Reduction in the colonization of Staphylococcus aureus on the skin surface under calcium-/magnesium-depleted conditions.

Excessive expansion of Staphylococcus aureus is associated with several skin diseases, including atopic dermatitis (AD). Recently, we have demonstrated that washing skins with ultra-pure soft water containing little bivalent metal ions improved skin conditions of atopic subjects. In this study, we investigated the roles of calcium or magnesium on the proliferation of S. aureus both in vitro and in vivo. Depletion of calcium and magnesium in the culture medium significantly suppressed the expansion of S. aureus growth. When S. aureus, diluted with water containing calcium/magnesium at the concentration of medium-hard water (83·0 mg l-1 as CaCO3 ) or the one that contains little calcium/magnesium, was applied onto the tape-stripped skin of Hos:HR-1 mice, growth of S. aureus in water without those minerals on the skin was suppressed. These results suggest that depletion of both calcium and magnesium abrogate the proliferation of S. aureus not only in the culture system but also on the skin surface of mice. Since colonization of S. aureus on the skin is well-known to exacerbate AD symptoms, usage of ultra-pure soft water containing less calcium and magnesium may improve the skin condition through the suppression of S. aureus growth on the skin of patients with skin problems. SIGNIFICANCE AND IMPACT OF THE STUDY: This study demonstrates the importance of calcium and magnesium for the colonization and growth of Staphylococcus aureus by using both in vitro culture systems and in vivo experiments on the murine skin. Our results indicate that the removal of these metal ions is probably beneficial for protecting the skin from S. aureus. Thus, using ultra-pure soft water without metal ions may improve the skin condition of patients with skin problems through the protection from S. aureus colonization.

Linoleic acid salt with ultrapure soft water as an antibacterial combination against dermato-pathogenic Staphylococcus spp.

AIMS: Skin colonization of Staphylococcus spp. critically affects the severity of dermatitis in humans and animals. We examined different types of fatty acid salts for their antibacterial activity against Staphylococcus spp. when used in ultrapure soft water (UPSW). We also evaluated their therapeutic effect on a spontaneous canine model of dermatitis. METHODS AND RESULTS: UPSW, in which Ca(++) and Mg(++) were replaced with Na(+) , was generated using a water softener with cation-exchange resin. Staphylococcus aureus (Staph. aureus), Staphylococcus intermedius (Staph. intermedius), and Staphylococcus pseudintermedius (Staph. pseudintermedius) were incubated with various fatty acid salts in distilled water (DW) or UPSW and the number of bacteria was counted. Among the fatty acids, oleic acid salt and linoleic acid (LA) salt reduced the number of these bacteria. Also, UPSW enhanced the antibacterial effect of LA on Staph. spp. In spontaneously developed itchy dermatitis in companion dogs, shampoo treatment with liquid soap containing 10% LA in UPSW improved skin conditions. CONCLUSIONS: LA salt showed antibacterial activity against Staph. spp. Treatment with soap containing LA with UPSW reduced clinical conditions in dogs with dermatitis. SIGNIFICANCE AND IMPACT OF THE STUDY: Because colonization of Staph. spp. on the skin exacerbates dermatitis, the use of LA-containing soap in UPSW may reduce unpleasant clinical symptoms of the skin.

Coffin-Siris syndrome is a SWI/SNF complex disorder.

Coffin-Siris syndrome (CSS) is a congenital disorder characterized by intellectual disability, growth deficiency, microcephaly, coarse facial features, and hypoplastic or absent fifth fingernails and/or toenails. We previously reported that five genes are mutated in CSS, all of which encode subunits of the switch/sucrose non-fermenting (SWI/SNF) ATP-dependent chromatin-remodeling complex: SMARCB1, SMARCA4, SMARCE1, ARID1A, and ARID1B. In this study, we examined 49 newly recruited CSS-suspected patients, and re-examined three patients who did not show any mutations (using high-resolution melting analysis) in the previous study, by whole-exome sequencing or targeted resequencing. We found that SMARCB1, SMARCA4, or ARID1B were mutated in 20 patients. By examining available parental samples, we ascertained that 17 occurred de novo. All mutations in SMARCB1 and SMARCA4 were non-truncating (missense or in-frame deletion) whereas those in ARID1B were all truncating (nonsense or frameshift deletion/insertion) in this study as in our previous study. Our data further support that CSS is a SWI/SNF complex disorder.

Domain-specific mutations in TGFB1 result in Camurati-Engelmann disease.

Camurati-Engelmann disease (CED, MIM 131300) is an autosomal dominant, progressive diaphyseal dysplasia characterized by hyperosteosis and sclerosis of the diaphyses of long bones. We recently assigned the CED locus to an interval between D19S422 and D19S606 at chromosome 19q13.1-q13.3, which two other groups confirmed. As the human transforming growth factor-1 gene (TGFB1) is located within this interval, we considered it a candidate gene for CED.

Skewed X chromosome inactivation failed to explain the normal phenotype of a carrier female with MECP2 mutation resulting in Rett syndrome.

Mutations in the X-linked MECP2 gene cause Rett syndrome, a neurodevelopmental disorder that exclusively affects girls. Females with the MECP2 mutations exhibit a broad spectrum of clinical presentations ranging from classical Rett syndrome to asymptomatic carriers, which can be explained by differences in X chromosome inactivation (XCI). Here, we report a family with a girl with Rett syndrome in whom a novel missense mutation in the MECP2 gene was transmitted through the maternal germ line. The carrier mother was asymptomatic and presented non-random XCI in the peripheral blood cells, which resulted in the X chromosome harboring the mutant allele that was predominantly active. Thus, the presence of non-random XCI in the peripheral blood cells did not provide an explanation for the normal phenotype of the carrier mother. This result suggests that mechanisms other than XCI may contribute to the phenotypic heterogeneity associated with MECP2 mutations.

A new approach for evaluation of left ventricular diastolic function: spatial and temporal analysis of left ventricular filling flow propagation by color M-mode Doppler echocardiography.

OBJECTIVES: To evaluate left ventricular diastolic function and differentiate the pseudonormalized transmitral flow pattern from the normal pattern, the propagation of left ventricular early filling flow was assessed quantitatively using color M-mode Doppler echocardiography. BACKGROUND: Because the propagation of left ventricular early filling flow is disturbed in the left ventricle with impaired relaxation, quantification of such alterations should provide useful indexes for the evaluation of left ventricular diastolic function. METHODS: Study subjects were classified into three groups according to the ratio of early to late transmitral flow velocity (E/A ratio) and left ventricular ejection fraction: 29 subjects with an ejection fraction > or = 60% (control group); 34 with an ejection fraction < 60% and E/A ratio < 1 (group I); and 25 with ejection fraction < 60% and E/A ratio > or = 1 (group II). The propagation of peak early filling flow was visualized by changing the first aliasing limit of the color Doppler signals. The rate of propagation of peak early filling flow velocity was defined as the distance/time ratio between two sampling points: the point of the maximal velocity around the mitral orifice and the point in the mid-left ventricle at which the velocity decreased to 70% of its initial value. High fidelity manometer-tipped measurement was performed in 40 randomly selected subjects. RESULTS: The rate of propagation decreased in groups I and II compared with that in the control group (33.8 +/- 13.8 [mean +/- SD] and 30.0 +/- 8.6 vs. 74.3 +/- 17.4 cm/s, p < 0.001, respectively) and correlated inversely with the time constant of left ventricular isovolumetric relaxation and the minimal first derivative of left ventricular pressure (peak negative dP/dt) (r = 0.82 and r = 0.72, respectively). CONCLUSIONS: Spatial and temporal analysis of filling flow propagation by color M-mode Doppler echocardiography was free of pseudonormalization and correlated well with the invasive variables of left ventricular relaxation.

Percutaneous mitral commissurotomy for restenosis after surgical commissurotomy: late efficacy and implications for patient selection.

OBJECTIVES: The results of percutaneous mitral commissurotomy were assessed in patients with restenosis after surgical commissurotomy. BACKGROUND: Balloon dilation is feasible in patients with restenosis after surgical commissurotomy, but little is known about its late efficacy. METHODS: We studied 232 patients who had undergone percutaneous mitral commissurotomy a mean of 16 +/- 8 years after surgical commissurotomy. Mean age was 47 +/- 14 years; 81 patients (35%) had valve calcification. All patients had restenosis with bilateral commissural fusion as assessed by echocardiography. Technical failure occurred in 9 patients and the procedure used a single balloon in 7 patients, a double balloon in 95, and the Inoue balloon in 121. RESULTS: Complications were death in 1 patient (0.4%) and mitral regurgitation >2/4 in 10 (4%); 191 patients (82%) had good immediate results (valve area > or =1.5 cm2 without regurgitation >2/4). Predictors of poor immediate results in multivariate analysis were older age (p < 0.001), lower initial valve area (p = 0.01) and the use of the double-balloon technique (p = 0.015). In the 175 patients who underwent follow-up, 8-year survival without operation and in New York Heart Association class I or II was 48 +/- 5%, and 58 +/- 6% after good immediate results. In this latter group, poor late functional results were predicted by higher cardiothoracic index (p < 0.0001), previous open-heart commissurotomy (p = 0.05) and lower final valve area (p < 0.0001) in a multivariate Cox model. CONCLUSIONS: Percutaneous mitral commissurotomy is safe and provides good immediate results in selected patients with restenosis after surgical commissurotomy. After good immediate results, the conditions of more than half of the patients remained improved at 8 years, enabling reoperation to be deferred.

Predicting gene regulation by sigma factors in Bacillus subtilis from genome-wide data.

MOTIVATION: Sigma factors regulate the expression of genes in Bacillus subtilis at the transcriptional level. We assess the accuracy of a fold-change analysis, Bayesian networks, dynamic models and supervised learning based on coregulation in predicting gene regulation by sigma factors from gene expression data. To improve the prediction accuracy, we combine sequence information with expression data by adding their log-likelihood scores and by using a logistic regression model. We use the resulting score function to discover currently unknown gene regulations by sigma factors. RESULTS: The coregulation-based supervised learning method gave the most accurate prediction of sigma factors from expression data. We found that the logistic regression model effectively combines expression data with sequence information. In a genome-wide search, highly significant logistic regression scores were found for several genes whose transcriptional regulation is currently unknown. We provide the corresponding RNA polymerase binding sites to enable a straightforward experimental verification of these predictions.

Diurnal rhythms of luteinizing hormone, follicle-stimulating hormone, testosterone, and estradiol secretion before the onset of female puberty in short children.

To investigate hormonal changes before the onset of female puberty, we measured LH and FSH in serum samples drawn every 20 min for 24 h and measured testosterone and estradiol hourly for 24 h. Seventeen girls (13 prepubertal and 4 early pubertal) of short stature, from 5.1-11.4 yr of age, participated in this study. LH and FSH were measured using a time-resolved immunofluorometric assay, and testosterone and estradiol were measured using a sensitivity RIA capable of detecting testosterone and estradiol concentrations of 10 and 2 pg/mL, respectively. Diurnal rhythms of LH, FSH, and testosterone were apparent in all subjects, including those aged 5-6 yr. Serum LH and FSH concentrations showed night-day variation in a pulsatile fashion. The serum testosterone concentration was elevated in the early morning in all subjects. The serum estradiol concentration was elevated in the early morning in 4 of 13 prepubertal subjects and all 4 early pubertal subjects. The diurnal pattern of the serum estradiol concentration was similar to that of the serum testosterone concentration. Mean 24-h LH and testosterone concentrations in prepubertal subjects who did not attain puberty for at least 1 yr were 0.07 U/L and 65 pg/mL, respectively, whereas those in prepubertal subjects who attained puberty within 1 yr (0.14 U/L and 106 pg/mL, respectively) were significantly higher. Furthermore, mean 24-h LH, FSH, testosterone, and estradiol concentrations increased with the onset of puberty. In conclusion, the diurnal rhythms of LH, FSH, and testosterone already exist at 5-6 yr of age, and serum LH and testosterone levels increase before the onset of puberty. These results suggest that preparation for the onset of female puberty may begin in 5- to 6-yr-old girls.

Diurnal rhythms of luteinizing hormone, follicle-stimulating hormone, and testosterone secretion before the onset of male puberty.

To investigate hormonal change before the onset of male puberty, we measured LH and FSH in serum samples drawn every 20 min for 24 h and measured testosterone hourly for 24 h. Forty-six boys (32 prepubertal and 14 pubertal) of short stature, between 4.4-19.3 yr of age, participated in this study. LH and FSH were measured using a time-resolved immunofluorometric assay, and testosterone was measured using high sensitivity RIA capable of detecting a testosterone concentration of 0.01 ng/mL. Diurnal rhythms of LH, FSH, and testosterone were apparent in all subjects, including those aged 4-5 yr. Serum LH and FSH concentrations showed night-day variation in a pulsatile fashion. The serum testosterone concentration was elevated at early morning in all subjects. Mean 24-h LH, FSH, and testosterone concentrations of prepubertal subjects who did not attain puberty for at least 3 yr were 0.10 U/L, 0.63 U/L, and 0.06 ng/mL, respectively, whereas those of prepubertal subjects who attained puberty within 1 yr (0.54 U/L, 1.68 U/L, and 0.10 ng/mL, respectively) were significantly higher. Furthermore, mean 24-h LH, FSH, and testosterone concentrations increased with developing puberty. All of the 46 subjects showed positive cross-correlation between the LH and testosterone time series. The mean lag time from the LH to the testosterone time series in the prepubertal subjects who attained puberty within 1 yr (4.7 +/- 2.4 h, mean +/- SD) was shorter than that in the prepubertal subjects who attained puberty after at least 3 yr (7.3 +/- 2.2 h). This lag time decreased with developing puberty, plateauing at 1.4 +/- 0.9 h at midpuberty. Thus, the diurnal rhythms of LH, FSH, and testosterone already exist at 4-5 yr of age; serum LH, FSH, and testosterone levels increase before the onset of puberty; and a time delay is observed between the LH and testosterone time series that decreases before the onset of puberty.

Developmentally delimited emergence of more orderly luteinizing hormone and testosterone secretion during late prepuberty in boys.

To quantitate changing feedback control in the GnRH-LH/FSH-testosterone axis in male puberty, we here quantitate the orderliness of hormone release patterns using the regularity (pattern-sensitive) statistic, approximate entropy (ApEn), in 46 eugonadal boys representing 6 genitally defined stages of normal puberty. ApEn is a single variable, model-free, and scale-independent barometer of coordinate signaling or integrative regulation within a coupled neuroendocrine axis. Accordingly, we quantitated ApEn of LH profiles obtained by immunofluorometric assay of sera sampled every 20 min for 24 h. LH ApEn declined remarkably between early prepuberty (genital stage I-A: mean bone age, 4.6 +/- 1.6 yr; testis volume, <3 mL for at least 3 succeeding yr) and late prepuberty (genital stage I-C: bone age, 8.7 +/- 1.8 yr; testis volume, <3 mL for up to 1 yr thereafter; P: = 0.00019), which indicates the acquisition of more regular LH release patterns in late prepuberty. Maximal LH orderliness occurred in puberty stage II (bone age, 10.7 +/- 1.0 yr; testis volume, 2.8 +/- 0.4 mL). The LH secretory process was more disorderly in mid- and later puberty (Tanner stages III and IV). Transpubertal variations in testosterone ApEn manifested a similar tempo, i.e. the greatest regularity of testosterone secretion (lowest ApEn) emerged in Tanner genital stage II (P: < 10(-)(7)), with less orderly patterns evident both earlier and later in sexual development. In contrast, FSH ApEn values remained invariant of pubertal status. Analysis of bihormonal coupling using the theoretically related bivariate cross-ApEn statistic disclosed maximal 2-hormone synchrony for LH and testosterone secretion in genital stage II (P: = 0.031), with relative deterioration of coordinate LH and testosterone release patterns both before and after. LH and FSH release became maximally synchronous at the end of prepuberty (genital stage I-C; P: = 0.029), and FSH and testosterone synchrony peaked in pubertal stage III (P: = 0.037). As mean 24-h serum concentrations of LH, FSH, and testosterone rose transpubertally by 35-fold (LH), 68-fold (FSH), and 70-fold (testosterone), respectively, we infer that pubertal developmental stage per se rather than level of hormone output dictates coordinate GnRH-LH/FSH-testosterone secretion. In summary, in eugonadal boys, the regularity of 24-h LH and testosterone secretory patterns undergoes well defined pubertal stage-specific control. No sexually developmentally delimited regulation is inferable for FSH. The concept of temporally biphasic puberty-dependent variations in neurohormone secretory regularity contrasts with the unidirectional rise in daily hormone output. Accordingly, we infer that late prepuberty and early puberty (Tanner genital stages IC and II) embody a physiologically unique sexual developmental window, marked by transiently enhanced LH and testosterone feedback stability in boys. Whether analogous plasticity of hypothalamo-pituitary-gonadal interactions unfolds during female adolescence is not known.

Involvement of activator protein in the activation of tryptophan hydroxylase by cAMP-dependent protein kinase.

The tryptophan hydroxylase activity of the crude extract from rat brain stem was stimulated approximately 2-fold by incubation with cAMP analogues under protein phosphorylating conditions. The cAMP-dependent activation process of the enzyme needed not only cAMP-dependent protein kinase but also activator protein. The kinetic properties of the enzyme activated by cAMP-dependent protein kinase were very similar to those of the enzyme activated by calmodulin-dependent protein kinase II.

Frequency and prognostic value of cardiac troponin I elevation after coronary stenting.

Mild myocardial injuries after coronary angioplasty are associated with adverse late outcomes. The incidence and prognostic value of this phenomenon when using cardiac troponin I (cTnI) after stent implantation is unknown. We studied cTnI and creatine kinase (CK) release in 109 patients after stenting. Clinical success was achieved in 103 patients (94%). In-hospital major adverse coronary events were: death in 1 patient, Q-wave myocardial infarction in 1 patient, and non-Q-wave myocardial infarction in 2 patients. Twenty-nine patients (27%) had postprocedural cTnI increase, 16 (15%) had CK elevation. No preprocedural variables predicted marker elevation. Marker release was related to the occurrence of in-lab complications (59% vs 29% [p = 0.004 for cTnI] and 69% vs 32% [p = 0.011 for CK]). In 34% no explanation was found for cTnI increase. Success was more frequent in patients without cTnI elevation (100% vs 86%, p <0.001). The negative predictive value of cTnI increase was 100% for in-hospital major adverse coronary events (MACE), whereas its positive predictive value was 14%. cTnI and CK concordant elevation was associated with more intra- and postprocedural adverse events. During a mean follow-up of 8+/-3 months, major adverse coronary events were: death in 2 patients, myocardial infarction in 2 patients, and repeat PTCA in 8 patients. cTnI elevation was not predictive of these late MACE. cTnI elevation is common after stenting, and is related to the occurrence of in-lab complications. Its isolated elevation is not a good predictor of MACE. Patients with concordant cTnI and CK elevation seem to be at higher risk of in-hospital MACE.

Late results of percutaneous mitral commissurotomy for calcific mitral stenosis.

The aim of this study was to assess late results of percutaneous mitral commissurotomy (PMC) in calcific mitral stenosis and to identify predictors to improve patient selection. We analyzed 422 patients who underwent PMC for calcific mitral stenosis. The extent of calcium was graded from 1 to 4 by fluoroscopy: 227 patients (53%) were graded 1, 125 (30%) graded 2, 55 graded 3 (13%), and 15 graded 4 (4%). The procedure failed in 15 patients, used a single balloon in 11, a double balloon in 126, and the Inoue balloon in 270. In-hospital mortality was 1.2%. Good immediate results (valve area >/=1.5 cm(2) without mitral regurgitation >2/4), were obtained in 321 patients (76%). Multivariate analysis identified 5 predictors of good immediate results: a younger age (p = 0.0004), a lesser degree of stenosis (p = 0.0005), a smaller extent of calcium (p = 0.04), the use of the Inoue balloon (p = 0.015), and a larger effective balloon dilating area (p = 0.006). Good functional results, defined as survival with no further intervention and in New York Heart Association class I or II, were 36 +/- 4% at 8 years. The predictors of good functional results after good immediate results were a younger age (p = 0.04), a lower pre-PMC New York Heart Association class (p <0.0001), sinus rhythm (p = 0.0006), a smaller extent of calcium (p = 0.02), and a lower gradient after PMC (p <0.0001). Despite a frequent deterioration on follow-up after PMC for calcific mitral stenosis, the predictive analysis suggests that PMC may be useful in deferring surgery in selected patients with mild to moderate calcific deposits, who have otherwise favorable characteristics.

Effects of adrenoceptor agonists and antagonists on smooth muscle cells and neuromuscular transmission in the guinea-pig renal artery and vein.

In the guinea-pig renal artery and vein, the membrane potential was -66.8 mV and -46.8 mV, the length constant 0.54 mm and 0.43 mm, and the time constant 240 ms and 98 ms, respectively. The maximum slope of the depolarization produced by a 10 fold increase [K]o was 46 mV in the renal artery and 39 mV in the renal vein. Noradrenaline (NA over 5 X 10(-7)M in the artery and over 10(-7)M in the vein) depolarized the membrane and slightly reduced the membrane resistance, assessed from relative changes in the amplitude of electrotonic potential. The action of NA was suppressed by prazosin in the artery but by yohimbine in the vein, i.e. the alpha 1-adrenoceptor is present in the extrajunctional muscle membrane in the renal artery while the alpha 2-adrenoceptor is present in the renal vein. Dopamine and isoprenaline did not modify the membrane properties. In the renal artery, repetitive perivascular nerve stimulation (0.1 ms, 50 Hz, 5 shocks) evoked excitatory junction potential (e.j.p.). Applications of guanethidine (10(-6) M) or tetrodotoxin (3 X 10(-7) M) abolished the generation of the e.j.p.. Low concentrations of phentolamine (5 X 10(-7) M), prazosin (10(-7) M) and yohimbine (5 X 10(-7) M) enhanced the e.j.p. amplitude, while high concentrations of phentolamine (10(-5) M) and prazosin (greater than 10(-5) M) reduced the amplitude of e.j.p.s. NA, dopamine and clonidine consistently suppressed the amplitude of e.j.ps, at any given concentration over 10(-7) M. Spontaneous generated miniature e.j.ps (m.e.j.ps) were recorded on rare occasions. Phentolamine and yohimbine both at 5 x 10(-7) M and prazosin 10(-7) M increased the appearance of m.e.j.ps. 5 In the renal vein, repetitive nerve stimulation failed to generate the e.j.p. Sympathetic innervation to this tissue seems to be sparse. 6 Specificity of innervation and adrenoceptors present on smooth muscle cells in both the renal artery and vein are discussed, and the presynaptic regulation ofNA release is compared with findings in other vascular tissues.

Effects of prostaglandin I2 and carbocyclic thromboxane A2 on smooth muscle cells and neuromuscular transmission in the guinea-pig mesenteric artery.

1 In the guinea-pig mesenteric arteries neither prostacyclin (PGI(2)) nor carbocyclic thromboxane A(2) (cTxA(2)) affected membrane potential in concentrations below 1 x 10(-6) M. Increasing the concentration to 3 x 10(-6) M either slightly hyperpolarized or depolarized the membrane with little change in membrane resistance.2 At a concentration of 1 x 10(-7) M, the amplitude of the first e.j.p. and the enlarged amplitudes of the subsequent e.j.ps evoked by trains of stimuli were reduced consistently by PGI(2) or cTxA(2). Facilitation was unaffected by either agent.3 The inhibitory actions of PGI(2) were partly overcome by increased concentrations of 5 mM [Ca](o) and were accelerated by a reduced concentration of 1.25 mM [Ca](o).4 The amplitude of the contraction evoked by perivascular nerve stimulation was inhibited to a greater extent by PGI(2) than by cTxA(2) at concentrations below 1 x 10(-6) M.5 The contraction evoked by 5 x 10(-6) M noradrenaline (NA) or excess concentrations of 20.2 mM [K](o) was enhanced by 1 x 10(-8) M - 1 x 10(-6) M cTxA(2) and suppressed by 1 x 10(-8) M - 1 x 10(-6) M PGI(2). The minimum concentration of cTxA(2) required to produce the contraction was 1 x 10(-8) M.6 These results indicate that transmission at the neuromuscular junction was inhibited consistently by PGI(2) or cTxA(2), presumably due to inhibition of NA release by suppression of the Ca influx at the nerve terminals. Whereas PGI(2) inhibited, cTxA(2) enhanced the mechanical response by a direct action on the smooth muscle cells.

Actions of isosorbide dinitrate on smooth muscle cells of rabbit vascular tissues.

To investigate the mechanism of the anti-anginal actions of isosorbide dinitrate (ISDN), the effects of this agent on smooth muscle cells of intact and skinned preparations of the rabbit mesenteric artery and vein, and of the coronary artery were studied. ISDN (less than 10(-5) M) had no effect on the membrane potential or resistance of smooth muscle cells of the mesenteric artery and vein under resting conditions, nor when the membrane was depolarized by the presence of various concentrations of [K]o or noradrenaline (NA). The amplitude of spike evoked by outward current pulse after pretreatment with 10 mM tetraethylammonium (TEA) in the mesenteric artery was slightly inhibited by application of 10(-5) M ISDN. The K-induced and NA-induced contractions in the mesenteric artery were not affected by 10(-5) M ISDN, while those evoked in the mesenteric vein were inhibited in concentrations above 10(-6) M. The amplitude and facilitation of excitatory junction potentials evoked by perivascular nerve stimulation in the mesenteric artery were not affected by 10(-5) M ISDN. In skinned muscles, the free calcium concentration (pCa)-tension relationships observed in the mesenteric artery and vein were not affected by 10(-5) M ISDN. This agent had no effect on Ca accumulation into and Ca release from the stores in muscle cells of the mesenteric artery and vein, in skinned preparations. In the rabbit coronary artery, the membrane potential, resistance and spike evoked in the presence of 10 mM TEA were not affected by application of 10(-5) M ISDN. The contraction evoked by excess concentrations of [K]o was not affected. The contraction evoked by a low concentration of acetylcholine (3 X 10(-7) M) but by high concentrations (greater than 10(-6) M) was slightly inhibited by 10(-5) M ISDN. A tonic contraction induced in 39 mM [K]o was reduced by 10(-5) M nitroglycerine but not by 10(-5) M ISDN. Thus in rabbit vascular tissues, ISDN mainly acts on the venous system in vitro. The induced vasodilatation may lead to a reduction in the venous return and hence, reduce oxygen consumption in the cardiac muscles. This effect of ISDN may relate to the anti-anginal actions.

Onset of spermatogenesis is accelerated by gestational administration of 1,2,3,4,6,7-hexachlorinated naphthalene in male rat offspring.

We treated pregnant rats with 1 microg/kg body weight/day 1,2,3,4,6,7-hexachlorinated naphthalene (1,2,3,4,6,7-HxCN) on days 14-16 of gestation and examined the effects on the reproductive systems of their male offspring at various phases of sexual maturation. Sperm count in the cauda epididymidis did not change in 1,2,3,4,6, 7-HxCN-treated rats on postnatal day 89, the age of sexual maturity, but the sperm count in the cauda epididymidis did increase to approximately 180% of the control value on postnatal day 62. In addition, homogenization-resistant testicular spermatids increased to approximately 160% of the control value on postnatal day 48, and the percent of postmeiotic tubules increased to approximately 190% of the control value on postnatal day 31 in this group. These results indicate that the onset of spermatogenesis was accelerated in the 1,2,3,4,6,7-HxCN rats. Serum concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) had already reached the maximum level on postnatal day 31 in the 1,2,3,4,6, 7-HxCN group, suggesting that the onset of LH and FSH secretions from the pituitary gland was also accelerated and that this endocrine disruption was the cause of early onset of spermatogenesis in this group. In the fat of 1,2,3,4,6,7-HxCN-treated dams, 5.75+/-2.81 ppb 1,2,3,4,6,7-HxCN was detected when offspring were weaned. This concentration was 5-10 times higher than that found in human adipose tissue.

Autosomal dominant inheritance in Setleis syndrome.

Setleis syndrome is characterized by bitemporal skin depressions resembling forceps marks, abnormalities of the eyelashes, and "leonine" facial appearance. The cause is unknown, although autosomal recessive inheritance has been proposed. Recently, two families were reported in which one of the parents of a patient with Setleis syndrome showed mild manifestations, suggesting autosomal dominant inheritance. We describe a 9-month-old Japanese boy with typical Setleis syndrome. His father, who has normal intelligence, has bitemporal focal dermal dysplasia but a normal face. His paternal second cousin also has Setleis syndrome. This family shows autosomal dominant inheritance including father-to-son transmission of Setleis syndrome with variable expressivity and reduced penetrance. Careful examination of the relatives of patients with Setleis syndrome is recommended.

Hypoglycemia in Coffin-Siris syndrome.

We describe a further patient with the Coffin-Siris syndrome who presented at 4 months with recurrent hypoglycemia attacks. Detailed examination was undertaken at 7 months but the cause of hypoglycemia was not detected. Hypoglycemia seems to be a previously undescribed finding in the Coffin-Siris syndrome.