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.

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.

Oral concentration of volatile sulphur compounds in stressed rats.

Stress has been identified as a halitosis-inducing factor. Halitosis may be measured by the determination of oral volatile sulphur compound levels (VSC). Since immobilization and swimming are two experimental protocols widely used to induce stress in laboratory animals, the aim of this work was to investigate the influence of stress on VSC in rats. Male Wistar rats were submitted to three swimming or immobilization sessions over consecutive days. The oral VSC increased 3 h after the first and third swimming or immobilization sessions. The results in the present study support the hypothesis that stress may be an etiological factor in halitosis. Also, the animal experimental design may represent a new approach to research concerning the relationship between halitosis and stress.

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.

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.

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.

[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.

[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.

1,5-Benzoxathiepin derivatives. III. Optical resolution of methyl (+/-)-cis-3-hydroxy-4-[3-(4-phenyl-1-piperazinyl)propyl]-3,4-dihydro- 2H-1,5-benzoxathiepin-4-carboxylate hydrochloride ((+/-)-CV-5197) with selective 5-hydroxytryptamine2(5-HT2)-antagonistic activity.

The selective 5-HT2-receptor antagonist, methyl (+/-)-cis-3-hydroxy-4-[3-(4-phenyl-1-piperazinyl)propyl]-3,4-dihydro-2H- 1,5-benzoxathiepin-4-carboxylate hydrochloride ((+/-)-CV-5197) was resolved in high optical purity using (R)-(-)- and (S)-(+)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphates ((R)-(-)- and (S)-(+)-BNP). The absolute configuration of (+)-CV-5197 was determined to be 3S,4R by X-ray crystallographic analysis. In the binding assay, it was demonstrated that (+)-CV-5197 was a more active isomer (IC50 = 23 nM +/- 6.3) for 5-HT2 receptor binding than the (-)-enantiomer (IC50 = 1600 nM +/- 82). (+)-CV-5197 completely inhibited the 5-HT-induced contraction of the isolated pig coronary artery at a concentration of 3 x 10(-7) M, whereas (-)-CV-5197 showed little antagonistic activity, even at 3 x 10(-4) M. Thus, the agreement between the results of the binding assays and the biological activities for the 3S,4R enantiomer of CV-5197 suggests that its physiological activity is probably exerted through 5-HT2-receptor antagonism.

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.

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.

Adrenoleukodystrophy associated with cerebral arteriovenous malformation.

Adrenoleukodystrophy (ALD) is now considered to be an X-linked recessive peroxisomal disorder. We report the case of a patient with ALD associated with a left parietal arteriovenous malformation (AVM) who deteriorated progressively six months after recovery from a hemorrhage of the AVM. Serial CT scans and MR imagings showed progressive demyelination spreading from the affected area. This case suggests that local brain damage due to AVM hemorrhage may accelerate the progress of demyelination.

[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.

[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.

[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.