Maternal ethanol exposure is associated with decreased plasma zinc and increased fetal abnormalities in normal but not metallothionein-null mice

BACKGROUND: Ethanol profoundly affects fetal development, and this is proposed to be due primarily to a transient fetal zinc (Zn) deficiency that arises from the binding of Zn by metallothionein (MT) in the maternal liver. Zn homeostasis and fetal outcome were investigated in normal (MT+/+) and metallothionein-null (MT-/-) mice in response to ethanol exposure. METHODS/RESULTS: Mice were treated with saline or ethanol (0.015 m/g intraperitoneally at 0 and 4 hr) on day 8 of gestation (Gd8), and the degree of fetal dysmorphology was assessed on Gd18. The incidence of external abnormalities was significantly increased in offspring from MT+/+ dams exposed to ethanol, where 27.4% of fetuses were affected. MT-/- ethanol-, MT+/+ saline-, and MT-/- saline-treated dams had fetuses in which the frequencies of abnormalities were 2.2, 6.4, and 6.9%, respectively. To investigate Zn homeostasis, nonpregnant mice were killed at intervals over 16 hr after ethanol injection. Liver MT concentrations in MT+/+ mice were increased 20-fold by 16 hr, with a significant elevation evident by 4 hr, whereas liver Zn levels were also significantly increased by 2 hr and maintained for 16 hr. In parallel with these changes, plasma Zn concentrations in MT+/+ mice decreased by 65%, with minimum levels of 4.5+/-0.3 micromol/liter at 8 hr. Conversely, MT-/- mice exhibited increased plasma Zn concentrations, with peak values of 20.8+/-0.3 observed at 4 hr. CONCLUSION: These findings link the teratogenic effect of ethanol to the induction of maternal MT and the limitation of fetal Zn supply from the plasma.     

Basal forebrain lesions produce a dissociation of trial-dependent and trial-independent memory performance

The behavioral effects of lesions in the basal forebrain (BF) of rats were evaluated using two tasks. The BF lesions included both the nucleus basalis magnocellularis (NBM) and the medial septal area (MSA). The first task was a Stone maze, which has 14 consecutive choice points and is a task of complex, trial-independent memory. BF lesions did not impair choice accuracy in this task. The second task was a win-shift spatial discrimination in a radial arm maze, which requires trial-dependent memory. BF lesions produced a significant decrease in choice accuracy in this task. These results demonstrate that BF lesions impair trial-dependent (working) memory but not trial-independent reference memory, and that task difficulty is not the sole factor determining whether BF lesions produce behavioral impairments.     

Cryopreservation of all prezygotes in patients at risk of severe hyperstimulation does not eliminate the syndrome, but the chances of pregnancy are excellent with subsequent frozen-thaw transfers

In-vitro fertilization patients (n = 15) at risk of ovarian hyperstimulation syndrome (OHSS) (oestradiol > or =4500 pg/ml on the day of human chorionic gonadotrophin administration and 25 or more follicles of intermediate or large size) underwent aspiration of all follicles and cryopreservation of all fertilized oocytes at the pronuclear stage. Patients were monitored for up to 2 weeks post- retrieval. Subsequent transfer of cryopreserved-thawed embryos was performed in programmed cycles using exogenous oestrogen and progesterone for endometrial preparation. Two patients (13%) developed OHSS necessitating hospitalization and vaginal aspiration of ascitic fluid. Two other patients (13%) developed moderate OHSS requiring ascitic fluid vaginal aspiration in the office setting, with dramatic improvement of the condition. Subsequent transfer of cryopreserved- thawed embryos yielded a clinical pregnancy rate of 58% per transfer and ongoing or delivery rates of 42 and 67% per transfer and per patient respectively. By eliminating pregnancy potential with cryopreservation of all prezygotes and examining the pregnancy potential with subsequent cryopreserved-thawed transfers, it is concluded that OHSS is reduced, but not eliminated for patients at risk. Subsequent transfer of cryopreserved-thawed prezygotes in a programmed cycle with exogenous steroids yields an excellent pregnancy rate.      

ICOS+ Th cells produce distinct cytokines in different mucosal immune responses

T cell activation, differentiation and effector functions depend on signals delivered through the antigen-specific TCR and non-clonal costimulatory receptors on the T cell. Activated T cells express the inducible costimulator (ICOS). We examined the co-expression of ICOS with Th cytokines in mucosal immune responses. ICOS+CD4+ Th cells expressed strikingly different cytokines depending on the type of infection encountered and the cells' anatomical localization. In the Th2-dominated response to Schistosoma mansoni, ICOS expression of CD4+ cells isolated from the liver was strongly associated with the expression of IL-5, IL-10, IL-13, and T1/ST2, but not with the chemokine receptor CXCR5, a pattern consistent with Th2 effector cells. In the secondary lymphatic organs of schistosome-infected mice, ICOS expression was randomly correlated with Th2 effector-cytokines, but positively correlated with CXCR5 expression; a pattern consistent with follicular Th cells. In Th cells isolated from gut or liver of mice infected with Toxoplasma gondii, ICOS expression was positively correlated with IFN-gamma production. Finally, in the severe combined immunodeficiency transfer colitis model, ICOS expression was strongly positively associated with IFN-gamma and IL-2. Thus, ICOS appears to costimulate distinct effector functions in different immune responses, depending on factors such as the nature of the antigen encountered and localization and chronicity of the immune response.     

The Noncolonic Microbiome: Does it Really Matter?

About 100 trillion microorganisms compose the microbiome of the gastrointestinal tract and are predominantly found within the colon. Until recently, few bacteria were thought to inhabit the normal healthy esophagus and stomach. However, contemporary studies using molecular techniques have contradicted these assumptions. In this review, we summarize the pertinent findings of these studies that demonstrate established, complex mixed-microbial communities within the foregut in both health and disease. These studies contribute to improved understanding of interactions between the host immunity and the microbiome that may ultimately allow for novel therapeutic targets.     

Granulocyte macrophage colony-stimulating factor-driven respiratory mucosal sensitization induces Th2 differentiation and function independently of interleukin-4

The development of T helper (Th)2 responses is a key step in the pathogenesis of asthma. Interleukin (IL)-4 is thought to be important, although not strictly necessary, for Th2 differentiation, although triggers of IL-4-independent Th2 polarization have not been identified. We examined whether IL-4 is necessary for Th2-polarized responses during granulocyte macrophage colony-stimulating factor (GM-CSF)-driven respiratory mucosal sensitization. Balb/c wild type (WT) or IL-4 knockout (4KO) mice were exposed to aerosolized ovalbumin (OVA) in the context of airway GM-CSF expression. We examined the extent of Th2 polarization using real-time quantitative polymerase chain reaction on lymph node mRNA, flow cytometric analysis of lung Th cells, and measurement of cells, cytokines, and immunoglobulins in bronchoalveolar lavage (BAL) and serum. GATA-3 and CCR3, -4, and -8 were expressed in the lymph nodes of WT and 4KO mice at similar levels, as were IL-5 and IL-13 levels in the BAL, T1/ST2 on lung Th cells, and BAL eosinophils after recall challenge. With the exception of immunoglobulin production, expression of GATA-3, CCR-3, -4, -8, IL-5, and T1/ST2, and the generation of blood eosinophilia, were intact in mice doubly deficient in both IL-4 and IL-13. We conclude that IL-4 is not required for the generation of Th2-polarized responses in the presence of GM-CSF.     

Genetic linkage of the tricho-dento-osseous syndrome to chromosome 17q21

Tricho-dento-osseous syndrome (TDO), MIM# 190320, is transmitted as a highly penetrant autosomal dominant trait that is characterized by variable clinical expression. The principal clinical features include kinky/curly hair in infancy, enamel hypoplasia, taurodontism, as well as increased thickness and density of cranial bones. Possible genetic linkage has been reported for TDO with the ABO blood group locus, but the gene defect remains unknown. We have identified four multiplex families (n = 63, 39 affected, 24 unaffected) from North Carolina segregating TDO. We previously have excluded a major locus for TDO in the ABO region for these families. Utilizing a genome-wide search strategy, we obtained conclusive evidence for linkage of the TDO syndrome locus to markers on chromosome 17q21 (D17S791, Z max = 10.54, Theta = 0.00) with no indication of genetic heterogeneity. Multipoint analysis suggests the TDO locus is located in a 7 cM chromosomal segment flanked by D17S932 and D17S941. This finding represents the first step towards isolation and cloning of the TDO gene. Identification of this gene has important implications for understanding normal and abnormal craniofacial development of hair, teeth and bone.