Hypothermia for the treatment of neonatal ischemic encephalopathy: is the genie out of the bottle?

Evidence suggests that hypothermia for hypoxic ischemic encephalopathy in the term neonate may decrease the risk of death or neurodevelopmental impairment. The objective of this study was to determine how hypothermia has been incorporated into practice. An anonymous survey was sent to medical directors of United States neonatal intensive care units (NICUs) in October 2005. We received completed surveys from 441 (54.5%) of 809 of NICUs. Only 6.4% of respondents used hypothermia. The most common method was total body cooling (64.3%) compared with head cooling (25%) or both (10.7%). At centers that did not offer hypothermia, 29% transferred infants to an institution that did. Centers that offered hypothermia were more likely at academic institutions (76.9%) compared with private practices (11.5%; p < 0.001). Hypothermia was more likely offered at institutions that offered extracorporeal membrane oxygenation (ECMO; 57%) than centers where ECMO was not offered (43%; p < 0.001). There has not been widespread use of hypothermia. There are a variety of protocols used. As results of further outcome studies become available, educational efforts and national practice guidelines will be essential.     

Ectopic bone formation in rats: the importance of the carrier

Much research has been done to develop the ideal bone graft substitute (BGS). One approach to develop this ideal BGS is the use of growth factors, but for this approach osteoprogenitor cells are needed at the site of reconstruction. An alternative is a cell-based approach, where enough cells are provided to form bone in a carrier material. In previous studies of our group, titanium (Ti) carriers have been used, because of the excellent mechanical properties and the bone-compatibility of this material. On the other hand, calcium phosphate (CaP) ceramics are known for their excellent osteoconductivity. The aim of this study is to investigate the influence of the carrier in a cell-based bone regeneration approach, whereby we hypothesize that CaP-ceramic implants will induce more bone formation than Ti-fiber implants, in the same animal model as our previous experiment. Ti-fiber mesh implants and ceramic implants were seeded with rat bone marrow cells (RBM) and implanted subcutaneously. Histological analysis after one, three and six weeks showed differences in the way of bone formation in the two groups: bone appeared to grow from the center to the periphery of the implant in the titanium group, while bone formation in the ceramic group occurred through the whole implant. Histomorphometrical analysis after one week showed very limited bone formation for both the titanium and ceramic group. At three weeks, the amount of bone formation was increased till about 10% for the titanium group and 18% for the ceramic group. No significant difference between the two groups could be observed. In the six week group, the bone formation was 6% (Ti) and 23% (CaP), respectively (P < 0.001). Further, bone formation started earlier in the CaP-ceramic scaffolds than in the Ti scaffolds. Our hypothesis could be confirmed: ceramic implants induce more bone formation than titanium implants.     

De-stabilization of the positive vago-vagal reflex in bulimia nervosa

Bulimia nervosa is characterized by consuming large amounts of food over a defined period with a loss of control over the eating. This is followed by a compensatory behavior directed at eliminating the consumed calories, usually vomiting. Current treatments include antidepressants and/or behavioral therapies. Consensus exists that these treatments are not very effective and are associated with high relapse rates. We review evidence from literature and present original data to evaluate the hypothesis that bulimia involves alterations in vago-vagal function. Evidence in support of this include (1) laboratory studies consistently illustrate deficits in meal size, meal termination, and satiety in bulimia; (2) basic science studies indicate that meal size and satiation are under vagal influences; (3) anatomical, behavioral and physiological data suggest that achieving satiety and the initiation of emesis involve common neural substrates; (4) abnormal vagal and vago-vagal reflexive functions extend to non-eating activational stimuli; and (5) studies from our laboratory modulating vagal activation have shown significant effects on binge/vomit frequencies and suggest a return of normal satiation. We propose a model for the pathophysiology of bulimia based upon de-stabilization of a bi-stable positive vago-vagal feedback loop. This model is not meant to be complete, but rather to stimulate anatomical, psychobiological, and translational neuroscience experiments aimed at elucidating the pathophysiology of bulimia and developing novel treatment strategies.     

Dll3 is expressed in developing hair cells in the mammalian cochlea.

Notch mediates the process of lateral inhibition that controls the production of hair cells in the inner ear. Hair cells are known to express Notch ligands Dll1 and Jag2, which signal through Notch1 in adjacent supporting cells. However, recent genetic and pharmacological studies indicate that the level of Notch-mediated lateral inhibition is greater than can be accounted for by Dll1 and Jag2. Here, we report that another Notch ligand, Dll3, is expressed in developing hair cells, in a pattern that overlaps that of Dll1 and Jag2. We analyzed the cochleae of Dll3(pu) mutant mice, but did not detect any abnormalities. However, earlier studies have demonstrated that there is functional redundancy among Notch ligands in cochlear development and loss of one ligand can be at least partially compensated for by another. Thus Dll3 may play a role in lateral inhibition similar to that of Dll1 and Jag2.     

Effortful control as modifier of the association between negative emotionality and adolescents' mental health problems

This study examined the extent to which effortful control moderated the risk of internalizing or externalizing problems associated with high negative emotionality in a Dutch population sample of pre- and early adolescents (N = 1,922). Internalizing and externalizing problems were assessed with the Child Behavior Checklist, Youth Self-Report, and Teacher Checklist of Psychopathology. Temperament (effortful control, fearfulness, frustration) was assessed with the parent version of the Revised Early Adolescent Temperament Questionnaire. The effects of fearfulness and frustration appeared to be attenuated by high levels of effortful control. The associations differed between the two domains of mental health investigated: effortful control reduced the effect of fearfulness on internalizing problems and the effect of frustration on externalizing problems. The effects were stronger for externalizing problems and similar for preadolescent (age 11) and adolescent (age 13/14) outcomes.     

Age-related changes in rostral basal forebrain cholinergic and GABAergic projection neurons: relationship with spatial impairment

Both cholinergic and GABAergic projections from the rostral basal forebrain contribute to hippocampal function and mnemonic abilities. While dysfunction of cholinergic neurons has been heavily implicated in age-related memory decline, significantly less is known regarding how age-related changes in codistributed GABAergic projection neurons contribute to a decline in hippocampal-dependent spatial learning. In the current study, confocal stereology was used to quantify cholinergic (choline acetyltransferase [ChAT] immunopositive) neurons, GABAergic projection (glutamic decarboxylase 67 [GAD67] immunopositive) neurons, and total (neuronal nuclei [NeuN] immunopositive) neurons in the rostral basal forebrain of young and aged rats that were first characterized on a spatial learning task. ChAT immunopositive neurons were significantly but modestly reduced in aged rats. Although ChAT immunopositive neuron number was strongly correlated with spatial learning abilities among young rats, the reduction of ChAT immunopositive neurons was not associated with impaired spatial learning in aged rats. In contrast, the number of GAD67 immunopositive neurons was robustly and selectively elevated in aged rats that exhibited impaired spatial learning. Interestingly, the total number of rostral basal forebrain neurons was comparable in young and aged rats, regardless of their cognitive status. These data demonstrate differential effects of age on phenotypically distinct rostral basal forebrain projection neurons, and implicate dysregulated cholinergic and GABAergic septohippocampal circuitry in age-related mnemonic decline.     

Shigella flexneri IpaH(7.8) facilitates escape of virulent bacteria from the endocytic vacuoles of mouse and human macrophages

The behavior of Shigella flexneri ipaH mutants was studied in human monocyte-derived macrophages (HMDM), in 1-day-old human monocytes, and in J774 mouse macrophage cell line. In HMDM, strain pWR700, an ipaH(7.8) deletion mutant of S. flexneri 2a strain 2457T, behaved like the wild-type strain 2457T. This strain caused rapid host cell death by oncosis, and few bacterial CFU were recovered after incubation in the presence of gentamicin as previously described for 2457T-infected HMDM. However, analysis of bacterial compartmentalization within endocytic vacuoles with gentamicin and chloroquine indicated that more pWR700 than 2457T was present within the endocytic vacuoles of HMDM, suggesting that ipaH(7.8) deletion mutant transited more slowly from the vacuoles to the cytoplasm. In contrast to findings with HMDM, CFU recovered from pWR700-infected mouse J774 cells were 2 to 3 logs higher than CFU from 2457T-infected J774 cells. These values exceeded CFU recovered after infection of J774 cells with plasmid-cured avirulent strain M4243A1. Incubation with gentamicin and chloroquine clearly showed that pWR700 within J774 cells was mostly present within the endocytic vacuoles. This distribution pattern was similar to that seen with M4243A1 and contrasted with the pattern seen with 2457T. Complementation of pWR700 with a recombinant clone expressing ipaH(7. 8) restored the intracellular distribution of bacteria to that seen with the wild-type strain. Strains with deletions in ipaH(4.5) or ipaH(9.8), however, behaved like 2457T in both HMDM and J774 cells. The distribution profile of pWR700 in 1-day-old monocytes was similar to that seen in J774 cells. Like infected J774 cells, 1-day-old human monocytes demonstrated apoptosis upon infection with virulent Shigella. These results suggest that a role of the ipaH(7. 8) gene product is to facilitate the escape of the virulent bacteria from the phagocytic vacuole of monocytes and macrophages.     

Scar sign of renal oncocytoma: Magnetic resonance imaging appearance and lack of specificity

This case report illustrates the magnetic resonance imaging (MRI) appearance of a typically asymptomatic renal oncocytoma as a homogeneous mass of medium signal with a stellate central region of decreased signal, representing the central scar. The MRI was correlated with computed tomography (CT), ultrasound (US), and gross pathologic appearance. The appearance of a central scar is not specific for oncocytoma and does not exclude renal cell carcinoma, as illustrated by a second case.