Evidence for non-genomic transmission of ecological information via maternal behavior in female rats

Maternal behavior is flexible and programs offspring development. Using a novel manipulation, we demonstrate that rat maternal behavior is sensitive to ecologically relevant stimuli. Long-Evans hooded rat dams (F0) and pups were exposed to a predator condition (cat odor) or a control condition (no odor) for 1 h on the day of parturition. Predator-exposed F0 dams displayed significantly more maternal behavior (licking/grooming, arched-back nursing) relative to control-exposed dams across five subsequent observation days. Female offspring (F1) were raised to adulthood, bred and maternal behavior was observed. F1 dams reared by a predator-exposed F0 dam displayed significantly higher maternal behavior relative to F1 dams reared by a control-exposed F0 dam across 5 days of observation. Increased levels of maternal behavior in predator-reared (PR) F1 dams were evident even in F1 females that had been cross-fostered (CF) from a control-exposed F0 dam, suggesting a non-genomic transmission of increased levels of maternal behavior. Lactating PR F1 dams had significantly elevated estrogen receptor alpha and beta mRNA in the medial preoptic area relative to control-reared (CR) F1 dams. Furthermore, among CR F1 dams, there was no significant difference between those dams that had been CF from predator-exposed F0 dams and those that had been sham CF. These results support the hypothesis that flexible rat maternal behavior can shape offspring development according to current environmental conditions. The results also suggest that estrogen signaling may be part of an epigenetic mechanism by which changes in maternal behavior are passed from F0 to F1 dams.     

Why is sterility virulence most common in sexually transmitted infections? Examining the role of epidemiology

Sterility virulence, or the reduction in host fecundity due to infection, occurs in many host–pathogen systems. Notably, sterility virulence is more common for sexually transmitted infections (STIs) than for directly transmitted pathogens, while other forms of virulence tend to be limited in STIs. This has led to the suggestion that sterility virulence may have an adaptive explanation. By focusing upon finite population models, we show that the observed patterns of sterility virulence can be explained by consideration of the epidemiological differences between STIs and directly transmitted pathogens. In particular, when pathogen transmission is predominantly density invariant (as for STIs), and mortality is density dependent, sterility virulence can be favored by demographic stochasticity, whereas if pathogen transmission is predominantly density dependent, as is common for most directly transmitted pathogens, sterility virulence is disfavored. We show these conclusions can hold even if there is a weak selective advantage to sterilizing.     

Preventive health care, 1999 update: 3. Follow-up after breast cancer

OBJECTIVE: To make recommendations to physicians who provide follow-up care for women who have been treated for early-stage breast cancer. OPTIONS: Combination of blood tests, bone scans, liver echography and chest radiography for detection of distant disease; physical examination with or without mammography for detection of contralateral breast cancer; and physical examination with or without mammography for detection of ipsilateral recurrent disease after breast-conserving therapy. OUTCOMES: Survival, disease recurrence and quality-of-life measures for distant disease, local recurrence of disease and disease in the contralateral breast. EVIDENCE: A MEDLINE search for relevant articles published between January 1966 and January 1998 with the MeSH terms "breast neoplasms" and "neoplasm recurrence" (local and distant) with limits to "human" was done. A subsequent MEDLINE search using the MeSH terms "breast neoplasms," "neoplasm recurrence," "local/diagnosis" and "mammography" was done to address issues of mammography. The literature search was reviewed by a medical librarian and 2 breast cancer specialists to ensure completeness. BENEFITS, HARMS AND COSTS: Breast cancer is the most common cancer in Canadian women and is the second leading cause of death after lung cancer. Even with early-stage breast cancer, recurrence after treatment for primary breast cancer is frequent. Traditionally, follow-up has been felt to facilitate early detection and improve survival. Randomized controlled trials (RCTs) have shown that routine screening (blood tests and diagnostic imaging) for distant disease does not alter survival or quality of life over routine physical examination. In an underpowered secondary analysis of RCT data, the detection of contralateral breast cancer did not affect survival. However, there have been no RCTs examining the role of mammography and physical examination and their effect on survival in the detection of contralateral breast cancer. The sensitivity and specificity of mammography after local excision and radiotherapy is unknown. There have been no RCTs examining the role of mammography or physical examination, or both, and their effect on survival in the detection of ipsilateral breast recurrence. VALUES: The strength of evidence was evaluated using the methods of the Canadian Task Force on Preventive Health Care. A high value was placed on interventions that changed survival. When evidence was available, high value was also placed on interventions that affected quality of life. RECOMMENDATIONS: There is good evidence not to include blood work and diagnostic imaging as part of screening for distant disease (grade E recommendation). There is no evidence to suggest that mammography decreases mortality by detecting ipsilateral disease in the conservatively treated breast; however, there is indirect evidence that it may be beneficial (grade C recommendation). There is no direct evidence to suggest that physical examination or mammography, or both, should be used to detect contralateral breast cancer; however, there is indirect evidence that it may be beneficial (grade C recommendation). VALIDATION: The findings of this analysis were reviewed through an iterative process by the members of the Canadian Task Force on Preventive Health Care.     

HLA-class II genes modify outcome of Toxoplasma gondii infection

Associations between Human Leukocyte Antigen (HLA) (i.e. human major histocompatibility complex [MHC]) genes and susceptibility to infections and inflammatory processes have been described, but causal relationships have not been proven. We characterized effects of HLA-DQ alleles on outcome of congenital toxoplasma infection and found that among Caucasians, the DQ3 gene frequency was significantly higher in infected infants with hydrocephalus (0.783) than infected infants without hydrocephalus (0.444) or published normal controls (0.487). We then developed a novel animal model to definitively determine the effect of these HLA DQ molecules on the severity of toxoplasmosis. Human MHC-Class II transgenes reduced parasite burden and necrosis in brains of mice infected with Toxoplasma gondii. Consistent with the observed association between DQ3 and hydrocephalus in human infants, in the murine model the DQ3(DQ8; DQB1*0302) gene protected less than DQ1 (DQ6; DQB1*0601). Our findings definitively prove a cause and effect relationship between human MHC genes and resistance to infection, provide novel means to characterise human immune responses that are protective or pathogenic in infections, and are important for vaccine development.     

Success and failure of single-modality treatment for early prostate cancer

Many men who undergo radical prostatectomy or radiotherapy for early prostate cancer have an excellent outcome; however, a significant proportion subsequently experience disease recurrence and/or cancer-related death. Adjuvant hormonal therapy after treatment of curative intent is given with the aim of eradicating undetected cancer cells outside the surgical margins or radiation field and/or micrometastatic disease. In the analogous setting of early breast cancer, adjuvant hormonal therapy is already established as standard care. Efficacy and tolerability data from the ongoing bicalutamide ('Casodex') Early Prostate Cancer program are expected to determine the role of adjuvant hormonal therapy with antiandrogens in early prostate cancer.     

Deletion of N-terminal amino acids from human lecithin:cholesterol acyltransferase differentially affects enzyme activity toward alpha- and beta-substrate lipoproteins

Lecithin:cholesterol acyltransferase (LCAT) is the enzyme responsible for generation of the majority of the cholesteryl esters (CE) in human plasma. Although most plasma cholesterol esterification occurs on high-density lipoprotein (HDL), via alpha-LCAT activity, esterification also occurs on low-density lipoprotein (LDL) via the beta-activity of the enzyme. Computer threading techniques have provided a three-dimensional model for use in the structure-function analysis of the core and catalytic site of the LCAT protein, but the model does not extend to the N-terminal region of the enzyme, which may mediate LCAT interaction with lipoprotein substrates. In the present study, we have examined the functional consequences of deletion of the highly conserved hydrophobic N-terminal amino acids (residues 1-5) of human LCAT. Western blot analysis showed that the mutant proteins (Delta 1-Delta 5) were synthesized and secreted from transfected COS-7 cells at levels approximately equivalent to those of wild-type hLCAT. The secreted proteins had apparent molecular weights of 67 kDa, indicating that they were correctly processed and glycosylated during cellular transit. However, deletion of the first residue of the mature LCAT protein (Delta 1 mutant) resulted in a dramatic loss of alpha-LCAT activity (5% of wild type using reconstituted HDL substrate, rHDL), although this mutant retained full beta-LCAT activity (108% of wild-type using human LDL substrate). Removal of residues 1 and 2 (Delta 2 mutant) abolished alpha-LCAT activity and reduced beta-LCAT activity to 12% of wild type. Nevertheless, LCAT Delta 1 and Delta 2 mutants retained their ability to bind to rHDL and LDL lipoprotein substrates. The dramatic loss of enzyme activity suggests that the N-terminal residues of LCAT may be involved in maintaining the conformation of the lid domain and influence activation by the alpha-LCAT cofactor apoA-I (in Delta 1) and/or loss of enzyme activity (in Delta 1-Delta 5). Since the Delta 1 and Delta 2 mutants retain their ability to bind substrate, other factor(s), such as decreased access to the substrate binding pocket, may be responsible for the loss of enzyme activity.     

Conjugative transfer of clostridial shuttle vectors from Escherichia coli to Clostridium difficile through circumvention of the restriction barrier

Members of the Dr family of adhesins of Escherichia coli recognize as a receptor the Dr(a) blood-group antigen present on the complement regulatory and signalling molecule, decay-accelerating factor (DAF). One member of this family, the Dr haemagglutinin, also binds to a second receptor, type IV collagen. Structure/function information regarding these adhesins has been limited and domains directly involved in the interaction with DAF have not been determined. We devised a strategy to identify amino acids in the Dr haemagglutinin that are specifically involved in the interaction with DAF. The gene encoding the adhesive subunit, draE, was subjected to random mutagenesis and used to complement a strain defective for its expression. The resulting mutants were enriched and screened to obtain those that do not bind to DAF, but retain binding to type IV collagen. Individual amino acid changes at positions 10, 63, 65, 75, 77, 79 and 131 of the mature DraE sequence significantly reduced the ability of the DraE adhesin to bind DAF, but not collagen. Over half of the mutants obtained had substitutions within amino acids 63-81. Analysis of predicted structures of DraE suggest that these proximal residues may cluster to form a binding domain for DAF.     

Electrogenic ion transport in the intestine of the Australian common brushtail possum, <Emphasis Type="Italic">Trichosurus vulpecula</Emphasis>: indications of novel transport patterns in a marsupial

In this study, electrogenic ion transport in the intestine of the Australian common brushtail possum, Trichosurus vulpecula was investigated. In the ileum, a Na(+)-dependent, phloridzin- and amiloride-insensitive short-circuit current ( Isc) was present. Mucosal glucose stimulated a further phloridzin-sensitive, dose-dependent increase in Isc. A Na(+)-dependent, ouabain-sensitive Isc was also present in the caecum and colon. In the proximal and distal colon, amiloride (100 micro mol l(-1), mucosal) inhibited this Isc by 81+/-4% and 65+/-3%, respectively and the Ki for amiloride (approximately 1 micro mol l(-1)) was consistent with the inhibition of a classical epithelial Na(+) channel. In the caecum, 50% of the Isc was inhibited by amiloride (100 micro mol l(-1), mucosal). The amiloride-insensitive Isc in the colon was not due to electrogenic Cl(-) secretion, as serosal bumetanide (100 micro mol l(-1)) had no effect on the Isc. Furthermore, the secretagogues forskolin (10 micro mol l(-1)), carbachol (100 micro mol l(-1)) and dibutyryl-cAMP or dibutyryl-cGMP (100 micro mol l(-1)) did not stimulate electrogenic Cl(-) secretion by the colon. These results indicate that the transport properties of the hindgut of the possum differ significantly from those of eutherian mammals and may be associated with different functions of the hindgut of possums when compared to eutherian mammals.