Maternal Smoke Exposure Impairs the Long-Term Fertility of Female Offspring in a Murine Model.

The theory of fetal origins of adult disease was first proposed in 1989, and in the decades since, a wide range of other diseases from obesity to asthma have been found to originate in early development. Because mammalian oocyte development begins in fetal life it has been suggested that environmental and lifestyle factors of the mother could directly impact the fertility of subsequent generations. Cigarette smoke is a known ovotoxicant in active smokers, yet disturbingly 13% of Australian and 12% of US women continue to smoke throughout pregnancy. The focus of our investigation was to characterize the adverse effects of smoking on ovary and oocyte quality in female offspring exposed in utero. Pregnant mice were nasally exposed to cigarette smoke for 12 wk throughout pregnancy/lactation, and ovary and oocyte quality of the F1 (maternal smoke exposed) generation was examined. Neonatal ovaries displayed abnormal somatic cell proliferation and increased apoptosis, leading to a reduction in follicle numbers. Further investigation found that altered somatic cell proliferation and reduced follicle number continued into adulthood; however, apoptosis did not. This reduction in follicles resulted in decreased oocyte numbers, with these oocytes found to have elevated levels of oxidative stress, altered metaphase II spindle, and reduced sperm-egg interaction. These ovarian and oocyte changes ultimately lead to subfertility, with maternal smoke-exposed animals having smaller litters and also taking longer to conceive. In conclusion, our results demonstrate that in utero and lactational exposure to cigarette smoke can have long-lasting effects on the fertility of the next generation of females

Bioavailability in soils

The consumption of locally-produced vegetables by humans may be an important exposure pathway for soil contaminants in many urban settings and for agricultural land use. Hence, prediction of metal and metalloid uptake by vegetables from contaminated soils is an important part of the Human Health Risk Assessment procedure. The behaviour of metals (cadmium, chromium, cobalt, copper, mercury, molybdenum, nickel, lead and zinc) and metalloids (arsenic, boron and selenium) in contaminated soils depends to a large extent on the intrinsic charge, valence and speciation of the contaminant ion, and soil properties such as pH, redox status and contents of clay and/or organic matter. However, chemistry and behaviour of the contaminant in soil alone cannot predict soil-to-plant transfer. Root uptake, root selectivity, ion interactions, rhizosphere processes, leaf uptake from the atmosphere, and plant partitioning are important processes that ultimately govern the accumulation ofmetals and metalloids in edible vegetable tissues. Mechanistic models to accurately describe all these processes have not yet been developed, let alone validated under field conditions. Hence, to estimate risks by vegetable consumption, empirical models have been used to correlate concentrations of metals and metalloids in contaminated soils, soil physico-chemical characteristics, and concentrations of elements in vegetable tissues. These models should only be used within the bounds of their calibration, and often need to be re-calibrated or validated using local soil and environmental conditions on a regional or site-specific basis.Mike J. McLaughlin, Erik Smolders, Fien Degryse, and Rene Rietr

Conformational changes in α7 acetylcholine receptors underlying allosteric modulation by divalent cations

Allosteric modulation of membrane receptors is a widespread mechanism by which endogenous and exogenous agents regulate receptor function. For example, several members of the nicotinic receptor family are modulated by physiological concentrations of extracellular calcium ions. In this paper, we examined conformational changes underlying this modulation and compare these with changes evoked by ACh. Two sets of residues in the α7 acetylcholine receptor extracellular domain were mutated to cysteine and analyzed by measuring the rates of modification by the thiol-specific reagent 2-aminoethylmethane thiosulfonate. Using Ba2+ as a surrogate for Ca2+, we found a divalent-dependent decrease the modification rates of cysteine substitutions at M37 and M40, residues at which rates were also slowed by ACh. In contrast, Ba2+ had no significant effect at N52C, a residue where ACh increased the rate of modification. Thus divalent modulators cause some but not all of the conformational effects elicited by agonist. Cysteine substitution of either of two glutamates (E44 or E172), thought to participate in the divalent cation binding site, caused a loss of allosteric modulation, yet Ba2+ still had a significant effect on modification rates of these residues. In addition, the effect of Ba2+ at these residues did not appear to be due to direct occlusion. Our data demonstrate that modulation by divalent cations involves substantial conformational changes in the receptor extracellular domain. Our evidence also suggests the modulation occurs via a binding site distinct from one which includes either (or both) of the conserved glutamates at E44 or E172

Can contracts be both plain and precise?

One argument against the use of plain language in legal documents is that it is impossible to convey legal meanings in plain language with the same precision as in specialist legal discourse (Hunt, 2003). We tested this claim by redrafting an extract from a lease agreement into plain English in three stages, producing three versions of the extract in progressively plainer English. We submitted these with the original lease agreement to a senior advocate to elicit his opinion on whether the plain-language versions of the extract are equivalent to the original in legal force. Various differences between the versions are analysed using lexical semantics and Systemic Functional Grammar (as described in Halliday & Matthiessen, 2004). This analysis reveals that the redrafted versions could easily be altered to eliminate the difference between them and the original extract, and that ‘plain language’ as conceived by redrafters of official documents may be easy for non-experts to read, but more difficult for experts. This demonstrates that a ‘one-size-fits-all’ approach to readability is often not tenable, and that plain-language activists can learn much from research (such as Street, 1993) which asserts the existence of a plurality of literacies

Obesity and renal cell cancer – a quantitative review

Obesity has been associated with an increased risk of renal cell cancer among women, while the evidence for men is considered weaker. We conducted a quantitative summary analysis to evaluate the existing evidence that obesity increases the risk of renal cell cancer both among men and women. We identified all studies examining body weight in relation to kidney cancer, available in MEDLINE from 1966 to 1998. The quantitative summary analysis was limited to studies assessing obesity as body mass index (BMI, kg m−2), or equivalent. The risk estimates and the confidence intervals were extracted from the individual studies, and a mixed effect weighted regression model was used. We identified 22 unique studies on each sex, and the quantitative analysis included 14 studies on men and women, respectively. The summary relative risk estimate was 1.07 (95% CI 1.05–1.09) per unit of increase in BMI (corresponding to 3 kg body weight increase for a subject of average height). We found no evidence of effect modification by sex. Our quantitative summary shows that increased BMI is equally strongly associated with an increased risk of renal cell cancer among men and women. © 2001 Cancer Research Campaignhttp://www.bjcancer.co

Urbanisation and incidence of acute lymphocytic leukaemia among United States children aged 0–4

Acute lymphocytic leukaemia (ALL) incidence among children under 5 years of age was examined, utilising data from 24 United States cancer registries. County-based incidence rates among white children were compared across four levels of urbanisation: large and small metropolitan counties, and adjacent and nonadjacent rural counties. In metropolitan areas, the incidence of ALL was lower among blacks (rate ratio (RR)=0.38, confidence interval (CI)=0.33–0.44) and among Asians/Pacific Islanders (RR=0.78, CI=0.63–0.97) than among whites. Among white children, the incidence of ALL decreased across the four strata of urbanisation, from 67 to 62 to 65 to 54 cases per million person-years at-risk (two-sided trend P=0.009), such that rates were significantly lower in the most remote rural counties than in the most populous metropolitan counties (RR=0.80, 95% CI=0.70–0.91)

Novel role of cPLA2α in membrane and actin dynamics

Actin-directed processes such as membrane ruffling and cell migration are regulated by specific signal transduction pathways that become activated by growth factor receptors. The same signaling pathways that lead to modifications in actin dynamics also activate cPLA2α. Moreover, arachidonic acid, the product of cPLA2α activity, is involved in regulation of actin dynamics. Therefore, it was investigated whether cPLA2α plays a role in actin dynamics, more specifically during growth factor-induced membrane ruffling and cell migration. Upon stimulation of ruffling and cell migration by growth factors, endogenous cPLA2α and its active phosphorylated form were shown to relocate at protrusions of the cell membrane involved in actin and membrane dynamics. Inhibition of cPLA2α activity with specific inhibitors blocked growth factor-induced membrane and actin dynamics, suggesting an important role for cPLA2α in these processes

Rituximab in B-Cell Hematologic Malignancies: A Review of 20 Years of Clinical Experience

Rituximab is a human/murine, chimeric anti-CD20 monoclonal antibody with established efficacy, and a favorable and well-defined safety profile in patients with various CD20-expressing lymphoid malignancies, including indolent and aggressive forms of B-cell non-Hodgkin lymphoma. Since its first approval 20 years ago, intravenously administered rituximab has revolutionized the treatment of B-cell malignancies and has become a standard component of care for follicular lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, and mantle cell lymphoma. For all of these diseases, clinical trials have demonstrated that rituximab not only prolongs the time to disease progression but also extends overall survival. Efficacy benefits have also been shown in patients with marginal zone lymphoma and in more aggressive diseases such as Burkitt lymphoma. Although the proven clinical efficacy and success of rituximab has led to the development of other anti-CD20 monoclonal antibodies in recent years (e.g., obinutuzumab, ofatumumab, veltuzumab, and ocrelizumab), rituximab is likely to maintain a position within the therapeutic armamentarium because it is well established with a long history of successful clinical use. Furthermore, a subcutaneous formulation of the drug has been approved both in the EU and in the USA for the treatment of B-cell malignancies. Using the wealth of data published on rituximab during the last two decades, we review the preclinical development of rituximab and the clinical experience gained in the treatment of hematologic B-cell malignancies, with a focus on the well-established intravenous route of administration. This article is a companion paper to A. Davies, et al., which is also published in this issue

Null Mutations in EphB Receptors Decrease Sharpness of Frequency Tuning in Primary Auditory Cortex

Primary auditory cortex (A1) exhibits a tonotopic representation of characteristic frequency (CF). The receptive field properties of A1 neurons emerge from a combination of thalamic inputs and intracortical connections. However, the mechanisms that guide growth of these inputs during development and shape receptive field properties remain largely unknown. We previously showed that Eph family proteins help establish tonotopy in the auditory brainstem. Moreover, other studies have shown that these proteins shape topography in visual and somatosensory cortices. Here, we examined the contribution of Eph proteins to cortical organization of CF, response thresholds and sharpness of frequency tuning. We examined mice with null mutations in EphB2 and EphB3, as these mice show significant changes in auditory brainstem connectivity. We mapped A1 using local field potential recordings in adult EphB2−/−;EphB3−/− and EphB3−/− mice, and in a central A1 location inserted a 16-channel probe to measure tone-evoked current-source density (CSD) profiles. Based on the shortest-latency current sink in the middle layers, which reflects putative thalamocortical input, we determined frequency receptive fields and sharpness of tuning (Q20) for each recording site. While both mutant mouse lines demonstrated increasing CF values from posterior to anterior A1 similar to wild type mice, we found that the double mutant mice had significantly lower Q20 values than either EphB3−/− mice or wild type mice, indicating broader tuning. In addition, we found that the double mutants had significantly higher CF thresholds and longer onset latency at threshold than mice with wild type EphB2. These results demonstrate that EphB receptors influence auditory cortical responses, and suggest that EphB signaling has multiple functions in auditory system development