Entrainment of the circadian clock in the liver by feeding.

Circadian rhythms of behavior are driven by oscillators in the brain that are coupled to the environmental light cycle. Circadian rhythms of gene expression occur widely in peripheral organs. It is unclear how these multiple rhythms are coupled together to form a coherent system. To study such coupling, we investigated the effects of cycles of food availability (which exert powerful entraining effects on behavior) on the rhythms of gene expression in the liver, lung, and suprachiasmatic nucleus (SCN). We used a transgenic rat model whose tissues express luciferase in vitro. Although rhythmicity in the SCN remained phase-locked to the light-dark cycle, restricted feeding rapidly entrained the liver, shifting its rhythm by 10 hours within 2 days. Our results demonstrate that feeding cycles can entrain the liver independently of the SCN and the light cycle, and they suggest the need to reexamine the mammalian circadian hierarchy. They also raise the possibility that peripheral circadian oscillators like those in the liver may be coupled to the SCN primarily through rhythmic behavior, such as feeding.

Resetting central and peripheral circadian oscillators in transgenic rats.

In multicellular organisms, circadian oscillators are organized into multitissue systems which function as biological clocks that regulate the activities of the organism in relation to environmental cycles and provide an internal temporal framework. To investigate the organization of a mammalian circadian system, we constructed a transgenic rat line in which luciferase is rhythmically expressed under the control of the mouse Per1 promoter. Light emission from cultured suprachiasmatic nuclei (SCN) of these rats was invariably and robustly rhythmic and persisted for up to 32 days in vitro. Liver, lung, and skeletal muscle also expressed circadian rhythms, which damped after two to seven cycles in vitro. In response to advances and delays of the environmental light cycle, the circadian rhythm of light emission from the SCN shifted more rapidly than did the rhythm of locomotor behavior or the rhythms in peripheral tissues. We hypothesize that a self-sustained circadian pacemaker in the SCN entrains circadian oscillators in the periphery to maintain adaptive phase control, which is temporarily lost following large, abrupt shifts in the environmental light cycle.

Clinical-diffusion mismatch defined by NIHSS and ASPECTS in non-lacunar anterior circulation infarction.

OBJECTIVES: Instead of the mismatch in MRI between the perfusion-weighted imaging (PWI) lesion and the smaller diffusion-weighted imaging (DWI) lesion (PWI-DWI mismatch), clinical-DWI mismatch (CDM) has been proposed as a new diagnostic marker of brain tissue at risk of infarction in acute ischemic stroke. The Alberta Stroke Program Early CT Score (ASPECTS) has recently been applied to detect early ischemic change of acute ischemic stroke. The present study applies the CDM concept to DWI data and investigated the utility of the CDM defined by the NIH Stroke Scale (NIHSS) and ASPECTS in patients with non-lacunar anterior circulation infarction. METHODS: Eighty-seven patients with first ever ischemic stroke within 24 hours of onset with symptoms of non-lacunar anterior circulation infarction with the NIHSS score>or=8 were enrolled. Initial lesion extent was measured by the ASPECTS on DWI within 24 hours, and initial neurological score was measured by the NIHSS. As NIHSS>or=8 has been suggested as a clinical indicator of a large volume of ischemic brain tissue, and the majority of patients with non-lacunar anterior infarction with score of NIHSS<8 had lesions with ASPECTS>or=8 on DWI, so CDM was defined as NIHSS>or=8 and DWI-ASPECTS 8>or=. We divided patients into matched and mismatched patient groups, and compared them with respect to background characteristics, neurological findings, laboratory data, radiological findings and outcome. RESULTS: There were 35 CDM-positive patients (P group, 40.2%) and 52 CDM-negative patients (N group , 59.8%). P group patients had a higher risk of early neurological deterioration (END) than N group patients (37.1% vs 13.5%, p<0.05), which were always accompanied by lesion growth defined by 2 or more points decrease on ASPECTS (36 to 72 hours after onset on CT). The NIHSS at entry were significantly lower in the P group, but there was no difference in the outcome at three months measured by the modified Rankin Scale. However, CDM was not an independent predictor of END by multiple logistic regression analysis. CONCLUSIONS: Patients with CDM had high rate of early neurological deterioration and lesion growth. CDM defined as NIHSS>or=8 and DWI-ASPECTS>or=8 can be another marker for detecting patients with tissue at risk of infarction, but more work is needed to clarify whether this CDM method is useful in acute stroke management.

Deteriorating ischemic stroke in 4 clinical categories classified by the Oxfordshire Community Stroke Project.

BACKGROUND AND PURPOSE: The aim of this study was to investigate the frequency, possible predictive factors, and prognosis of deteriorating ischemic stroke in 4 clinical categories according to the classification of the Oxfordshire Community Stroke Project (OCSP). METHODS: A total of 350 patients with first-ever ischemic stroke who presented within 24 hours of onset were enrolled. Based on the OCSP criteria, cerebral infarctions were divided into the following 4 clinical categories: total anterior circulation infarcts (TACI), partial anterior circulation infarcts (PACI), lacunar infarcts (LACI), and posterior circulation infarcts (POCI). Clinical deterioration was defined as a decrease of >/=1 points in the Canadian Neurological Scale (CNS) (in TACI, PACI, and LACI) or Rankin Scale (RS) (in POCI) during 7 days from the onset. In each clinical category, deteriorating (D) and nondeteriorating (ND) patients were compared in terms of their background characteristics, risk factors, vital signs, laboratory data, and cranial CT at the time of hospitalization. The acute-phase mortality and functional outcome were also compared. RESULTS: The subjects comprised 86 patients (24.6%) with TACI, 63 (18.0%) with PACI, 141 (40.3%) with LACI, and 60 (17.1%) with POCI. Overall, 90 patients (25.7%) deteriorated. The frequency was very high in TACI (41.9%), followed by LACI (26.2%) and POCI (21.7%), whereas it was very low in PACI (6. 3%). There were some clinical variables that differed significantly between D and ND groups. In the patients with TACI, early abnormalities of the cranial CT and significant stenoses in corresponding arteries were more frequent in the D than the ND group. In those with LACI, the CNS and hematocrit were lower in the D than the ND group. In those with POCI, cerebral atrophy was more severe and significant stenoses in vertebrobasilar arteries were more frequent in the D than ND group. The mortality of the D groups of patients with TACI and POCI exceeded 35%, and the functional outcome was worse in the D group than in the ND group of patients with TACI, LACI, and POCI. CONCLUSIONS: The frequency of deterioration in acute ischemic stroke significantly differed among the OCSP subgroups, and deterioration worsened the prognosis. There were some factors that could predict deterioration: early CT findings in TACI, large-artery atherosclerosis in TACI and POCI, and stroke severity in LACI. Further research to find sophisticated radiological and chemical markers appears to be needed.

Sequence and expression of a gene encoding a ribosomal protein S4 homolog from Drosophila melanogaster.

We describe a Drosophila melanogaster cDNA clone encoding an amino acid (aa) sequence 75% identical to human ribosomal protein S4 (RPS4). The D. melanogaster RPS4 has 260 aa, if the NH2-terminal methionine is removed after translation of the mRNA. The mRNA for the protein is about 1 kb in length and is detected throughout the developmental stages tested (i.e., embryo, larva, pupa and adult). The cDNA clone hybridizes to two sites on the X chromosome, 1B1-2 and 3A3-6.

Identification of the mammalian homologues of the Drosophila timeless gene, Timeless1.

We have identified novel mammalian homologues of a Drosophila clock gene, timeless, and designated them as human TIMELESS1 (hTIM1) and mouse Timeless1 (mTim1), respectively. These genes were mapped by FISH to chromosomal regions 12q12-13 in human and 10D3 in mouse. The deduced amino acid sequences of hTim1 and mTim1 proteins were 1208 and 1197 amino acids in length and shared 83% identity. Northern blot analysis identified a single transcript of 4.5 kb expressed widely in many tissues examined. Unlike the Drosophila counterpart, the levels of the mTim1 transcript exhibited no prominent circadian oscillation in the mouse brain.

Polymyositis-dermatomyositis and non-Hodgkin's lymphoma.

An association between polymyositis-dermatomyositis (PM/DM) and malignancy has been reported. However, controversy exists regarding a direct causal relationship between the two diseases. We describe a patient who had had PM and subsequently developed non-Hodgkin's lymphoma, and discuss the possibility of their causal relation.

[Clinical investigation of striatocapsular infarction].

We investigated the clinical profile, etiological factors, neuropsychological features and radiological characteristics of 17 cases of striatocapsular infarction (SCI). SCI was defined as the following CT criteria: the area of infarction included the internal capsule and striatum, the maximum diameter of the lesion exceeded 2.0 cm without cortical involvement. There were 9 men and 8 women with mean age of 58 years. Five patients had lesions mainly involving the caudate head (anterior type) and the other 12 had lesions mainly involving the putamen (lateral type), 6 with left side lesion and 6 with right side lesion. Motor weakness was observed in all patients, and the upper extremities were preferentially involved, while in 9 patients face, upper and lower extremities were simultaneously involved. Etiological investigation revealed that 8 patients were cardioembolic stroke, 2 were artery-to-artery embolism and 2 were MCA stem occlusive disease, while the remaining 5 were undetermined. When compared with patients with lacunar infarction (LI), patients with SCI had significantly more frequent cardioembolic sources (47% vs 17%, p < 0.05) and less frequent hypertension (41% vs 80%, p < 0.01). In acute phase, neuropsychological abnormalities were found in 15 patients. Anterior type patients had psychiatric symptoms such as abulia, depression and agitation, while left lateral type patients had aphasia and right lateral type patients had hemispatial neglect or anosognosia. These symptoms gradually improved, although in most patients subtle abnormalities lasted over chronic phase. In 11 out of 13 patients who underwent SPECT using 99mTc-HMPAO, blood flow was decreased in overlying cerebral cortex besides the infarcted area.(ABSTRACT TRUNCATED AT 250 WORDS)

[Type of syndrome, location, size and etiology of capsular lacunar infarction].

We investigated the types of clinical syndrome, location, sizes and presumed causes of 49 patients with capsular lacunar infarction. Clinical syndromes were classified according to Fisher's criteria into pure motor hemiparesis (PM), sensorimotor stroke (SM) and ataxic hemiparesis (AH) including dysarthria clumsy hand syndrome. Cases who had higher brain dysfunctions or brainstem syndromes were excluded. The size of infarcts was expressed as the volume on brain CT. All patients underwent 12-lead ECG and 2-dimension echocardiography. Twenty three patients (47%) underwent angiography or carotid ultrasonography. Lesion sites on CT were divided into three groups, i.e., perforating branch of ACA (PACA), perforating branch of MCA (PMCA) and anterior choroidal artery (AC). Lesion sizes of AH were significantly smaller than those of SM and tended to be smaller than those of PM. In AH patients, no cardioembolic sources nor large arterial lesions could be detected, whereas 40% in SM patients and 30% in PM patients had cardioembolic sources and 33% in SM patients and 75% of PM patients had large arterial lesions. The lesion volume was classified into two groups, larger and smaller than 1 ml. The larger volume group had more frequent cardioembolic sources than the small volume group (42% and 17% respectively, p less than 0.05), but no significant difference in frequency of large artery lesions was found among the two groups. Patients with "large striatocapsular infarct" had frequent cardiac and arterial lesions (60% and 40% respectively). Patients with AC territory infarction had more infrequent but not significant cardiac and arterial lesions than patients with PMCA territory infarction. All patients with PACA territory infarction presented PM.(ABSTRACT TRUNCATED AT 250 WORDS)

[Neuropsychological comparison between dementia of Alzheimer type and multiple subcortical infarction by easily applicable test battery].

We compared the neuropsychological findings between dementia of Alzheimer type (DAT) and multiple subcortical infarction (MSI) using easily applicable test battery. Patients with DAT (N = 27) fulfilled the criteria of NINCDS-ADRDA for probable DAT and belonged to the mild degree in the DSM-III-R criteria for dementia. Patients with MSI (N = 30) scored more than 7 points in Hachinski Ischemic Score and were physically independent (Rankin Disability Scale < or = 3). Patients with DAT showed significantly more impaired performance than MSI in Mini-Mental State Examination, copy and delayed recall of Rey-Osterrieth Complex Figure Test and trial 5 of Rey Auditory-Verbal Learning Test, while patients with MSI achieved fewer categories and made more perseverative errors on Wisconsin Card Sorting Test than patients with DAT. Among these tests, delayed recall of Rey-Osterrieth Complex Figure Test seemed to be the most sensitive to discriminate DAT from MSI. These findings were thought to be compatible with the pathological facts that the degenerative process progresses from temporo-parietal lobe in DAT and frontal-subcortical region in MSI.

[A case of diagnostic dyspraxia without ideomotor apraxia by callosal lesion].

A case of diagnostic dyspraxia was reported. A 57-year-old right handed male had been suffering from the lack of cooperation between his right and left hands for six months. Except for decreased deep tendon reflexes in all extremities, there were no abnormal findings on neurological examination. On neuropsychological examination, he was attentive, well orientated and his spontaneous speech, comprehension, naming, repetition and reading were intact. There was peculiar dissociative behavior between his right and left hands. For instance, he put a cigarette or coin in the pocket with his right hand then his left hand took out and replaced them, and he buttoned his shirts with his right hand but then unbuttoned with his left hand. These left hand oppositional behavior to his right hand were triggered by voluntary activities of his right hand. Left unilateral agraphia was also revealed but ideomotor apraxia, compulsive manipulation of tools and grasp reflex were not demonstrated. T1-weighted MRI demonstrated irregular low signal intensity areas extending from the genu to the body of the corpus callosum. No definite lesion was detected in the medial aspect of the frontal lobe. Only small numbers of diagnostic dyspraxia have been reported and such cases without ideomotor apraxia or medial frontal lesion are even rare. MRI is very useful for detecting the lesion of the corpus callosum.

[A case of primary low spinal fluid pressure syndrome complicated by bilateral subdural hematoma--study of the cerebrospinal fluid circulation].

A 43-year-old man with no history of trauma or neurosurgical procedure was admitted our hospital because of orthostatic headache made worse in upright position. Spinal fluid pressure was 0 mmH2O, and CT scan revealed wide cortical sulci and ventricles. In the 26th hospital day he had severe headache and CT scan revealed bilateral subdural hematoma, then neurosurgical procedure was done. About 2 months later, he was relieved of the headache and spinal fluid pressure returned to normal. We performed lumbar isotope cisternography and isotope choroid plexography in our case when low spinal fluid pressure and normalized pressure. Isotope cisternography revealed the radioactivity counts decreased rapidly in low pressure and normal in normal pressure. On the other hand isotope choroid plexography was almost no difference between low and normal pressure. Our data suggest that primary low spinal fluid pressure syndrome is not caused by hypoproduction, but by an undetectable leak from a minute tear in a spinal root sleeve or hyperabsorption at the spinal arachnoid membrane.

[Accuracy of three-step diagnosis in discriminating subtypes of acute ischemic stroke].

The aim of this study is to evaluate the accuracy of three-step diagnosis in discriminating subtypes of acute ischemic stroke. A total of 120 consecutive patients with first-ever ischemic stroke, admitted to one general hospital, were prospectively studied. In the first step (within 24 hours of clinical onset), the first diagnosis was made according to clinical symptoms and signs, and patients were subdivided into four groups according to the classification of Oxfordshire Community Stroke Project: lacunar infarcts (LACI), total anterior circulation infarcts (TACI), partial anterior circulation infarcts (PACI), and posterior circulation infarcts (POCI). In the second step (24 hours to 72 hours from the onset), neuroimaging diagnosis was performed by CT and/or MRI. Four lesion sites were classified: 1) small subcortical infarction < or = 1.5 cm in diameter in the perforating artery territory (SSI), 2) supratentorial cortical or striatocapsular infarction (CI), 3) low-flow infarction (LFI) which includes centrum semiovale infarct and internal junctional infarct, and 4) posterior circulation infarction other than SSI (PI). In the third step, etiological diagnosis was made by examination including trans-thoracic echocardiography and MRA (3-D, PC). In accordance with the TOAST Study, the presumed stroke mechanism was categorized as either small-vessel occlusion (lacune), cardioembolism (CE), large-artery atherosclerosis (LAA), or others. The majority of patients with TACI, PACI or POCI showed the corresponding lesions on CT or MRI, while only 69% of LACI patients demonstrated SSI. Seventy-five percent of patients with TACI were categorized as CE in the third diagnosis, while the etiology of the patients with PACI was either CE or LAA in equal numbers. Only 60% of LACI patients were classified as lacune and 21% of them as LAA. Patients with LACI but classified as LAA usually had atypical clinical symptoms (e.g. monoparesis) and lesions other than SSI. The positive predictive value (PPV) of lacune in the combination of LACI and SSI was 0.75. Eighty-two percent of patients with CE had atrial fibrillation (af), which was the most frequent cardioembolic source. When patients with TACI or PACI had af, the PPV of CE was 0.93, but when they did not, the PPV of LAA was only 0.68. The etiology of POCI was variable. In conclusion, the agreement of the three-step diagnosis is considerable, but more rigorous clinical examination is needed for some clinical groups (POCI and LACI) and the etiological diagnosis of LAA.

[A case of cortical blindness confirmed by single photon emission computerized tomography and visual evoked potential].

We reported a rare case of cortical blindness in cerebral ischemia following post-anoxic state confirmed by single photon emission computerized tomography (SPECT) and visual evoked potential. A 45-year-old woman who had been suffering from bronchial asthma was admitted to our hospital because of sudden progressive dyspnea and depressed consciousness. When she arrived at the hospital by ambulance, she was in hypoxic state and fell into cardiac arrest. Her respiratory condition gradually improved with respirator assistance, and she recovered consciousness, but complained of bilateral visual loss. She had no history of any neurological or psychiatric illness, nor of drug abuse. On neurological examination, she was alert and oriented. Light reflex, optic fundi, extraocular movement and other neurological findings were all normal, with the exception of bilateral blindness. EEG showed generalized slow background activity, but cranial CT scan and MRI showed no abnormalities. 99mTc-HMPAO SPECT indicated hypoperfusion in prominent bilateral occipital and parietal lobes. Simultaneous recordings of pattern reversal visual evoked potential (VEP) and electroretinograms (ERG) using transient checkerboard pattern reversal in 15 min and 30 min checks were recorded. The results showed normal b waves but absent P100 in the bilateral eyes. From the patient's neurological symptoms and the results of SPECT and VEP, she was diagnosed as cortical blindness in post-anoxic state. On the 30th hospital day, her visual acuity and visual fields improved, but she was suspected of having visual agnosia. Eighty-five days after the onset of the neurological abnormalities, no traces of visual disturbances were observed.(ABSTRACT TRUNCATED AT 250 WORDS)

[Neuropsychological investigation in multiple sclerosis].

We studied neuropsychological performance in 10 patients with multiple sclerosis (MS). Neuropsychological test batteries consisted of Mini-Mental State Examination, Digist Span, Paired Associate Learning Test (PAL), Benton Visual Retention Test, Kohs Block-Design Test, Digit Symbol Subtest in WAIS, 'Kanahiroi" Test, Verbal Fluency and Wisconsin Card Sorting Test. In accordance with cerebral lesions on MRI, patients were divided into three groups. A: Multiple-confluent lesions, B: Discrete lesions, C: No lesion. In MS patients as a whole, performance of PAL, "Kanahiroi" Test and Verbal Fluency were significantly impaired compared with 10 age and education matched normal controls (p < 0.05), while other tests were not. In four out of five patients of A group, more than four neuropsychological tests showed below mean -2SD score of normal controls, whereas in patients of B and C group, less than three neuropsychological tests showed below -2SD score of normal controls. In conclusion, severity of cognitive impairment in patients with MS correlated with lesion extent on MRI. Patients with MS exhibited significant cognitive impairment on tasks of recent memory and mental processing speed. It is suggested that MS patients show the features of subcortical dementia.

[A case of astrocytoma of corpus callosum presented diagnostic dyspraxia].

A case of astrocytoma whose first clinical presentation was diagnostic dyspraxia was reported. A 38-year-old right-handed male experienced funny motion of his left hand triggered by voluntary movement of his right hand. One day, he tried to insert a coin into the vending machine with his right hand, then the left hand was against the other. One month after that event, he experienced headache and vertigo. On admission, there were no abnormal findings on neurological examination. On neuropsychological examination, he was cooperative, well orientated and attentive, and there were no callosal disconnection symptoms. Frontal lobe function tests were slightly impaired. T1-weighted MRI demonstrated irregular mixed signal intensity mass lesion extending from the genu to the body of the corpus callosum and the cingulate gyrus. This lesion was slightly enhanced with Gd-DTPA. Biopsy was performed and histological diagnosis was fibrillary astrocytoma. After irradiation and chemotherapy, he was discharged from the hospital without evident neurological deficit. About 20 cases of diagnostic dyspraxia have been reported and almost all of them were caused by cerebro-vascular disease. This is the first case of brain tumor who presented diagnostic dyspraxia.

A study on gastric ulcers induced by long-term fasting in rats.

The present study was performed to investigate the roles of intragastric pH and PAS positive mucus as to the incidence of gastric ulcers after long-term fasting in rats. Gastric ulcers in the forestomach and corpus were found at 4 and 6 days after fasting, respectively. The intragastric pH was significantly reduced at 1, 2, 3, 4, 6 and 7 days after fasting, but tended to have returned to control levels at 8 days. PAS positive mucus was significantly increased at 2 to 7 days, but there was no significant change at 8 days. From these results, it seems that the aggressive factor is not involved, but attenuation of the defensive factor is important as to the incidence of this type of ulcer. As one of the causes of this attenuation, a decrease in the gastric mucus volume was suggested.

[Clinicopathological study of early cancer-like advanced gastric cancer].

We had clinicopathologically studied early cancer-like advanced gastric cancer in relation to peptic ulcer (UI). Early cancer-like advanced cancers with the difficulty to distinguish from early gastric cancer were selected for materials. Result were as followed: 1) Early cancer-like advanced cancers were consisted of 133 lesions, of which 128 lesions (96.2%) had peptic ulcer in cancerous lesion (73 lesions were active stage and 55 lesions were scarring stage). 2) Early cancer-like advanced cancers were 17.0% in all advanced gastric cancers. Proper muscle cancer (in which depth of cancerous invasion is up to proper muscle coat) was more common in early cancer-like advanced cancers than in Borrmann type advanced cancers. 3) Early cancer-like advanced cancers with peptic ulcer showed wide intramucosal cancerous infiltration. Thus, average of maximum diameter was 51.8 mm. 4) Those ulcer were commonly reaching to proper muscle coat or subserosa. Submucosal fibrosis was prominent and scattered proliferation of tumor cells were often seen within fibrosis. 5) Extent of cancerous infiltration in mucosa was more wide than that in submucosa. The above findings have led us to consider that early cancer-like advanced cancers have grown because of high degree submucosal fibrosis by the deep ulcerations due to "malignant cycle".