Different X-linked KDM5C mutations in affected male siblings: is maternal reversion error involved?

Genetic reversion is the phenomenon of spontaneous gene correction by which gene function is partially or completely rescued. However, it is unknown whether this mechanism always correctly repairs mutations, or is prone to error. We investigated a family of three boys with intellectual disability, and among them we identified two different mutations in KDM5C, located at Xp11.22, using whole-exome sequencing. Two affected boys have c.633delG and the other has c.631delC. We also confirmed de novo germline (c.631delC) and low-prevalence somatic (c.633delG) mutations in their mother. The two mutations are present on the same maternal haplotype, suggesting that a postzygotic somatic mutation or a reversion error occurred at an early embryonic stage in the mother, leading to switched KDM5C mutations in the affected siblings. This event is extremely unlikely to arise spontaneously (with an estimated probability of 0.39-7.5 × 10(-28) ), thus a possible reversion error is proposed here to explain this event. This study provides evidence for reversion error as a novel mechanism for the generation of somatic mutations in human diseases.

Coexistence of insulin-derived amyloidosis and an overlying acanthosis nigricans-like lesion at the site of insulin injection.

A 59-year-old patient with diabetes mellitus had been treated with human recombinant insulin for 4 years. He developed a solid mass on his left abdomen at the insulin injection site, which had an overlying pigmented verrucous plaque and keratinized papules, similar to acanthosis nigricans (AN). On histological examination, the mass was found to contain a deposit of amyloid in the dermis, with hyperkeratosis, papillomatosis and acanthosis in the epidermis. Using immunohistochemistry, the amyloid deposits were found to be positive for insulin. A few cases of localized insulin-derived amyloid deposits at injection sites have been reported previously, but none had significant epidermal changes. The coexistence of dermal insulin-derived amyloidosis and an overlying AN-like change, as found in our patient, has not been reported previously, to our knowledge. The presence of a tumour-like lesion at the injection site should be carefully examined, as injection of insulin into amyloid deposits can result in insulin resistance.

Cholinergic drugs reverse AF64A-induced impairment of passive avoidance learning in rats.

The cholinergic neurotoxin AF64A was administered to rats in order to produce learning impairment to test the effect of cholinergic drugs. Seven days after receiving an intracerebroventricular injection of AF64A (2.5-7.5 nmol), rats were subjected to one-trial passive avoidance acquisition and tested 24 h later. Learning was significantly impaired at 3.75 nmol AF64A, a dose at which significant reduction in acetylcholine level and choline acetyltransferase and acetylcholinesterase activity in the hippocampus was observed but changes in monoamine levels in the hippocampus, general behavior, or sensory sensitivity were not observed. Arecoline (4 mg/kg, IP) and physostigmine (0.1 mg/kg, IP) significantly decreased the learning impairment produced by AF64A (3.75 nmol) when given before the acquisition of passive avoidance learning but not when given after the acquisition or before the 24 h retention test. These drugs and oxotremorine (0.1 mg/kg, IP) given immediately after the acquisition, however, improved passive avoidance retention when the interval between the acquisition and the test was shortened to 1 h. These results indicate that the impairment of learning in AF64A-treated rats is caused by a memory retention deficit and suggest that such impairment can be effectively ameliorated by cholinergic drugs.

Correlation between rotational behaviors and neurochemical changes associated with damage of rat striatum: Analysis using unilateral microinjection of kainic acid.

The correlation between rotational behaviors and neurochemical changes associated with the striatal damage induced by an unilateral microinjection of kainic acid were investigated. Shortly after the unilateral striatal injection of kainic acid, rats exhibited contralateral rotational behaviors, and these changes were antagonized by the simultaneous striatal injection of haloperidol. On the other hand, systemic injection of methamphetamine to animals having the lesion on nigro-striatal dopaminergic neurons exhibited ipsilateral turnings. In addition, it was found that the release of [(14)C]dopamine from striatal slices was increased by the in vitro addition of kainic acid. Following 2 days after the striatal injection of kainic acid and thereafter, the rats exhibited ipsilateral rotational behaviors and microinjection of muscimol into the ipsilateral substantia nigra of these animals altered turning movements to a contralateral type. Simultaneous nigral injection of bicuculline antagonized to the muscimol-induced contralateral turnings. These results suggest that the increase of dopamine release from dopaminergic neurons in the striatum may be involved in the occurrence of contralateral turning behaviors observed shortly after the striatal kainic acid treatment. The present results also suggest that changes in the functional states of striatonigral GABA-ergic neurons may play an important role in the occurrence of ipsilateral rotational movements at a late stage following the striatal injection of this agent.

Hepatocellular carcinoma with tumor thrombus extending into the right atrium: report of a successful resection with the use of cardiopulmonary bypass.

Hepatocellular carcinoma with a tumor thrombus extending into the right atrium has been considered beyond the reach of resection. These patients usually die within a short period because of pulmonary embolism, heart failure, or cancer progression. The only treatment is hepatic resection with removal of the tumor thrombus. A 38-year-old woman underwent left lobectomy with removal of the tumor thrombus with the use of cardiopulmonary bypass. The patient had an uneventful course and is doing well 15 months after surgery, without signs of recurrence. We have proved that hepatic resection with removal of a tumor thrombus extending into the right atrium can be carried out successfully. The next problem is whether the lives of these patients can be prolonged by this operation.

Excitatory effects of adenosine receptor agonists and antagonists on neurotransmission in guinea pig superior collicular slices.

Adenosine has excitatory actions on neurotransmission in the superior colliculus. To investigate whether adenosine A1 or A2 receptors are involved in mediating these excitatory actions, the effect of A1 and A2 receptor agonists and antagonists on the evoked postsynaptic potentials (PSP) in the superficial grey layer were tested using slices of the superior colliculus. Application of both A1 agonists, such as CHA, R-PIA, and the A2 agonist, CGS-21680 increased the amplitude of the PSP. The increase in PSP amplitude occurred gradually over 20-30 min after application of these adenosine agonists. Application of the A1 antagonist 8-CPT, and the A2 antagonists, DMPX and CGS-15943, increased the amplitude of the PSP and could not antagonize the excitatory effect of adenosine. These results suggest that the mechanism of the excitatory effect of adenosine cannot be explained by the classical concept of A1 and A2 adenosine receptor subtypes which were identified by their effect on adenylate cyclase activity.

The protective effect of hypothermia on the recovery of neural activity after deprivation of oxygen and glucose: study of slices from the hippocampus and superior colliculus.

The effect of hypothermia on the tolerance of the cortex and brain stem to anoxic insult was investigated using slices from the hippocampus and superior colliculus of the guinea pig. The postsynaptic potential (population spikes) was recorded in the granule cell layer of the hippocampal slices after electrical stimulation to the perforant path. In the case of the superior collicular slices, the postsynaptic field potential was recorded in the superficial gray layer (SG) after stimulation to optic layer (OL). Perfusion medium deprived of oxygen and glucose completely blocked the electrical activity which subsequently recovered after reintroduction of oxygen and glucose. Monitoring the electrical activity, we studied the effect of temperature (37 degrees C, 35 degrees C, 33 degrees C and 30 degrees C) during deprivation of oxygen and glucose on the survival time of each slice. With mild hypothermia (35 degrees C) the survival time of slices from the superior colliculus was 15 min whereas that of hippocampal slices was 10 min. At 33 degrees C and 30 degrees C the hypothermia had a similar protective effect on the survival time in both slices from hippocampus and superior colliculus. These results suggest that there is a regional difference in the resistance of brain tissue to anoxia, and the brain stem is more resistant to anoxia than the cortex under mild hypothermic condition (35 degrees C).

Poliomyelitis-like illness after acute asthma (Hopkins syndrome): a histological study of biopsied muscle in a case.

A case of Hopkins syndrome is presented. The patient was a 4-year-old boy who developed weakness of the right leg 2-3 days after a mild asthmatic attack. Needle electromyography revealed fasciculation discharges in the right gastrocnemius muscle. A histological study of the biopsied right quadriceps femoris muscle revealed scattered atrophic fibers, indicating lesions in the anterior horn cells of the spinal cord. This is the first reported case of Hopkins syndrome including muscle pathology.

The assessment of methyl mercaptan, an important clinical marker for the diagnosis of oral malodor.

OBJECTIVE: This study aimed to determine the clinical assessment of volatile sulfur compound (VSCs) for the evaluation of noticeable oral malodor using gas chromatography (GC). METHODS: The oral malodor of 127 adult patients was investigated using the organoleptic test and GC, and the relation between the organoleptic evaluation and VSCs were analyzed. RESULTS: The optimum cut-off values of CH3SH, H2S and total VSC (CH3SH + H2S) to discriminate between the patients with and without noticeable oral malodor were obtained from ROC curves, and determined to be 0.44, 1.10 and 2.20 ng/10 ml, respectively. The logistic regression was analyzed for estimation of the association between an organoleptic evaluation greater than a slight level and the groups with CH3SH, H2S or total VSC with concentrations above the optimum cut-off value. Only CH3SH showed an independent association with noticeable oral malodor. CONCLUSIONS: It was evident that CH3SH was a more useful marker for the evaluation of oral malodor than H2S. Moreover, it appears CH3SH is the predominant causative factor of noticeable oral malodor.

The relationship between the presence of periodontopathogenic bacteria in saliva and halitosis.

OBJECTIVE: To evaluate the association between the presence of periodontal pathogenic bacteria in saliva and halitosis in mouth air. DESIGN: Cross-sectional microbiological and clinical oral examination of adult patients. SUBJECTS: 101 adult patients (25 males, 76 females) who attended the Preventive Dentistry and Breath Odour Clinic of Kyushu Dental College. Their average age was 50.0+/-13.5 years old (mean +/- SD). SETTING: The subjects were classified into three groups: halitosis subjects with a probing depth (PD) > or = 4mm (P group), halitosis subjects without PD > or = 4mm (H group), and non-halitosis subjects without PD > or = 4mm (C group). METHODS: All subjects received a periodontal examination. Volatile sulphur compounds (VSC: hydrogen sulphide and methyl mercaptan) were measured using gas chromatography. The presence of Bacteroides forsythus, Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans and Prevotella intermedia in the saliva was detected by polymerase chain reaction. RESULTS AND CONCLUSION: The presence of B. forsythus, P. gingivalis and P. intermedia influenced the production of VSC. Specifically, the presence of B. forsythus in subjects with periodontitis was strongly correlated to the concentration of VSC in mouth air.

[Ossifying fibroma of the cranial vault. Case report].

A 68-year-old female was admitted with mild headache in the right frontal region. Physical and neurological findings were normal. Plain X-rays revealed a poorly circumscribed, osteoblastic lesion in the right frontal bone. Computed tomography scan showed that the diploic space was destroyed but that the inner and outer tables were intact. On 99mTc bone scan, a hot lesion was visible in the same region. The lesion was expressed as a low-signal intensity area on T1-weighted magnetic resonance (MR) image and as a high-signal intensity area on T2-weighted MR image. The tumor was broadly resected together with peripheral normal bone, and cranioplasty using a resin plate was performed. The tumor was mainly composed of mature, regularly aligned bone (lamellar bone) and intermingled fibrous tissue. Ossifying fibroma is a rare, benign fibro-osseous tumor that mainly involves the craniofacial bone. A few cases involving the cranial vault alone have been reported. The relevant literature is reviewed, and discussion focuses on the differential diagnosis between ossifying fibroma and monostotic fibrous dysplasia.

[Intraosseous meningioma. Case report].

An 82-year-old female was admitted with slowly progressive aphasia and right hemiparesis, accompanied by a hard, 5 x 5 cm subcutaneous swelling in the left frontotemporal region. Plain X-ray film showed a well-circumscribed round radiolucency in the left pterional region. Computed tomography (CT) scans showed an intraosseous mass lesion, homogeneously enhanced postcontrast, extending to the intracranial cavity. Bone CT demonstrated a concave appearance and partial destruction of the inner table, strongly suggesting an intradiploic origin of the tumor. Left carotid angiography revealed the mass supplied by the middle meningeal artery. Left frontotemporal craniectomy demonstrated that the inner surface of the skull was destroyed, and the dura was compressed but not invaded. Histological examination found meningotheliomatous meningioma with many psammoma bodies.

[Clinical effects of lipo-prostaglandin E1 in patients with delayed cerebral vasospasm].

Prostaglandin (PG) E1 is a potent vasodilator on the peripheral vessels and also has an inhibitory action of platelet aggregation. Thus it is expected that PGE1 may be used for the treatment of cerebral vasospasm in aneurysmal subarachnoid hemorrhage. Lipo-PGE1, the lipid emulsified PGE1, is not destroyed in the lung, has much longer half life in the circulation than PGE1 which is rapidly inactivated in the lung. The effects of intravenous injection of lipo-PGE1 on the cerebral hemodynamics and the central conduction time (CCT) of the sensory evoked potential under vasospastic conditions has been studied in eight patients. All these 8 patients demonstrated severe angiographic vasospasm and signs of cerebral ischemia. The 15-20 micrograms of lipo-PGE1 was administered every eight hours for 5 to 7 days. Within 6 hours of the first lipo-PGE1 treatment, the regional cerebral blood flow (rCBF) and the CCT measurements were reported to document the effect of treatment. The average pretreatment of rCBF on the right anterior, middle and posterior cerebral artery were 46.6 +/- 6.8, 56.4 +/- 7.3 and 58.8 +/- 8.9 ml/100 g/min and on the left side were 52.1 +/- 9.2, 49.1 +/- 10.8 and 56.1 +/- 9.2 ml/100 g/min respectively. With treatment these flows increased to 53.0 +/- 6.9, 64.3 +/- 5.3 and 63.0 +/- 4.6 ml/100 g/min respectively on the right side and 60.8 +/- 9.4, 60.6 +/- 9.7 and 60.6 +/- 7.2 ml/100 g/min respectively on the left. The CCT also demonstrated the improvement from 6.36 msec to 6.21 msec by the initial PGE1 treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

[Three cases of acute interhemispheric subdural hematoma].

Traumatic acute subdural hematomas over the convexity of the cerebral hemispheres are often encountered, but acute interhemispheric subdural hematomas are rare. Fourty-eight cases of acute subdural hematomas was admitted to our hospital between 1977 and 1986, and three cases of them (6%) were located in the interhemispheric subdural space. In this paper, these three cases are reported with 20 documented cases. Case 1: an 81-year-old female was admitted to our hospital because of headache, nausea and vomiting. She hit her occiput a week ago. CT scan demonstrated contusion in the right frontal lobe and a high density in the interhemispheric space of the right frontal region. Her complaints disappeared gradually by conservative therapy and she returned to her social life. Case 2: a 50-year-old male fell downstairs and hit his vertex. As he lost consciousness, he was admitted to our hospital. He was stuporous and had left-hemiparesis. Skull X-ray film showed fracture line extending from the right temporal bone to the left parietal bone across the midline. CT scan revealed intracerebral hematoma in both frontal lobe and right parietal lobe and subarachnoid hemorrhage in the basal cistern and Sylvian fissure of the right side. And interhemispheric subdural hematoma in the right parietal region was visualized. Angiography demonstrated a lateral displacement of the right callosomarginal artery and an avascular area between the falx and the callosomarginal artery. After admission his consciousness recovered and convulsion was controlled by drug. Left-hemiparesis was improved by conservative therapy and he was discharged on foot.(ABSTRACT TRUNCATED AT 250 WORDS)

[A case of cerebral arteritis secondary to bacterial meningitis].

A 34-year-old female with Streptococcus pneumonia meningitis is presented. She deteriorated suddenly and CT scan revealed low density on the right basal ganglia and left centrum semiovale. Angiographic manifestations included arterial stenosis of the supraclinoid portion of ICA and the proximal portion of MCA. Systemic and intrathecal injections of the antibiotics were done and the treatments to the cerebral infarction were added but she became vegetative. During her clinical course hydrocephalus and hemorrhagic infarction occurred. The second angiography 4 months later showed no disappearance of the findings on the initial study. Arterial stenosis due to the cerebral arteritis with meningitis had been said to be caused by inflammatory change of the arterial wall, vasospasm and contrast media. It suggests by serial cerebral angiography that arterial stenosis is due not to vasospasm, but to the inflammatory change of the arterial wall.

[Prognosis of epilepsy in psychoneurologically normal children].

Prognosis of 175 psychoneurologically normal children with the onset of epilepsy after 18 months of age were studied. The remission rate of partial epilepsy (81 of 107 cases, 76%) was higher than that of generalized epilepsy (34 of 56 cases, 61%). Prognoses for patients with sleep epilepsy (52 of 62 cases, 84%) were better than those for patients with waking epilepsy (63 of 101 cases, 62%). Most (95%) of the children with sleep epilepsy had partial epilepsy, including benign childhood epilepsy with centrotemporal spike (BECT, 36 cases) and partial epilepsy other than BECT (23 cases). Benign courses were not limited to BECT patients. Generalized waking epilepsy other than absence had the lowest remission rate. Eleven children exhibited mild mental retardation on last examination. Most of them had atypical absence and/or myoclonic seizures with the onset of seizure before 3 years of age. It appeared important to classify the epileptic children with regard to time of seizure occurrence as well as seizure type to determine their prognoses.

[A case of three-year-old boy with periodic apnea during waking and sleep, severe psychomotor retardation and hypotonia].

We presented a 3-year-old boy, a product of consanguineous parents, with periodic apnea during waking and sleep states, severe psychomotor retardation and hypotonia. According to polysomnographical recordings, he exhibited frequent central apneas which decreased in frequency and regularity in the stage REM. He showed abnormal background EEG, undifferentiated sleep stage and very short duration of stage REM. The initiation of breathing after apnea was often accompanied with generalized muscles contraction like a startle response. In the waking state the apnea induced generalized muscular hypotonicity and the decline of wakefulness. Arterial CO2 and O2 saturation was within normal limits. It was suggested that the malfunction of the brain stem responsible for the control of breathing, sleep-wakefulness cycle and determination of sleep stages was closely connected with the pathogenesis of abnormal breathing patterns.

[Evaluation of CDDP administration into the body cavity].

CDDP (100 mg bolus) was administered into the body cavity for cancerous pleural effusion and ascites, and its effectiveness and pharmacokinetics were studied. The cases treated consisted of 7 of gastric cancer, 1 of pancreas cancer, 2 of lung cancer and 2 of breast cancer. A decrease in body cavity fluid was observed in all cases. The cases in which treatment was effective were broken down into CR 2 cases, PR 8 cases and NC 2 cases, the efficacy rate being 83%. This procedure produced distinctly fewer side effects than intravenous administration. Disturbance of renal function and G.I. symptoms were negligible, but anemia was often found. The free-CDDP levels in the body cavity fluid remained of over 1.0 microgram/ml after 12 hours and those in plasma remained after 1 hour. Intracavitary administration thus seems an excellent method that enables a drug to act on cancer cells directly at high concentrations over many hours.

[Intrapleural administration of CDDP against malignant pleural effusions in breast cancer].

Malignant pleural effusion in the patients with breast cancer commonly occurs, and is a life-threatening factor. The present paper shows the usefulness of intrapleural administration of CDDP in six cases. A decrease of pleural effusions was observed in all cases. Treatment was effective in two cases of CR and four cases of PR. A median survival from initiation of intrapleural therapy is 17 months (range 2-47 months). This procedure produced distinctly fewer side effects than intravenous administration. The results of this trials suggest that CDDP should be considered as an active agent in the treatment of malignant pleural effusion in the patients with breast cancer.

[Evaluation of tumor marker CA15-3 in breast cancer].

CA15-3, a new tumor marker for breast cancer, was determined in various malignant diseases including breast cancer and various benign diseases, and its clinical significance and usefulness were studied. In 18 normal individuals, the value of CA15-3 was 8.9 +/- 3.3 U/ml (mean +/- SD). In primary breast cancer, the positivity was 20% for Stage I, 0% for Stages II and III and 100% for Stage IV. Of 17 cases of recurrent breast cancer, 13 (77%) were shown to be positive. The therapeutic effect and the value of CA15-3 were well correlated with each other. As for other malignant tumors, positive cases were observed in 50% of recurrent cancer of the stomach and in 14% of malignant tumors of the biliary system. All of these cases were terminal-stage cancers. The CEA value determined simultaneously showed a good correlation, r = 0.87 (p less than 0.01) with CA15-3 in malignant tumors other than breast cancer. In breast cancer, however, the correlation between the two was low, r = 0.18. These results suggest that CA15-3 is not necessarily useful in the diagnosis of primary breast cancer, but is useful as an indicator of the effect of therapy for recurrent breast cancer and for the prediction of recurrence.