Evaluation of colonic myoelectrical activity in health and functional disorders.

Electrical activity of the colon was investigated in six healthy volunteers and 22 patients presenting functional colonic disorders associated with pain, constipation, or diarrhoea. Myoelectrical activity during 10 hours, including two daily meals, was recorded from eight groups of nickel-chrome electrodes using a 1.5 m length probe introduced by the rectal route. Electromyograms of volunteers consisted of slow waves at two distinct rhythms, approximately 3 and 10 cycles per minute, during 16 to 28% of the recording time respectively for each site. Action potentials were also recorded as 11 to 80 short spike bursts (SSB) per hour lasting 1.5 to 3.5 s at any site and 20-26 long spike bursts (LSB) per hour, lasting 17 to 21 s, occurring in series of four to eight propagated bursts. Additional high-velocity propagated bursts were recorded during the three hour postprandial period. Three typical changes in spike activity patterns were detected: an increase by 170-420% of the number of SSB associated to a high spiking activity was recorded in 13 patients (group I), the absence of SSB, a low spiking activity level and only 3 to 8 LSB per hour (group II), in six patients; and the postprandial response was absent (group III) in three other investigated patients. Evidence for three groups of motor disturbances and their possible relation to clinical manifestations of functional disorders is presented.     

Combined antegrade and retrograde dilation: a new endoscopic technique in the management of complex esophageal obstruction

BACKGROUND: Esophageal strictures that cause complete obstruction are often difficult to dilate with standard bougienage techniques. METHODS: A new technique was developed and applied, combined antegrade and retrograde dilation, for dilatation of complex esophageal strictures. The stomach is accessed and an endoscope (9.8 mm diameter) is directed under fluoroscopy in a retrograde fashion into the distal esophagus. A guidewire with a hydrophilic coating is advanced through the stricture and then pulled through the mouth with a simultaneously placed proximal endoscope. The guidewire is then used as a guide for antegrade esophageal dilatation. RESULTS: Ten patients with complex esophageal strictures (with and without fistulas) were treated with this technique. Three required a second combined antegrade and retrograde dilation procedure. All strictures were dilated and no perforations occurred. CONCLUSIONS: Combined antegrade and retrograde dilation is a safe and effective technique for dilation of complex obstructing esophageal lesions.     

Colonic myoelectrical activity in IBS painless diarrhoea.

Colonic myoelectrical activity was recorded during 24 hours in 23 patients with painless diarrhoea and compared with a control group of 10 healthy subjects without digestive functional disorders. Diurnal fasting activity showed no significant difference in the total long spike bursts activity (LSB lasting greater than 7 seconds), but short spike bursts activity (SSB, lasting less than 7 seconds) was significantly lower (p less than 0.05) in diarrhoeal patients. A striking difference was observed in colonic response to eating, with an increased number of migrating long spike bursts (MLSB: mass movements) during the first postprandial hour in diarrhoeal patients (p less than 0.001), while short spike bursts (segmental activity) were almost absent in the rectosigmoid area. A marked decrease in the retrograde LSB activity was also observed in eight patients. During the night (from 2200 h to 0600 h) the number of migrating long spike bursts was increased in the diarrhoea group, but almost absent in controls (p less than 0.001). This study shows that colonic motor activity was altered in painless diarrhoea. These disturbances were not limited to the decreased SSB activity in the sigmoid, but involved the whole colon, with lower SSB activity and abnormal increase of migrating long spike bursts activity (MLSB) in postprandial and nocturnal periods.     

Opposite effects of kappa-opioid agonists on gastric emptying of liquids and solids in dogs

The influence of oral (p.o.) administration of kappa-(U-50488, tifluadom) and mu- (morphine, DAGO) opioid substances on gastric emptying of liquids and solids in a standard canned dog food meal was evaluated using a double-radiolabeled technique in dogs fitted with gastric cannulas. One hour after feeding, 28.6% +/- 3.6% (mean +/- SD) of the solid phase and 27.1% +/- 8.6% of the liquid phase of the meal had been emptied. Both U-50488 and tifluadom given orally (0.01-0.1 mg/kg) significantly increased (p less than 0.05) the 1-h emptying of the solid phase of the meal by 23.1%-49.6%. In contrast, both drugs significantly reduced emptying of liquids. These effects were not reproduced when similar doses were given intravenously. Oral administration of morphine or DAGO (0.01-0.1 mg/kg) did not affect gastric emptying, whereas an inhibited emptying of solids was observed for morphine at a higher dose (1 mg/kg p.o.). At a dose of 100 micrograms/kg i.v. both naloxone and MR 2266 (0.1 mg/kg) abolished the effects of orally administered U-50488 on gastric emptying of solids and liquids. It is concluded that kappa- but not mu-agonists act locally to alter gastric emptying of a standard meal in dogs, having opposite effects on solid and liquid phases. A selective local stimulation of kappa mucosal or submucosal receptors of the gastroduodenal area may explain such effects.     

Stimulation of gastrointestinal motility by loperamide in dogs

The effects of loperamide on gastrointestinal motility were investigated in conscious fasted dogs chronically fitted with strain-gauge transducers on the antrum, the jejunum, and the colon. Oral administration of loperamide (0.1 mg/kg) induced, after a delay of 20–30 min, a long-lasting (8–12 hr) stimulation of gastrointestinal motility associated with a disorganization of the cyclic activity at the three levels investigated. These effects were reproduced by a subcutaneous administration at the same dose and were antagonized by previous intravenous administration of naloxone or a quaternary opiate antagonist. Intracolonic administration (0.1 mg/kg) stimulated, after a delay of 20–30 min, colonic motility only. Intracerebroventricular loperamide (1 g/kg) induced a long-lasting (15–20 hr) inhibition of the gastric motility and a short (2-hr) disorganization of the jejunal motor profile. These data show that oral loperamide stimulates gastrointestinal motility in dogs and involves peripheral opiate receptors.     

Expresividad variable de una mutación fundadora en el gen EIF2AK4 en pacientes con enfermedad venooclusiva pulmonar hereditaria. Impacto en la supervivencia

Introduction and objectives

Hereditary pulmonary veno-occlusive disease (PVOD) has been associated with biallelic mutations in EIF2AK4 with the recent discovery of a founder mutation in Iberian Romani patients with familial PVOD. The aims of this study were phenotypical characterization and survival analysis of Iberian Romani patients with familial PVOD carrying the founder p.Pro1115Leu mutation in EIF2AK4, according to their tolerance to pulmonary vasodilators (PVD). Familial genetic screening was conducted, as well as assessment of sociocultural determinants with a potential influence on disease course.

Pro-inflammatory cytokines favor the emergence of ETV6-RUNX1-positive pre-leukemic cells in a model of mesenchymal niche

ETV6-RUNX1 (E/R) fusion gene, arising in utero from translocation t(12;21)(p13:q22), is the most frequent alteration in childhood acute lymphoblastic leukemia (ALL). However, E/R is insufficient to cause overt leukemia since it generates a clinically silent pre-leukemic clone which persists in the bone marrow but fails to out-compete normal progenitors. Conversely, pre-leukemic cells show increased susceptibility to transformation following additional genetic insults. Infections/inflammation are the most accredited triggers for mutations accumulation and leukemic transformation in E/R⁺ pre-leukemic cells. However, precisely how E/R and inflammation interact in promoting leukemia is still poorly understood. Here we demonstrate that IL6/TNFα/ILβ pro-inflammatory cytokines cooperate with BM-MSC in promoting the emergence of E/R⁺ Ba/F3 over their normal counterparts by differentially affecting their proliferation and survival. Moreover, IL6/TNFα/ILβ-stimulated BM-MSC strongly attract E/R⁺ Ba/F3 in a CXCR2-dependent manner. Interestingly, E/R-expressing human CD34⁺IL7R⁺ progenitors, a putative population for leukemia initiation during development, were preserved in the presence of BM-MSC and IL6/TNFα/ILβ compared to their normal counterparts. Finally, the extent of DNA damage increases within the inflamed niche in both control and E/R-expressing Ba/F3, potentially leading to transformation in the apoptosis-resistant pre-leukemic clone. Overall, our data provide new mechanistic insights into childhood ALL pathogenesis.     

Haploidentical transplantation in high-risk pediatric leukemia: A retrospective comparative analysis on behalf of the Spanish working Group for bone marrow transplantation in children (GETMON) and the Spanish Grupo for hematopoietic transplantation (GETH)

A total of 192 pediatric patients, median age 8.6 years, with high-risk hematological malignancies, underwent haploidentical stem cell transplantation (haplo-HSCT) using post-transplantation cyclophosphamide (PT-Cy), or ex vivo T cell-depleted (TCD) graft platforms, from January 1999 to December 2016 in 10 centers in Spain. Some 41 patients received an unmanipulated graft followed by PT-Cy for graft-vs-host disease (GvHD) prophylaxis. A total of 151 patients were transplanted with CD3-depleted peripheral blood stem cells (PBSCs) by either CD34⁺ selection, CD3⁺CD19⁺ depletion, TCRαβ⁺CD19⁺ depletion or CD45RA⁺ depletion, added to CD34⁺ selection for GvHD prophylaxis. The PBSCs were the only source in patients following ex vivo TCD haplo-HSCT; bone marrow was the source in 9 of 41 patients following PT-CY haplo-HSCT. Engraftment was achieved in 91.3% of cases. A donor younger than 30 years, and the development of chronic GvHD were positive factors influencing survival, whereas positive minimal residual disease (MRD) before transplant and lymphoid disease were negative factors. The probability of relapse increased with lymphoid malignancies, a donor killer-cell immunoglobulin-like receptor (KIR) haplotype A and positive MRD pretransplant. No difference was found in overall survival, disease-free survival or relapse incidence between the two platforms. Relapse is still of concern in both platforms, and it should be the focus of future efforts. In conclusion, both platforms for haplo-HSCT were effective and could be utilized depending on the comfort level of the center.