Growth factor and receptor malfunctions associated with human genetic deafness

A variety of different signaling pathways are necessary for development and maintenance of the human auditory system. Normal hearing allows for the detection of soft sounds within the frequency range of 20 to 20 000 Hz, but more importantly to perceive the human voice frequency band of 250 to 6000 Hz. Loss of hearing is common, and is a clinically heterogeneous disorder that can be caused by environmental factors such as exposure to loud noise, infections and ototoxic drugs. In addition, variants of hundreds of genes have been reported to disrupt processes required for hearing. Noncoding regulatory variants and variants of additional genes necessary for hearing remain to be discovered as many individuals with inherited deafness are without a genetic diagnosis, despite the advent of whole exome sequencing. Here, we discuss in detail some of these deafness-causing variants of genes encoding a ligand or its receptor. Spotlighted in this review are three growth factor-receptor-pairs EDN3/EDNRB, HGF/MET and JAG/NOTCH, which individually are necessary for normal hearing. We also offer our perspective on unanswered questions, future challenges and potential opportunities for treatments emerging from molecular genetic and mechanistic studies of deafness due to these causes.     

All-terrain vehicle injuries in children: injury patterns and prognostic implications

Background All-terrain vehicle (ATV) accidents are common in children. Our purpose was to identify imaging patterns associated with ATV injuries in children.Patients and methods The study group comprised 141 consecutive children admitted to a tertiary pediatric hospital following ATV accidents. Medical records were evaluated for demographics and patient outcome. All imaging studies were reviewed and abnormalities cataloged.Results Extremity fractures were the most common injuries in our study, occurring in 38% of patients. Lower extremity fractures were more common than upper extremity fractures. Partial foot amputation, an unusual injury, was present in three children. Torso injuries were present in 22% of the children. Pulmonary contusions, but not abdominal injuries, were significantly associated with long-term disability or death (p=0.01). Brain injuries occurred in 19% of the children and were significantly associated with death or long-term disability (p=<0.001). No association of brain injury and skull fracture was present.Conclusions A wide variety of injuries were identified in children with ATV accidents. Partial foot amputation, an unusual injury, was identified in three children. Brain injuries and lung contusions detected by computed tomography were associated with long-term disability and death. Radiologists need to be aware of injuries associated with ATV accidents.     

Regional socioeconomic factors and length of hospital stay: a case study in Appalachia

Journal of Public Health - The role of socioeconomic status (SES) of patients in health care outcomes has been investigated in many health care systems. The health care literature suggests that...     

Increased 5-HT Levels Following Repeated Administration of Nigella sativa L. (Black Seed) Oil Produce Antidepressant Effects in Rats

The seeds of Nigella sativa L., commonly known as black seed or black cumin, and its extracts are used in folk medicine in the Middle East and in Asian countries for the promotion of good health and as a remedy for many ailments. These seeds have many acclaimed medicinal properties such as broncho-dilatory, immunopotentiating, analgesic, anti-inflammatory, and hypotensive. In the present study, the antidepressant activity following the repeated administration of Nigella sativa L. oil has been monitored using the forced swim test. Rats treated with Nigella sativa L. oil exhibited a significant increase in struggling time after oral administration of Nigella sativa L. oil (0.1 ml/kg/day) for four weeks. Nigella sativa L. oil increased brain 5-HT levels and decreased 5-HT turnover (5-HT/5-HIAA ratio). Levels of tryptophan increased significantly in the brain and plasma following the repeated administration of Nigella sativa L. oil. Nigella sativa L. oil showed a potential antidepressant-like effect.     

Expression and Inducibility of Cytochrome P450s (CYP1A1, 2B6, 2E1, 3A4) in Human Cord Blood CD34+ Stem Cell-Derived Differentiating Neuronal Cells

The status of xenobiotic metabolism in developing human brain cells is not known. The reason is nonavailability of developing human fetal brain. We investigate the applicability of the plasticity potential of human umbilical cord blood stem cells for the purpose. Characterized hematopoietic stem cells are converted into neuronal subtypes in eight days. The expression and substrate-specific catalytic activity of the cytochrome P450s (CYPs) CYP1A1 and 3A4 increased gradually till day 8 of differentiation, whereas CYP2B6 and CYP2E1 showed highest expression and activity at day 4. There was no significant increase in the expression of CYP regulators, namely, aryl hydrocarbon receptor (AHR), constitutive androstane receptor (CAR), pregnane X receptor (PXR), and glutathione-S-transferase (GSTP1-1) during differentiation. Differentiating cells showed significant induction in the expression of CYP1A1, 2B6, 2E1, 3A4, AHR, CAR, PXR, and GSTP1-1 when exposed to rifampin, a known universal inducer of CYPs. The xenobiotic-metabolizing capabilities of these differentiating cells were confirmed by exposing them to the organophosphate pesticide monocrotophos (MCP), a known developmental neurotoxicant, in the presence and absence of a universal inhibitor of CYPs-cimetidine. Early-differentiating cells (day 2) were found to be more vulnerable to xenobiotics than mature well-differentiated cells. For the first time, we report significant expression and catalytic activity of selected CYPs in human cord blood hematopoietic stem cell-derived neuronal cells at various stages of maturity. We also confirm significant induction in the expression and catalytic activity of selected CYPs in human cord blood stem cell-derived differentiating neuronal cells exposed to known CYP inducers and MCP.     

A missense mutation disrupting a dibasic prohormone processing site in pro-opiomelanocortin (POMC) increases susceptibility to early-onset obesity through a novel molecular mechanism

The functional loss of both alleles of the human pro-opiomelanocortin (POMC) gene leads to a very rare syndrome of hypoadrenalism, red hair and early-onset obesity. In order to examine whether more subtle genetic variants in POMC might contribute to early-onset obesity, the coding region of the gene was sequenced in 262 Caucasian subjects with a history of severe obesity from childhood. Two children were found to be heterozygous for a missense mutation, R236G, which disrupts the dibasic cleavage site between beta melanocyte-stimulating hormone (beta-MSH) and beta-endorphin. Beta-TC3 cells transfected with the mutant POMC cDNA produced a mutant beta-MSH/beta-endorphin fusion protein. This fusion protein bound to the human melanocortin-4 receptor (hMC4R) with an affinity similar to its natural ligands, but had a markedly reduced ability to activate the receptor. This variant co-segregated with early-onset obesity over three generations in one family and was absent in 412 normal weight UK Caucasian controls. Combining the results in UK Caucasians with a new case-control study in French subjects and three previously published reports, mutations disrupting this processing site were present in 0.88% of subjects with early-onset obesity and 0.22% of normal-weight controls. These results suggest that the R236G mutation may confer an inherited susceptibility to obesity through the production of an aberrant fusion protein that has the capacity to interfere with central melanocortin signalling.