Neural plasticity and adult neurogenesis: the deep biology perspective

The recognition that neurogenesis does not stop with adolescence has spun off research towards the reduction of brain disorders by enhancing brain regeneration. Adult neurogenesis is one of the tougher problems of developmental biology as it requires the generation of complex intracellular and pericellular anatomies, amidst the danger of neuroinflammation. We here review how a multitude of regulatory pathways optimized for early neurogenesis has to be revamped into a new choreography of time dependencies. Distinct pathways need to be regulated, ranging from neural growth factor induced differentiation to mitochondrial bioenergetics, reactive oxygen metabolism, and apoptosis. Requiring much Gibbs energy consumption, brain depends on aerobic energy metabolism, hence on mitochondrial activity. Mitochondrial fission and fusion, movement and perhaps even mitoptosis, thereby come into play. All these network processes are interlinked and involve a plethora of molecules. We recommend a deep thinking approach to adult neurobiology.     

Using structural equation modelling to understand the contributors to anaemia among young Burkinabe children

Anaemia is a persistent problem among young Burkinabe children, yet population‐specific information on its determinants is scant. We used baseline data from an evaluation of Helen Keller International's Enhanced Homestead Food Production Program (n=1210 children) to quantify household‐, mother‐, and child‐level factors associated with anaemia in Burkinabe children aged 6‐12 months. We used structural equation modelling to assess a theoretical model, which tested four categories of factors: (a) household food security and dietary diversity, (b) household sanitation and hygiene (latrine and poultry access and bednet ownership), (c) maternal factors (anaemia, stress, cleanliness, and health, hygiene and feeding knowledge and practices), and (d) child nutrition and health (iron deficiency (ID), retinol binding protein (RBP), malaria, and inflammation). The model also included household socio‐economic status, size, and polygamy; maternal age and education; and child age and sex. Results showed that ID, malaria, and inflammation were the primary direct determinants of anaemia, contributing 15%, 10%, and 10%, respectively. Maternal knowledge directly explained improved child feeding practices and household bednet ownership. Household dietary diversity directly explained 18% of child feeding practices. Additionally, RBP, child age and sex, and maternal anaemia directly predicted child haemoglobin. Our findings suggest that program effectiveness could be increased by addressing the multiple, context‐specific contributors of child anaemia. For young Burkinabe children, anaemia control programs that include interventions to reduce ID, malaria, and inflammation should be tested. Other potential intervention entry points suggested by our model include improving maternal knowledge of optimal health, hygiene, and nutrition practices and household dietary diversity.     

Experimental arthritis induced by a clinical Mycoplasma fermentans isolate

Background  

Mycoplasma fermentans has been associated with rheumatoid arthritis. Recently, it was detected in the joints and blood of patients with rheumatoid arthritis, but it is not clear yet how the bacteria enter the body and reach the joints. The purpose of this study was to determine the ability of M. fermentans to induce experimental arthritis in rabbits following inoculation of the bacteria in the trachea and knee joints.     

Rotavirus diarrhea severity is related to the VP4 type in Mexican children

This report is of a community-based case control study to assess whether the severity of acute diarrhea by rotavirus (RV) in young children is associated with a particular VP7 (G) or VP4 (P) RV serotype. Five hundred twenty children younger than 2 years of age with diarrhea lasting less than 3 days were age and gender matched with 520 children with no diarrhea. The G and P serotypes were determined with specific monoclonal antibodies, and the VP4 serotype specificity in a subgroup was confirmed by genotyping. Infection with a G3 serotype led to a higher risk of diarrhea than infection with a G1 serotype. Infection with a G3-nontypeable-P serotype was associated with more severe gastroenteritis than infection with a G3 (or G1) P1A[8] serotype. A child with diarrhea-associated dehydration was almost five times more likely to be infected with a G3-nontypeable-P serotype than a child without dehydration (P < 0.001). Moreover, the two predominant monotypes within serotype P1A[8] had significantly different clinical manifestations. In this study, the severity of RV-associated diarrhea was related to different P serotypes rather than to G serotypes. The relationship between serotype and clinical outcomes seems to be complex and to vary among different geographic areas.     

New Calicivirus isolated from walrus

The nucleotide sequence and genome organization of a new member of Caliciviridae was determined. Cell culture inoculated with fecal matter from walrus was used to recover fragments of a new virus by Suppression Subtractive Hybridization (SSH). The isolate was identified as a member of the Vesivirus genus of Caliciviridae and designated the name Walrus Calicivirus (WCV). Sets of PCR primers spanning the entire putative genome were designed using known sequences of other vesiviruses. The assembled genome was 8289 nucleotides (nt) long and shared no more than 87% identity with sequences of the other members of the genus Vesivirus. The largest open reading frame (ORF1) between positions 4-5646 encoded a polyprotein. ORF2, found at position 5652-7778, encoded a putative capsid protein. ORF3 overlapped ORF2 and encoded a small basic protein. Comparative analysis of multiple caliciviral capsid proteins was performed to propose a uniform capsid structural organization for this viral family.     

Gonadoblastoma in Turner syndrome and Y-chromosome-derived material

The identification of Y-chromosome material is important in females with Ullrich-Turner syndrome (UTS) due to the risk of developing gonadoblastoma or other gonadal tumors. There is controversy regarding the frequency of the Y-chromosome-derived material and the occurrence of gonadoblastoma in these patients. The aim of our study was to evaluate a large number of patients with UTS, followed before and during the pubertal age for the prevalence of Y-chromosome derived material, the occurrence of gonadoblastoma, and the incidence of possible neoplastic degeneration. An unselected series of 171 patients with UTS (1-34 years old), diagnosed cytogenetically, was studied for Y-chromosome markers (SRY and Y-centromeric DYZ3 repeats). The follow-up was of 2-22 years; 101 of these patients were followed during pubertal age. Y-chromosome material was found in 14 patients (8%): 12 of these were gonadectomized (2.8-25.9 years). A gonadoblastoma was detected in four patients under 16 years of age: in two, Y-material was detected only at molecular analysis (at conventional cytogenetic analysis, one was included in the 45,X group and one in the X + mar group) and one had also an immature teratoma and an endodermal sinus carcinoma. The prevalence of gonadoblastoma in our series of gonadectomized UTS patients with Y-positive material was of 33.3% (4/12). Our data suggest that the age of appearance and the possibility of malignant degeneration of gonadoblastoma can occur early in life. These patients, in particular those with 45,X or a marker chromosome may benefit from molecular screening to detect the presence of Y-chromosome material; PCR is a rapid and inexpensive technique. At the moment, laparoscopy and preventive gonadectomy performed as soon as possible remain the procedures of choice for patients with UTS, when Y-chromosome has been identified, as we are still unable to predict a future malignant evolution of gonadoblastoma.     

KP544 amplifies the effects of nerve growth factor on cell differentiation and is neuroprotective

The ability of endogenous neurotrophins, including nerve growth factor (NGF), to promote the survival and development of neurons provides convincing evidence for their therapeutic potential, despite significant barriers to their successful clinical use. Many of these barriers might be surmountable, however, by strategies that enhance endogenous neurotrophin signaling. We evaluated a series of substituted pyrimidines for their ability to enhance the effects of NGF. KP544 [2‐amino‐5‐(4‐chlorophenylethynyl)‐4‐(4‐trans‐hydroxycyclohexylamino) pyrimidine] amplified NGF‐induced neurite outgrowth of PC12 cells approximately 2‐fold at 2 µM. KP544 also enhanced choline acetyltransferase activity, a marker of differentiation induced by either NGF or by cyclic AMP, by 3‐ to 8‐fold, with a 2‐fold amplification at 0.12–0.3 µM. This amplification occurred at all concentrations of NGF used including those that maximally stimulated the cells. KP544 did not increase the levels of phosphorylated mitogen‐activated protein kinases (MAPK) above that seen with NGF alone. These studies suggested that KP544 functions within the cell at a site that is downstream from or independent of MAPK signaling. NGF‐induced neurite outgrowth in a human cell line (SH‐SY5Y neuroblastoma cells) was also enhanced with KP544 treatment. Primary embryonic rat cortical cultures were used to extend the observations beyond the studies with the immortalized cell lines. In addition to effects on neurite outgrowth, KP544 protected these cells from glutamate‐induced death. Overall, the data suggest that KP544 can selectively interact in the differentiation pathway downstream of MAPK in a manner that amplifies nerve growth factor and cyclic AMP effects and is also neuroprotective. Drug Dev. Res. 62:49–59, 2004. © 2004 Wiley‐Liss, Inc.     

CD34+ cells from acute myeloid leukemia, myelodysplastic syndromes, and normal bone marrow display different apoptosis and drug resistance-associated phenotypes.

Myelodysplastic syndromes and acute myeloid leukemia (AML) are heterogeneous disorders in which conflicting results in apoptosis and multidrug resistance (MDR) have been reported. We have evaluated by multiparameter flow cytometry the expression of apoptosis- (APO2.7, bcl-2, and bax) and MDR-related proteins [P-glycoprotein (P-gp), multidrug resistance protein (MRP), and lung resistance protein (LRP)] specifically on bone marrow (BM) CD34+ cells, and their major CD32-/dim and CD32+ subsets, in de novo AML (n=90), high-risk myelodysplastic syndrome (n=9), and low-risk myelodysplastic syndrome (n=21) patients at diagnosis, and compared with normal BM CD34+ cells (n=6). CD34+ myeloid cells from AML and high-risk myelodysplastic syndrome patients displayed higher expression of bcl-2 (P <0.0001) and lower reactivity for APO2.7 (P=0.002) compared with low-risk myelodysplastic syndrome and normal controls. Similar results applied to the two predefined CD34+ myeloid cell subsets. No significant differences were found in the expression of P-gp, MRP, and LRP between low-risk myelodysplastic syndrome patients and normal BM, but decreased expression of MRP (P <0.03) in AML and high-risk myelodysplastic syndromes and P-gp (P=0.008) in high-risk myelodysplastic syndromes were detected. Hierarchical clustering analysis showed that low-risk myelodysplastic syndrome patients were clustered next to normal BM samples, whereas high-risk myelodysplastic syndromes were clustered together and mixed with the de novo AML patients. In summary, increased resistance to chemotherapy of CD34+ cells from both AML and high-risk myelodysplastic syndromes would be explained more appropriately in terms of an increased antiapoptotic phenotype rather than a MDR phenotype. In low-risk myelodysplastic syndromes abnormally high apoptotic rates would be restricted to the CD34- cell compartments.