Delineation of clinical features in Wiedemann-Steiner syndrome caused by KMT2A mutations.

Wiedemann-Steiner syndrome (WSS) is an autosomal dominant congenital anomaly syndrome characterized by hairy elbows, dysmorphic facial appearances (hypertelorism, thick eyebrows, downslanted and vertically narrow palpebral fissures), pre- and post-natal growth deficiency, and psychomotor delay. WSS is caused by heterozygous mutations in KMT2A (also known as MLL), a gene encoding a histone methyltransferase. Here, we identify six novel KMT2A mutations in six WSS patients, with four mutations occurring de novo. Interestingly, some of the patients were initially diagnosed with atypical Kabuki syndrome, which is caused by mutations in KMT2D or KDM6A, genes also involved in histone methylation. KMT2A mutations and clinical features are summarized in our six patients together with eight previously reported patients. Furthermore, clinical comparison of the two syndromes is discussed in detail.

Molecular genetic analysis of 30 families with Joubert syndrome.

Joubert syndrome (JS) is rare recessive disorders characterized by the combination of hypoplasia/aplasia of the cerebellar vermis, thickened and elongated superior cerebellar peduncles, and a deep interpeduncular fossa which is defined by neuroimaging and is termed the 'molar tooth sign'. JS is genetically highly heterogeneous, with at least 29 disease genes being involved. To further understand the genetic causes of JS, we performed whole-exome sequencing in 24 newly recruited JS families. Together with six previously reported families, we identified causative mutations in 25 out of 30 (24 + 6) families (83.3%). We identified eight mutated genes in 27 (21 + 6) Japanese families, TMEM67 (7/27, 25.9%) and CEP290 (6/27, 22.2%) were the most commonly mutated. Interestingly, 9 of 12 CEP290 disease alleles were c.6012-12T>A (75.0%), an allele that has not been reported in non-Japanese populations. Therefore c.6012-12T>A is a common allele in the Japanese population. Importantly, one Japanese and one Omani families carried compound biallelic mutations in two distinct genes (TMEM67/RPGRIP1L and TMEM138/BBS1, respectively). BBS1 is the causative gene in Bardet-Biedl syndrome. These concomitant mutations led to severe and/or complex clinical features in the patients, suggesting combined effects of different mutant genes.

Diagnosis of sex chromosomal abnormalities in neonatal intensive care units.

Neonates are hospitalized in the neonatal intensive care unit for complications arising during delivery or for the treatment of congenital anomalies. Some anomalies may warrant chromosomal analysis. We investigated all cases of neonates hospitalized in the NICU at Dokkyo Medical University Hospital between January 1990 and May 2011. Over the study period of 21 years and 5 months, 169 of 6,159 neonates (2.74%) were diagnosed with chromosomal abnormalities. Autosomal chromosomal aberrations were observed in 165 neonates (2.68%), and sex chromosome abnormalities in only 4 neonates (0.07%). Compared with previous studies, we found a much lower prevalence of sex chromosome abnormalities, despite a similar overall prevalence of chromosomal abnormalities. This seems to be due to the fact that sex chromosome abnormalities are likely to be clinically invisible in the NICU.

Survival of trisomy 18 cases in Japan.

The prognosis of trisomy 18 is lethal, but recently some long-term survival cases have been recognized. We report here the mortality rate of trisomy 18 based on our hospital data and sporadically published reports in Japan. We collected the 7 previously published reports of mortality and 31 cases from our hospital data with trisomy 18. Our data pool comprised a total of 179 cases of trisomy 18 from 8 institutions. The mortality rates within 24 hours, 7, 28, 60, 180, and 365 days from birth were 14.84% (19/128), 31.01% (40/129), 56.25% (72/128), 64.08% (66/103), 82.17% (106/129), and 90.90% (140/154), respectively. Fourteen of the 154 patients (9.09%) survived for more than 1 year. The Kaplan-Meier survival curves from 78 patients of 5 institutes suggest that trisomy 18 children who have survived over 7 months after birth may have a high probability of long-term survival. We should recognize not only that about 50% of infants with trisomy 18 die within 1 month after birth, but also that about 10% of patients survive over 1 year in Japan. These findings comprise Asia's first clinical statistics concerning trisomy 18, in which the data were collected from multiple institutions. This evidence is valuable in order to perform genetic counseling concerning the natural history of trisomy 18 not only in Japan but also in other countries.

Short rib-polydactyly syndrome: lethal chondrodysplasia associated with brain malformations in a 35-week-gestation infant.

This case report describes the neuropathological findings in an autopsy case of short rib-polydactyly syndrome (SRPS). The patient was a Japanese female neonate who was born at 35 weeks of gestation and died soon after birth due to severe cardiopulmonary insufficiency. Clinical and radiological findings were most consistent with SRPS type I (Saldino-Noonan type). General autopsy findings included situs inversus, persistent truncus arteriosus and endocardial cushion defect, hypoplastic lungs and adrenal glands, and vaginal atresia. Fixed brain weight was 330 g. Three different categories of pathological changes were detected in the brain. These were as follows: (1) multiple cyst formation in the parenchyma, (2) primary malformations of the nervous and mesenchymal tissues, and (3) deposition of an unusual substance in the cerebral white matter. The multiple cysts or cavities in the parenchyma may be due to severe hypoxic-ischemic insults related to the congenital heart anomaly. The primary malformations were summarized as follows: (1) capillary telangiectasia of the pia mater and choroid plexus, (2) olfactory dysplasia with asymmetry, (3) focal cortical dysplasia in the frontal lobe and cerebellum, (4) olivary dysplasia, and (5) enlargement of the posterior part of the lateral ventricle. Dysplastic changes of the nervous tissue can be classified into the group of neuronal migration disorders. Although biochemical properties of the unknown substance were not determined, it is considered to be some product derived from an inborn error of metabolism. Morphological data of SRPS is still scarce, and pathognomonic changes have not yet been elucidated. The present data suggests that coexistence of the nervous and mesenchymal malformations may be highly characteristic of SRPS.

Long-term survival of full trisomy 13 in a 14 year old male: a case report.

Long term survival for the cases of trisomy 13 into over a first decade is very rare. We reported here the case of a 14-year-old male karyotype with full type of trisomy 13. In this clinical phenomenon, the case had typical facial, finger and limb anomalies for trisomy 13. Arterial septal defect and patent ductus arteriosus were recognized using ultrasonography after birth. Major cerebral malformation such as holoprosencephaly or cerebellar hypoplasia were also not revealed. After 5 months of his age, artificial ventilation therapy for dyspnea associated with laryngomalacia was required. A tracheotomy was performed at 6 months of his age. After 12 years old, intractable partial epilepsy was recognized. For his partial seizures, a treatment with a combination of two anti-epileptic drugs, valproic acid and levetiracetam, were advised. Now he is alive for 14-years-old and he is the 4th longest surviving patient with full karyotype of trisomy 13.

Treatment with mild brain hypothermia for cardiopulmonary resuscitation after myoclonic seizures in infant with robertsonian type of trisomy 13.

Congenital chromosomal abnormality with trisomy 13 is known to be associated with poor life prognosis and lethal. Therefore, physician advice the patients be kept in intensive treatment with resuscitation and state of the art intensive care when sudden change in the general condition with this trisomy is observed. We report herein, the treatment with mild brain hypothermia therapy for cardiopulmonary resuscitation after myoclonic seizures in infant with Robertsonian type of trisomy 13 in intensive care unit. Our study indicated that brain hypothermia therapy and steroid pulse therapy on an infant who was believed to have post-resuscitation hypoxic encephalopathy was highly effective as the patient's general condition recovered to the original state after four months.

Time-dependent morphologic characteristics in angiographic chronic total coronary occlusions.

Intravascular ultrasound analysis of 70 chronic total occlusions (CTOs), conducted either before intervention or following dilation of a 1.5-mm balloon, showed that older CTOs have more complex plaque composition including a larger calcific burden. This may explain the adverse revascularization profile of older CTOs.

Effect of carvedilol on atrioventricular conduction in the ischemic heart.

We compared the effects of carvedilol on atrial-His and His-ventricular conduction with those of propranolol in isolated rat hearts. Hearts were perfused retrograde, and atrial-His and His-ventricular intervals were measured. The effective doses that increased conduction times by 25% were 10(-6) M for atrial-His and 3x10(-6) M for His-ventricular for propranolol, and 8x10(-8) M for atrial-His and 10(-8) M for His-ventricular for carvedilol. Prazosin did not affect the atrial-His and His-ventricular intervals. After ischemia-reperfusion, atrial-His and His-ventricular intervals increased to a greater extent with 10(-6) M carvedilol. To determine the direct membrane effect, we examined the transmembrane action potential in guinea pig papillary muscle. Both drugs decreased the maximum upstroke velocity equally. Our data indicate that carvedilol had a greater effect on atrioventricular conduction in the setting of ischemia-reperfusion than did propranolol. This effect of carvedilol was not due to its alpha-adrenoceptor blocking property or to a direct membrane effect.

ELISA for determination of immunoreactive free elastase and elastase in complex with alpha 1-antitrypsin in nasal secretions with sinusitis.

Sensitive double antibody sandwich ELISA methods was developed in order to quantify immunoreactive neutrophil elastase (NE) levels in nasal secretions with chronic sinusitis (CS). Microwell plate as a solid phase was coated with anti-NE antibody. Two different horseradish peroxidase (HRP) labelled antibodies used as the second antibody were anti-NE-HRP for measuring total (free + complexed) NE level and anti-alpha 1-antitrypsin (AT)-HRP for complexed NE level. Mean value of total NE was 31.0 +/- 20.7 micrograms/ml in nasal secretions from adult patients with CS, and the percentage of complexed NE in total NE was 33.7 +/- 21.4%. This sandwich ELISA is a useful method for measuring both total and complexed NE levels in nasal secretions.

Neutrophil elastase and its complex with alpha 1-antitrypsin in soluble and insoluble fractions of nasal secretions of chronic sinusitis.

Immunoreactive neutrophil elastase (NE) and its complex with alpha 1-antitrypsin (AT) was measured by double antibody enzyme linked immunosorbent assay (ELISA) in nasal secretions of chronic sinusitis (CS). Nasal secretions were separated into two fractions: PBS-soluble and insoluble fractions. Elastolytic activity was also examined. Mean value of total NE level was 31.0 micrograms/ml in the soluble fraction, which was significantly lower than that in the insoluble fraction (71.9 micrograms/ml, p less than 0.01). On the other hand, the percentage of complexed NE in total NE in the soluble fraction (33.7%) was significantly higher than that in the insoluble fraction (12.1%, p less than 0.01). Elastolytic activity in the soluble fraction (23.4 RFU) was significantly lower than that in the insoluble fraction (170.5 RFU, p less than 0.01). NE with elastolytic activity exists in nasal secretions of CS, and active-free NE in the insoluble fraction could be a major source of enhancement and continuation of mucosal inflammation.

Immunohistochemical detection of serous cells in nasal mucosa with monoclonal antibody against a component in human nasal secretion.

Secreting mechanisms of secretory cells in nasal mucosa and the changes of nasal secretions in chronic inflammatory sinusitis have been studied by the biochemical and histochemical methods. These methods could not clarify the changes of quality and quantity of nasal secretions and secretory cells. In order to obtain the specific marker for the secretions in different cells, we have produced monoclonal antibodies against a component in human nasal discharge. One antibody was selected for further characterization, because it stained submucosal serous cells specifically. This antibody stained the components of serous cells with molecular weight of 14 kD specifically, and was sensitive to periodate oxidation treatment. This antibody will be useful for detecting the subpopulation in secretory cells of human nasal mucosa, and may be serve as a biochemical probe for secretory activity of particular secretory cell types.

[Significance of measuring urinary 17-ketosteroid sulfates at the work-place].

We examined availability of urinary 17-KS-S to evaluate work and job strain by presented the results in two field research and one experiment. It became clear that urinary S/OH was a comprehensive parameter of thermal strain, under the combined load condition of temperature and exercise, and as an additional factor, under the various load conditions of air velocity. Significant changes of urinary S/OH before and after the rest break and holiday suggested that the findings reflected fatigue conditions. This suggestion was strongly supported by the finding that the values of urinary S/OH on the first day-off after a mid-night shift and those 1 to 3 days later were not able to recover to the value before the night shift. A ratio between urinary 17-KS-S and 17-OHCS, S/OH, suggests a method of evaluating the degree of strain and the condition of fatigue and over-fatigue by measuring these parameters and thus clarifying the work conditions and work-place environment.

[The quantitation of Pseudomonas aeruginosa elastase in suppurative chronic otitis media using a sensitive ELISA method].

A sensitive sandwich ELISA method has been developed in order to quantitate the Pseudomonas aeruginosa elastase (PE) of ear discharge from chronic suppurative otitis media (CSOM) patients. Samples were incubated with EDTA-2Na before ELISA in order to inhibit the PE activity which hydrolyzes anti-PE IgG antibody into smaller molecular fragments. Quantitation of PE in middle ear effusions (MEE) from 10 patients with chronic otitis media with effusion (OME) were also performed. In CSOM, 12 of 14 samples revealed a significant amount of PE from 0.6 microliter/ml to 62.1 microliters/ml, which was significantly higher than those in MEE (p less than 0.05). In MEE, 8 of 10 samples were under the detection limit. Two samples in CSOM with Pseudomonas aeruginosa infection had high levels of PE. The quantitation was linear, with a concentration from 5 ng PE/sample to 500 ng PE/sample. This ELISA system is a sensitive method for quantitation of PE requiring only very small samples.

[Neonatal transient hypothyroidism].

Neonatal screening for congenital hypothyroidism can detect permanent and transient hypothyroidism. The latter condition is called neonatal transient hypothyroidism. This may result from various causes, but, especially, it should be suspected whenever there is a history of maternal autoimmune thyroid disease, including Hashimoto thyroiditis, Graves disease, hypothyroidism on replacement therapy, or recurrent congenital hypothyroidism of a transient nature in subsequent siblings. Transplacental TSH-receptor antibodies may affect fetal or neonatal thyroid function. Although thyroid dysfunction may be transitory, long-term follow-up is desirable.