive for 10 days. As he recovered from the consciousness disturbance, he complained of difficulties in discrimination of common objects and in recognition of familiar faces. The patient was admitted to our hospital for the closer examination on July 29, 1985. There was no abnormality in the general physical examination on admission. Neurological examinations revealed no significant deficits except visual field disturbance. In the results of WAIS, the verbal IQ was 108, but the performance IQ was unmeasurable because of a presence of object agnosia. His spontaneous speech was fluent without paraphasia, perseveration or dysprosody. His auditory comprehension of spoken language and repetition were spared. Neuropsychological examinations revealed an impairment in the recent verbal memory, alexia, agraphia, object agnosia, color naming difficulty, prosopagnosia and visuospatial constructional disability. The patient exhibited three major neuropsychological characteristics. Firstly, the recognition of the objects which were presented by the photograph or line drawing was more severely impaired than the real objects. Secondly, the object naming difficulty was more pronounced in the presentation at an unusual angle than in the free presentation. Thirdly, the patient made poor performance in reproduction of the models by photographic presentation as compared with the presentation of the real models in the three-dimensional block construction test. The CT scan performed on January 4, 1985 demonstrated subcortical hematomas with surrounding edema in the temporo-occipital regions of both hemispheres.(ABSTRACT TRUNCATED AT 250 WORDS)

Inverse ocular bobbing (IOB) is an uncommon abnormal eye movement. Its characteristics are slow downward eye movement with rapid upward return, a nadir at the extreme of downgaze position and horizontal roving eye movement. We present a case of IOB associated with cerebral embolism and diabetes insipidus. A 69 year-old right-handed woman was admitted because of a consciousness disturbance. She had been well until November 10, 1983, when she was found dysarthric and left hemiplegic. On admission, she was stuporous. There were conjugate deviation to the right, central left facial and hypoglossal palsy, left hemiplegia with spasticity, left hyperreflexia with positive pathologic reflex and anosognosia. A CT scan performed on November 11 showed extensive hypodense area in the region supplied by the right middle cerebral artery. A right carotid angiography revealed multiple occlusions in the top of the right internal carotid artery with poor collateral circulation. After admission, the level of consciousness gradually deteriorated and became comatose on November 18, when the following abnormal eye movements were observed. Following spontaneous horizontal roving eye movement, both eyes deviated downward slowly from midposition, taking 1 to 2 seconds to reach the nadir. The eyes then remained in the position for 1 to 15 seconds, followed by a rapid return to the midposition. These abnormal eye movements are compatible with inverse ocular bobbing (IOB) described by Knobler. Electronystagmography detected typical IOB and spontaneous upward nystagmus. There was no evidence of hypoxia when these abnormal eye movements were present.(ABSTRACT TRUNCATED AT 250 WORDS)