SHOX mutations in dyschondrosteosis (Leri-Weill syndrome).

Dyschondrosteosis (DCS) is an autosomal dominant form of mesomelic dysplasia with deformity of the forearm (Madelung deformity; ref. 3). Based on the observation of XY translocations (p22,q12; refs 4-6) in DCS patients, we tested the pseudoautosomal region in eight families with DCS and showed linkage of the DCS gene to a microsatellite DNA marker at the DXYS233 locus (Zmax=6.26 at theta=0). The short stature homeobox-containing gene (SHOX), involved in idiopathic growth retardation and possibly Turner short stature, maps to this region and was therefore regarded as a strong candidate gene in DCS. Here, we report large-scale deletions (in seven families) and a nonsense mutation (in one family) of SHOX in patients with DCS and show that Langer mesomelic dwarfism results from homozygous mutations at the DCS locus.

Insulin-like growth factor I reverses interleukin-1beta inhibition of insulin secretion, induction of nitric oxide synthase and cytokine-mediated apoptosis in rat islets of Langerhans.

We have previously observed that treatment of rat islets of Langerhans with interleukin-1beta for 12 h results in nitric oxide-dependent inhibition of insulin secretion, while 48 h treatment increased rates of islet cell death by apoptosis. Here, we demonstrate that interleukin-1beta-mediated nitric oxide formation and inhibition of insulin secretion are significantly reduced by 24 h pretreatment of rat islets of Langerhans with insulin-like growth factor I (IGF-I). IGF-I decreased cytokine induction of nitric oxide synthase in islets. Use of an arginine analogue in culture or IGF-I pretreatment of islets were also effective in protecting islets against cytokine-mediated apoptotic cell death. We conclude that IGF-I antagonises inhibitory and cytotoxic effects of cytokines in rat islets.

Role of adenine nucleotides in insulin secretion from MIN6 pseudoislets.

Insulin secretion from MIN6 cells configured as cell aggregates by culture on a gelatin substrate (pseudoislets) is enhanced compared to that of MIN6 cells grown as monolayers on tissue culture plastic, indicating the importance of beta-cell-to-beta-cell proximity for insulin release. In this study we have shown that glucose induced a biphasic release of insulin from pseudoislets, whereas the amplitude and duration of the responses of equivalent monolayer cells were much reduced. Purinergic aqonists have been implicated in intercellular communication between beta-cells, so we investigated whether adenine nucleotides co-released with insulin are responsible for the enhanced secretory responses of pseudoislets. We have demonstrated that MIN6 cells express purinergic A(1) and P2Y receptors, and that adenine nucleotides increased [Ca(2+)](i) with an efficacy of agonists being ATP > ADP > AMP. However, neither suramin nor the more selective A(1) antagonist 1,3-dipropyl-8-cyclopentylxanthine reduced glucose-induced insulin secretion from pseudoislets, and stimulation of monolayer cells with a range of adenine nucleotides did not enhance glucose-induced secretion. These results suggest that enhanced secretion from MIN6 pseudoislets is not due to increased paracrine/autocrine action of adenine nucleotides.

[Slow ventricular tachycardia presenting in the antenatal period]. / Tachycardie ventriculaire lente de révélation anténatale.

The authors report two cases of slow ventricular tachycardia presenting in the antenatal period. One foetus had anasarca at 38 weeks' gestation. After birth, improved myocardial function contributed to the rapid resorption of the effusions. The other case was well tolerated in the foetal and neonatal periods. In both cases, Holter ECG recorded an intermittent ventricular arrhythmia with salvos of sustained ventricular tachycardia with a maximum rate of 185/min, only 10% higher than the underlying sinus rhythm, disappearing on acceleration of the sinus rhythm. The aetiological investigation was negative. Therapeutic abstention was supported by the spontaneously favourable outcome after 3 and 5 months. Slow ventricular tachycardia or accelerated idioventricular rhythms are usually considered to be benign but the case with foetal anasarca suggests that they should be carefully followed up in the neonatal period. In the absence of a consensus on management, therapeutic abstention implies regular cardiological examination until the arrhythmia has disappeared.

SHOX gene mutations and deletions in dyschondrosteosis or Leri-Weill syndrome.

Dyschondrosteosis is an autosomal dominant form of mesomelic dysplasia that is often combined with a deformity of the forearms called Madelung deformity. Based on the observation of X-Y translocations (p22,q12) in patients with dyschondrosteosis, the authors tested the pseudoautosomal region in eight affected families and showed linkage of the dyschondrosteosis gene to a microsatellite DNA marker at the DXYS233 locus (Zmax = 6.26 at theta = 0). Since the short stature homeobox-containing gene (SHOX) involved in idiopathic growth retardation and possibly Turner syndrome maps to this region, SHOX was regarded as a strong candidate gene for dyschondrosteosis. This article reports the detection of large-scale SHOX deletions in seven of the eight families and a nonsense mutation of SHOX in the remaining family affected with dyschondrosteosis. Additional evidence suggests that Langer mesomelic dwarfism results from homozygous mutations at the genetic locus responsible for dyschondrosteosis.

[Severe acute White-Spirit poisoning with pulmonary hypertension]. / Un cas d'intoxication aiguë sévère au White-Spirit avec hypertension artérielle pulmonaire.

UNLABELLED: The Authors report a case of acute White-Spirit poisoning with pulmonary hypertension associated to respiratory distress syndrome. CASE REPORT: A 14-month-old infant drank an unknown quantity of White-Spirit while his parents were painting. After he spontaneously vomited, he presented a seizure at the emergency department. After a 36 h stay in Pediatric Intensive Care Unit (PICU), acute lung injury required mechanical ventilation and vasoactive support. Cardiac ultrasounds showed pulmonary hypertension, which rapidly resolved with inhaled nitric oxide. The child was discharged of PICU after five days. Respiratory follow-up two months after poisoning was normal. CONCLUSION: Pulmonary hypertension should be checked for in case of White-Spirit ingestion complicated with severe acute lung injury.

[A case of atrial flutter after umbilical venous catheterization]. / Une observation de flutter auriculaire après pose de cathéter veineux ombilical.

UNLABELLED: Isolated atrial flutter is an extremely rare form of supraventricular tachycardia in the neonatal period. It may be initiated by central venous catheterization. CASE REPORT: A male infant was born at 35 weeks by cesarean section for placenta praevia. He was eutrophic. Apgar score was 10 at 1 and 5 minutes. He secondary developed a respiratory distress syndrome. He was then ventilated by nasal CPAP. Immediately after an umbilical venous catheterization, a tachycardia appeared without preexistent cardiac dysfunction. An intravenous dose of adenosine (Striadyne) showed a characteristic sawtooth pattern of P waves on inferior leads. The cardiac-US examination was normal. This atrial flutter was converted to normal sinus rhythm by transoesophageal pacing, without adjunction of antiarrhythmic drugs. The newborn was weaned from mechanical ventilation 48 hours later and discharged from hospital at seven days post natal age. His development and clinical examination were normal two months later. CONCLUSION: The isolated atrial flutter is rare in the neonate. It may be triggered by a venous catheterization. Transoesophageal atrial pacing is safe and effective for conversion.

[Peptidergic control of electrical activities in the magnocellular neurons of the hypothalamus]. / Contrôle peptidergique des activités électriques des neurones magnocellulaires de l'hypothalamus.

Although many peptides have been reported in the vicinity of hypothalamic magnocellular nuclei, their role in the control of neurohypophysial hormone release was only studied for few peptides: opiates, angiotensin II, substance P, CRF, oxytocin and vasopressin. Their effects are briefly recalled and then compared to the more detailed study of their role in the firing pattern of oxytocin and vasopressin neurones. This technique, in some cases, revealed the action site and mechanism of these peptides in the hypothalamo-neurohypophysial system.

[Influence of hospital location on short-term fate of premature infants born at 34 weeks of gestation]. / Influence du lieu d'hospitalisation sur le devenir à court terme des prématurés nés à 34 semaines d'aménorrhée.

In France, new care units have emerged in maternity wards for the treatment of moderate prematurity, called mother-child units (MCU). We compared the length of hospitalization between the MCUs and the neonatal units (NNUs) for premature infants born at 34 weeks of amenorrhea at Grenoble university hospital. This was a retrospective, single-center study, including 99 premature infants born from 34 of amenorrhea to 34 weeks+6 days between 2004 and 2009. Were included all premature 34-week infants hospitalized in the NNU or the MCU excluding those with respiratory distress, birth defects, and including infants whose birth weight was less than 1500g admitted to the neonatal intensive care unit or transferred secondarily to the MCU. The characteristics of both groups were similar apart from a lower birth weight in the NNU group (1892 vs. 2182g) and gestational age less than in the NNU group (34.1 vs. 34.3 SA). Our primary outcome, length of hospital stay, was significantly shorter in the MCU (15.4 vs. 20.7 days in the NNU, P<0.01) as well as the duration of nasogastric tube feeding (2.8 vs. 9.1 days, P<0.01). This difference remained after adjustment for birth weight and gestational age. Our retrospective study shows that the length of hospitalization of premature infants born at 34 weeks gestation and hospitalized in our center is significantly shorter when they are admitted to the MCU rather than neonatology. For this reason, this mode of hospitalization in maternity MCUs can be recommended.

Paired recordings from supraoptic and paraventricular oxytocin cells in suckled rats: recruitment and synchronization.

Oxytocin cells in the paraventricular (p.v.) and contralateral supraoptic (s.o.) nuclei were pair-recorded (with two micro-electrodes) in suckled rats after being anaesthetized with urethane (1.2 g/kg), to study the synchronization of their neurosecretory bursts, the importance of cell recruitment and their firing characteristics. The synchronization of paired bursts was determined by measuring the onset time-lag (time in milliseconds between the onset of two corresponding bursts) and the maximum firing time-lag (time in milliseconds between the two shortest interspike intervals for the corresponding bursts). For each cell, the characteristics studied were: the background activity and the frequency and amplitude (total number of spikes) of the neurosecretory bursts. All paired p.v.-s.o. cells recorded were activated simultaneously 12-18 s before each milk ejection. The onset of a burst could vary either way, up to 680 ms, in relation to the other (mean onset time-lag was 206 +/- 18 ms; n = 85) but the maximum activation periods fitted more closely, the mean maximum firing time-lag being 122 +/- 14 ms (n = 64). Both parameters varied randomly, in duration and order from one pair of cells to another, from one pair of bursts to another for successive bursts of a given pair of cells and independently, whether the cells were in the p.v. or the s.o. nucleus. However, in most cases, the neurosecretory burst with the highest amplitude began and reached its peak firing rate before the corresponding burst from the other cell. Cell recruitment was observed when the milk ejection reflex began, for both the p.v. and the s.o. cells. The bursts of the non-responsive cells developed progressively with the reflex, but, as soon as a cell was recruited, all its successive bursts were simultaneous with those of the first-recruited oxytocin cells. During a regular pattern of milk ejections, the mean background activity of sixty p.v. cells (3.1 +/- 0.2 spikes/s) was significantly higher than that of their s.o. counterparts (1.9 +/- 0.2 spikes/s). Nevertheless, the mean amplitude of the neurosecretory bursts of the sixty p.v. cells (49 +/- 3 spikes) did not differ significantly from that of their s.o. counterparts (55 +/- 4 spikes).(ABSTRACT TRUNCATED AT 400 WORDS)

Synchronization of oxytocin cells in the hypothalamic paraventricular and supraoptic nuclei in suckled rats: direct proof with paired extracellular recordings.

In suckled rats, neurosecretory bursts of two oxytocin cells located in two different magnocellular nuclei were almost simultaneous before each milk ejection. The time elapsing between the onset of two corresponding neurosecretory bursts varied in duration (from 0 to 368 ms) and in order from one pair of cells to another, from one pair of bursts to another for successive bursts of a given pair of cells and independently of whether one of the two cells belonged to the paraventricular or supraoptic nuclei. However, the neurosecretory burst with the highest amplitude began before the other corresponding burst in most cases. Possible inter- and intranuclear synchronization mechanisms are discussed.

Dermatomyositis associated with the presence of parvovirus B19 DNA in muscle.

We report a case of dermatomyositis associated with molecular evidence of parvovirus B19 DNA in two muscle biopsies collected 5 months apart. IgG- but not IgM-specific antibodies were detected in serum. None of four serum samples was positive for parvovirus B19 DNA. The two biopsies contained B19 VP1 sequences and the second one was also positive for NS1. This is the first report of viral parvovirus B19 DNA in muscle of a patient with dermatomyositis. Latent muscle infection may contribute to the clinical picture.

Intracytoplasmic sperm injection pregnancy with trisomy 20p and monosomy 22q in a newborn resulting from a balanced paternal translocation.

In infertile men who carry a balanced reciprocal translocation, intracytoplasmic sperm injection (ICSI) may induce a pregnancy with an abnormal karyotype. This report describes a previously unreported paternal reciprocal translocation leading to a chromosomally unbalanced ICSI pregnancy. The triplet pregnancy resulted in 1 normal girl, 1 physically normal boy with the same balanced paternal translocation, and a severely malformed boy with trisomy 20p and monosomy 22q who died in the neonatal period.

The myocardial lesions produced by the potassium channel opener aprikalim in monkeys and rats are prevented by blockade of cardiac beta-adrenoceptors.

Aprikalim is a potent, specific, and selective opener of ATP-sensitive K+ (KATP) channels. By virtue of this pharmacological property, aprikalim affords cardioprotection in experimental models of ischemia/reperfusion injury, and, at higher doses, also causes peripheral or coronary vasodilatation. Direct-acting peripheral vasodilators can cause myocardial lesions, particularly in rats and dogs. However, unexpectedly, aprikalim produced this effect also in monkeys. Thus, the primary aim of this investigation was to assess whether in monkeys these myocardial lesions were the direct or indirect consequence of the vascular effects of aprikalim. Cynomologus monkeys were given the beta-adrenoceptor antagonist nadolol (2 mg/kg p.o., twice daily) for 4 consecutive days. On the third and fourth day of the experiment, they received aprikalim (1 mg/kg p.o.). In another series, two monkeys carrying telemetry transmitters for blood pressure and heart rate measurements were also given aprikalim or its vehicle. Finally, aprikalim (1 mg/kg p.o. for 2 days) or its vehicle was administered to rats which were concurrently treated with the beta-adrenoceptor antagonist atenolol (5 mg/kg s.c.) or its vehicle. In cynomologus monkeys, aprikalim produced focal and multifocal myocardial necrosis of minimal to moderate intensity in or near the papillary muscles of the left ventricle. These effects were abrogated by nadolol. Similarly, necrotic lesions were caused by aprikalim only in those rats which had not been pretreated with atenolol. In monkeys, aprikalim produced a marked and long-lasting decrease in aortic blood pressure, accompanied by an even more prolonged tachycardia. These results demonstrate that aprikalim can produce myocardial necrosis not only in rats but also in monkeys. To our knowledge, this is the first time that such adverse effects are reported for a vasodilator in monkeys. More importantly, these effects were prevented by blocking cardiac beta-adrenoceptors. Thus, the myocardial lesions produced by aprikalim may be attributed to its profound and prolonged hemodynamic effects.

Prenatal diagnosis of female monozygotic twins discordant for Turner syndrome: implications for prenatal genetic counselling.

We describe a set of monozygotic (MZ) female twins, one of whom presented with a typical Turner syndrome (TS) phenotype and the other a normal female phenotype. Prenatal fetal ultrasonographic examination showed a monochorial diamniotic pregnancy with a hygroma colli and growth delay in Twin A and no anomalies in Twin B. Karyotypic analysis performed on fetal blood samples demonstrated a 46,XX/45,X (23/2) mosaicism in Twin A and a normal 46,XX chromosome constitution in Twin B. At birth, Twin A presented with a typical TS and Twin B had a normal female phenotype. Postnatal cytogenetic investigation of blood lymphocytes showed the same 46,XX/45,X mosaicism in both twins: 46,XX/45,X (40/7) in Twin A and 46,XX/45,X (40/5) in Twin B. Further investigations at the age of 10 months showed in Twin A a 46,XX/45,X (98/2) mosaicism in lymphocytes and 100% of 45,X (50 analysed cells) in fibroblasts, and in Twin B a normal 46,XX (100 analysed cells) chromosome constitution in lymphocytes but a mild 46,XX/45,X (78/2) mosaicism in fibroblasts. Monozygosity was confirmed by molecular analysis. To our knowledge, this is the first report of prenatal diagnosis of MZ female twins discordant for TS. Review of reported sets of MZ female twins (eight cases) or triplets (one case) discordant for TS shows, as in the present case, that the phenotype correlates better with the chromosomal distribution of mosaicism in fibroblasts than in lymphocytes. In the blood of MZ twins chimerism may modify the initial allocation of the mosaicism. These results suggest that, in cases of prenatal diagnosis of MZ female twins discordant for TS, the phenotype of each twin would be better predicted from karyotype analysis of cells from amniotic fluid than from fetal blood.

Glucagon decreases cytokine induction of nitric oxide synthase and action on insulin secretion in RIN5F cells and rat and human islets of Langerhans.

Nitric oxide synthase, induced by cytokines in insulin-containing cells, produces nitric oxide which inhibits function and may promote cell killing. Since glucagon was shown to prevent inducible nitric oxide synthase (iNOS) expression in rat hepatocytes it was of interest to examine the action of glucagon (and cyclic AMP) on iNOS induction in insulin-producing cells. Cultured RIN5F cells and primary rat and human islets of Langerhans were treated with interleukin 1beta (IL-1beta) or a combination of cytokines, and were co-treated or pre-treated with glucagon. In RIN5F cells, the activity of iNOS induced by IL-1beta (10 pM, 24 h), was significantly reduced by glucagon (1000 nM), which raises cyclic AMP, and by forskolin (1-10 microM), a non specific activator of adenylate cyclase. Glucagon and forskolin also decreased iNOS expression in RIN5F cells, and rat and human islets, as shown by Western blotting. The inhibitory action of IL-1beta (100 pM, 24 h) on rat islet insulin secretion was partially reversed by 1-h pre-treatment with glucagon (10-1000 nM), while the contrasting stimulatory effect of 48-h treatment with cytokines on insulin secretion from human islets was similarly prevented by glucagon (1000 nM) pre-treatment. These results suggest that glucagon inhibits iNOS expression in insulin-containing cells and imply that glucagon could modulate the inhibitory effects of cytokines.