Intact goal‐directed control in treatment‐seeking drug users indexed by outcome‐devaluation and Pavlovian to instrumental transfer: critique of habit theory

Animal studies have demonstrated that chronic exposure to drugs of abuse impairs goal‐directed control over action selection indexed by the outcome‐devaluation and specific Pavlovian to instrumental transfer procedures, suggesting this impairment might underpin addiction. However, there is currently only weak evidence for impaired goal‐directed control in human drug users. Two experiments were undertaken in which treatment‐seeking drug users and non‐matched normative reference samples (controls) completed outcome‐devaluation and specific Pavlovian to instrumental transfer procedures notionally translatable to animal procedures (Experiment 2 used a more challenging biconditional schedule). The two experiments found significant outcome‐devaluation and specific Pavlovian to instrumental transfer effects overall and there was no significant difference between groups in the magnitude of these effects. Moreover, Bayes factor supported the null hypothesis for these group comparisons. Although limited by non‐matched group comparisons and small sample sizes, the two studies suggest that treatment‐seeking drug users have intact goal‐directed control over action selection, adding uncertainty to already mixed evidence concerning the role of habit learning in human drug dependence. Neuro‐interventions might seek to tackle goal‐directed drug‐seeking rather than habit formation in drug users.     

Enteral feeding reduces endothelial nitric oxide synthase in the caudal intestinal microvasculature of preterm piglets

The initiation of enteral feeding represents a challenge to the neonatal intestinal microcirculation, especially in preterms where it predisposes to necrotizing enterocolitis (NEC). We hypothesized that a structural microvascular deficiency may occur when enteral feeding is initiated in preterm piglets susceptible to NEC. Stereologic volume densities of a pan-endothelial marker (vWF), and the main vasodilator endothelial nitric oxide synthase (eNOS), were determined along the small intestine of 1) unfed preterm piglets, 2) piglets receiving total parenteral nutrition (TPN) for 2-3 d, and 3) piglets fed 2 d sow's colostrum (TPN+SOW) or milk formula (TPN+FOR) following TPN. In the mucosa, vWF-density decreased in a cranio-caudal direction. A corresponding mucosal eNOS gradient appeared only after initiating enteral feeding. In TPN+SOW, eNOS induction may lag behind the mucosal growth of the caudal region. In TPN+FOR, formula-related factors (i.e. bacteria, cytokines) may suppress mucosal eNOS, indicated by increased stress-sensitive nuclear HIF1alpha staining. The low mucosal endothelial eNOS density was related to the presence of NEC lesions, maybe via increased hypoxia-sensitivity, especially in the caudal region as indicated by nuclear HIF1alpha-staining. Our results suggest an insufficient structural adaptation of the microvasculature to enteral feeding, especially of mucosal eNOS, which may lead to NEC.     

Targeting von Willebrand factor and platelet glycoprotein Ib receptor

Atherothrombotic events, such as acute coronary syndrome or stroke, are the result of platelet activation. Von Willebrand factor (vWF), a multimeric glycoprotein, plays a key role in aggregation of platelets, especially under high-shear conditions. Acting as bridging element or ligand between damaged endothelial sites and the glycoprotein Ib (GPIb) receptor on platelets, vWF is responsible for platelet adhesion and aggregation. This vWF activation and further platelet aggregation mainly occurs under high shear stress present in small arterioles or during deficiency of the vWF-cleaving protease ADAMTS13. There are several substances targeting vWF itself or its binding receptor GPIb on platelets. Two antibodies are directed against vWF: AJW200, an IgG4 humanized monoclonal antibody, and 82D6A3, a monoclonal antibody of the collagen-binding A-3 domain of vWF. ALX-0081 and ALX-0681 are bivalent humanized nanobodies targeting the GPIb binding site of vWF. Aptamers are oligonucleotides with drug-like properties that share some of the attributes of monoclonal antibodies. ARC1779 is a second-generation, nuclease-resistant aptamer, binding to the activated vWF A1 domain and ARC15105 is a chemically advanced follower with an assumed higher affinity to vWF. Antibodies targeting GPIbα are h6B4-Fab, a murine monoclonal antibody; GPG-290, a recombinant, chimeric protein containing the amino-terminal 290 amino acids of GPIbα linked to human IgG1 Fc; and the monoclonal antibody SZ2. There are a number of promising preclinical results and development of some agents (AJW 200, ARC1779 and ALX-0081) has already reached Phase II trials.     

Paternal deletion 6q24.3: a new congenital anomaly syndrome associated with intrauterine growth failure, early developmental delay and characteristic facial appearance

Deletions of the long arm of chromosome 6 are relatively uncommon and to date minimal genotype-phenotype correlations have been observed. We report on three unrelated patients with de novo paternal interstitial deletions of 6q24.3. FISH mapping was used to delineate the minimal region of overlap between these three patients. Although all three patients had different size deletions and different breakpoints, two of the patients shared a 2.5 Mb region of overlap and strikingly similar facial features including a triangular face, frontal bossing with metopic prominence, short and upward-slanting palpebral fissures, asymmetry of upper eyelids, hooded eyelids, shallow orbits, prominent inferior orbital crease, wide mouth, and long and flat philtrum. They also had redundant skin, joint laxity, a small thorax, and early developmental delay. The smallest region of overlap between all three patients was a region of deletion less than 1 Mb; all had a history of IUGR and postnatal short stature without overt radiologic skeletal anomalies. The dysmorphic features, early developmental and growth delay may be due to the hemizygous state for one of the genes in the deleted region of two of the patients or to a long range effect of the deletion on expression of other genes. In addition, since imprinted genes have been reported in this region, paternal deletion of an imprinted gene in all three patients may contribute to the growth phenotype. We propose that this is a new congenital malformation syndrome associated with a paternal deletion of 6q24.3.