Exome sequencing reveals novel and recurrent mutations with clinical impact in blastic plasmacytoid dendritic cell neoplasm.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a very rare disease that currently lacks genomic and genetic biomarkers to assist in its clinical management. We performed whole-exome sequencing (WES) of three BPDCN cases. Based on these data, we designed a resequencing approach to identify mutations in 38 selected genes in 25 BPDCN samples. WES revealed 37-99 deleterious gene mutations per exome with no common affected genes between patients, but with clear overlap in terms of molecular and disease pathways (hematological and dermatological disease). We identified for the first time deleterious mutations in IKZF3, HOXB9, UBE2G2 and ZEB2 in human leukemia. Target sequencing identified 29 recurring genes, ranging in prevalence from 36% for previously known genes, such as TET2, to 12-16% for newly identified genes, such as IKZF3 or ZEB2. Half of the tumors had mutations affecting either the DNA methylation or chromatin remodeling pathways. The clinical analysis revealed that patients with mutations in DNA methylation pathway had a significantly reduced overall survival (P=0.047). We provide the first mutational profiling of BPDCN. The data support the current WHO classification of the disease as a myeloid disorder and provide a biological rationale for the incorporation of epigenetic therapies for its treatment.

Distribución intraneural del nervio cubital / Intraneural distribution of the ulnar nerve

Objetivo. Estudiar la distribución fascicular del nervio cubital en la zona del codo para aplicar estos fundamentos en la técnica de transferencia nerviosa del cubital. Material y método. Se realizó la disección de 12 extremidades superiores criopreservadas inyectadas con látex. Tras la localización del nervio cubital se disecó intraneuralmente con gafas lupa para efectuar una descripción de su formación y recorrido. Resultados. En la zona proximal del codo la segregación de los fascículos extrínsecos no estaba definida ya que la variabilidad anatómica, en grosor y número, hizo difícil identificar a sus componentes. En el codo encontramos una diferenciación morfológica clara y distal al codo se apreciaron claramente los fascículos destinados a formar las ramas del nervio. Los fascículos del nervio cubital efectuaban un trayecto en espiral en su progresión distal. Discusión. La disposición microanatómica de los fascículos del nervio cubital alrededor del codo es más complicado que lo descrito en la literatura, lo que hace recomendable la utilización de registros intraoperatorios para localizar las fibras destinadas a la musculatura extrínseca e intrínseca y fibras sensitivas para efectuar la técnica de Oberlin, o al menos utilizar un estimulador eléctrico para su identificación (AU)

Objective. To study the fascicular distribution of ulnar (cubital) nerve in the elbow area in order to apply these fundamentals to the ulnar nerve transfer technique. Material and method. Twelve cryopreserved arms, injected with latex were dissected. After locating the ulnar nerve, intraneural dissection was performed using magnifying glasses in order to describe its formation and trajectory. Results. Segregation of the extrinsic fascicles was not well defined in the elbow area as the anatomical variability, in thickness and number, made it difficult to identify its components. A clear morphological differentiation was observed in the elbow and the fascicles destined to form nerve branches were clearly seen distal to the elbow. The ulnar nerve fascicles have a spiral trajectory in its distal progression. Discussion. The micro-anatomical layout of the ulnar nerve fascicles around the elbow is more complicated than that described in the literature, which makes it advisable to use surgical records to locate the fibres destined for the extrinsic and intrinsic musculature. Sensitive fibres are required to perform the Oberlin technique, or at least the use of an electrical stimulator to identify them (AU)

Cysteine string protein-alpha is essential for the high calcium sensitivity of exocytosis in a vertebrate synapse.

Cysteine string protein (CSPalpha) is a synaptic vesicle protein present in most central and peripheral nervous system synapses. Previous studies demonstrated that the deletion of CSPalpha results in postnatal sensorial and motor impairment and premature lethality. To understand the participation of CSPalpha in neural function in vertebrates, we have studied the properties of synaptic transmission of motor terminals in wild-type and CSPalpha knockout mice. Our results demonstrate that, in the absence of CSPalpha, fast Ca2+-triggered release was not affected at postnatal day (P)14 but was dramatically reduced at P18 and P30 without a change in release kinetics. Although mutant terminals also exhibited a reduction in functional vesicle pool size by P30, further analysis showed that neurotransmission could be 'rescued' by high extracellular [Ca2+] or by the presence of a phorbol ester, suggesting that an impairment in the fusion machinery, or in vesicle recycling, was not the primary cause of the dysfunction of this synapse. The specific shift to the right of the Ca2+ dependence of synchronous release, and the lineal dependence of secretion on extracellular [Ca2+] in mutant terminals after P18, suggests that CSPalpha is indispensable for a normal Ca2+ sensitivity of exocytosis in vertebrate mature synapses.

Continuous suction irrigation: prospective bacteriological study.

Twenty-eight patients with osteoarticular infection, were treated with a continuous irrigation suction system after surgical debridement. The mean age was 48 years (17-80 years). The average irrigation time was 11,7 days (6-16 days). After the surgical procedure, a bacteriological analysis of irrigation fluid was made every 3 or 4 days. The bacteriological study was qualitative and quantitative. The results showed that 22 patients (78,5%) had a colonization of the irrigation fluid by microorganisms different from the initial microorganism. In 11 patients (39,3%) the colonization was polymicrobial. The incidence of colonization of the system, increased with the irrigation time: 7,4% at third day, 22,2% at sixth day, 63,1% at tenth day and 87,5% at fourteenth day (quantitative cultures). This increase was more notable between the sixth and the tenth day.

Prenatal and postnatal corticosteroid therapy to prevent neonatal necrotizing enterocolitis: a controlled trial.

To determine whether prenatal corticosteroid therapy would reduce the incidence of neonatal necrotizing enterocolitis (NEC), we assigned a total of 466 women admitted in premature labor either to receive placebo (group A, n = 256), if delivery was expected to occur within 24 hours of admission, or to receive betamethasone (group B, n = 210) if delivery was expected to take place more than 24 hours after admission. All women were free of severe medical complications or drug therapy; cases of intrauterine growth retardation or premature rupture of the membranes were excluded. Their newborn infants, excluding malformed, congenitally infected, and growth-retarded infants, were enrolled in the study unless they had died before the age of 10 postnatal days. Babies born to group A mothers (n = 248) were further assigned to a treatment group (group A1, n = 130) receiving dexamethasone, 2 mg/kg/day by intravenous injection during the first 7 days of life, or to a control group (group A2, n = 118) receiving 10% dextrose solution placebo. Group B infants (prenatal betamethasone, n = 205) received neither treatment nor placebo. The incidence of NEC in group A1 was 6.9% (9/130), and in group A2 it was 14.4% (17/118) (p less than 0.05). In group B the incidence was 3.4% (7/205); this was much lower than in group A2 (p less than 0.01) and lower than in group A combined (10.4%) (p less than 0.01). There was no death from NEC and no surgical intervention among group B patients. The mortality rate for group A1 (11%) was lower than for group A2 (56%) (p less than 0.02). There were fewer indications for surgical intervention for NEC in group A1 than in group A2. Histologic studies confirmed bowel ischemia in all specimens analyzed. These data support the hypothesis that the incidence of NEC is significantly reduced after prenatal steroid treatment. Although postnatal therapy with steroids does not decrease the incidence as effectively as prenatal therapy, it improves clinical outcome of NEC.