Potential impact of antiretroviral therapy and screening on cervical cancer mortality in HIV-positive women in sub-Saharan Africa: a simulation

Background

Despite having high cervical cancer incidence and mortality rates, screening for cervical precancerous lesions remains infrequent in sub-Saharan Africa. The need to screen HIV-positive women because of the higher prevalence and faster progression of cervical precancerous lesions may be heightened by the increased access to highly-active antiretroviral therapy (HAART). Policymakers need quantitative data on the effect of HAART and screening to better allocate limited resources. Our aim was to quantify the potential effect of these interventions on cervical cancer mortality.

Methods and Findings

We constructed a Markov state-transition model of a cohort of HIV-positive women in Cameroon. Published data on the prevalence, progression and regression of lesions as well as mortality rates from HIV, cervical cancer and other causes were incorporated into the model. We examined the potential impact, on cumulative cervical cancer mortality, of four possible scenarios: no HAART and no screening (NHNS), HAART and no screening (HNS), HAART and screening once on HAART initiation (HSHI), and HAART and screening once at age 35 (HS35). Our model projected that, compared to NHNS, lifetime cumulative cervical cancer mortality approximately doubled with HNS. It will require 262 women being screened at HAART initiation to prevent one cervical cancer death amongst women on HAART. The magnitudes of these effects were most sensitive to the rate of progression of precancerous lesions.

Conclusions

Screening, even when done once, has the potential of reducing cervical cancer mortality among HIV-positive women in Africa. The most feasible and cost-effective screening strategy needs to be determined in each setting.     

Loss of gremlin delays primordial follicle assembly but does not affect female fertility in mice

The transforming growth factor beta (TGFB) protein family is renowned for its diverse roles in developmental biology including reproduction. Gremlin is a member of the differential screening-selected gene aberrative in neuroblastoma (DAN)/cerberus family of bone morphogenetic protein (BMP) antagonists. Recent studies on gremlin focus on its involvement in embryonic skeletal, lung, and kidney development. To define the role of gremlin (Grem1) in female reproduction, we analyzed postnatal folliculogenesis using global and conditional knockout (cKO) mice for gremlin. Grem1(-/-) mice die within 48 h after birth, and ovaries collected from neonatal Grem1(-/-) mice demonstrated reduced oocyte numbers and delayed primordial follicle development. Transplanting Grem1(-/-) neonatal ovaries showed that folliculogenesis proceeded to large antral follicle stage, but Grem1(-/-) ovaries contained corpora lutea-like structures not found in control-transplanted ovaries. However, Grem1 cKO mice had comparable fertility to control mice. These data suggest that gremlin plays a previously uncharacterized role in the regulation of oocyte numbers and the timing of primordial follicle development, but either it is not required for later folliculogenesis or its loss is possibly compensated by other BMP antagonists.     

Characterization and inheritance of the Anthocyanin fruit (Aft) tomato

Tomato (Lycopersicon esculentum) accession LA1996 with the Anthocyanin fruit (Aft) gene has dark green foliage, elevated anthocyanin expression in the hypocotyls of seedlings, and anthocyanin in the skin and outer pericarp tissues of the fruit. Interest in the health benefits and antioxidant capacity of anthocyanins led to this study of the genetic potential for increased levels of this important class of phytonutrients in tomato fruit. In order to conform to tomato gene nomenclature rules, we propose changing the symbol Af for Anthocyanin fruit to Aft. Segregation ratios of anthocyanin expression in F(2) and BC(1) populations of a cross between the processing tomato UC82B and LA1996 were consistent with a single dominant gene hypothesis. Anthocyanin expression was reduced in backcross populations compared to F(2 )populations. Anthocyanin concentration, as measured by the pH differential method, of pigment-rich pericarp and skin tissues from LA1996 was estimated to be 20.6 mg/100 g and 66.5 mg/100 g, respectively. Anthocyanidin composition was characterized by high-performance liquid chromatography (HPLC). Fruit of accession LA1996 contained predominantly petunidin, followed by malvidin and delphinidinin. Lycopene, beta-carotene, phytoene, and phytofluene levels were similar to those of normal tomatoes and lower than those found in high pigment tomatoes.     

Susceptibility of fruit from diverse apple and crabapple germplasm to attack from apple maggot (Diptera: Tephritidae)

Apple maggot, Rhagoletis pomonella (Walsh) (Diptera: Tephritidae), is a pest of major concern to apple, Malus x domestica (Borkh.) production in eastern North America. Host plant resistance to apple maggot among apple germplasm has been previously evaluated among a small number of exotic Malus accessions and domestic hybrid selections. However, a large number of exotic accessions housed in USDA collections have never been evaluated for their susceptibility to apple pests. Additionally, previous reports of resistance need to be confirmed under both field conditions and with more rigorous laboratory evaluations. Thus, studies were conducted to evaluate the susceptibility of a number of Malus accessions housed at the USDA Plant Genetic Resources Unit "core" collection. Contrary to earlier published reports, these results suggest that some selections previously described as "resistant" are in fact susceptible to both oviposition damage and larval feeding damage by apple maggot. One domestic, disease-resistant apple accession, 'E36-7' is resistant to survival of apple maggot larvae except when the fruit is nearly ripe in late fall. This is the first report of an apple cultivar that is confirmed to be resistant to larval feeding of apple maggot. Although adults can successfully oviposit on all accessions examined, larval survival was zero in a number of small-fruited crabapple accessions classified as resistant in previous studies and also in two accessions, Malus tschonoskii (Maxim) C. K. Schneid. and M. spectabilis (Aiton) Borkh., that have not been previously evaluated.     

Mutations affecting starch synthase III in Arabidopsis alter leaf starch structure and increase the rate of starch synthesis

The role of starch synthase (SS) III (SSIII) in the synthesis of transient starch in Arabidopsis (Arabidopsis thaliana) was investigated by characterizing the effects of two insertion mutations at the AtSS3 gene locus. Both mutations, termed Atss3-1 and Atss3-2, condition complete loss of SSIII activity and prevent normal gene expression at both the mRNA and protein levels. The mutations cause a starch excess phenotype in leaves during the light period of the growth cycle due to an apparent increase in the rate of starch synthesis. In addition, both mutations alter the physical structure of leaf starch. Significant increases were noted in the mutants in the frequency of linear chains in amylopectin with a degree of polymerization greater than approximately 60, and relatively small changes were observed in chains of degree of polymerization 4 to 50. Furthermore, starch in the Atss3-1 and Atss3-2 mutants has a higher phosphate content, approximately two times that of wild-type leaf starch. Total SS activity is increased in both Atss3 mutants and a specific SS activity appears to be up-regulated. The data indicate that, in addition to its expected direct role in starch assembly, SSIII also has a negative regulatory function in the biosynthesis of transient starch in Arabidopsis.     

Neonatal Maternal Deprivation Response and Developmental Changes in Gene Expression Revealed by Hypothalamic Gene Expression Profiling in Mice

Neonatal feeding problems are observed in several genetic diseases including Prader-Willi syndrome (PWS). Later in life, individuals with PWS develop hyperphagia and obesity due to lack of appetite control. We hypothesized that failure to thrive in infancy and later-onset hyperphagia are related and could be due to a defect in the hypothalamus. In this study, we performed gene expression microarray analysis of the hypothalamic response to maternal deprivation in neonatal wild-type and Snord116del mice, a mouse model for PWS in which a cluster of imprinted C/D box snoRNAs is deleted. The neonatal starvation response in both strains was dramatically different from that reported in adult rodents. Genes that are affected by adult starvation showed no expression change in the hypothalamus of 5 day-old pups after 6 hours of maternal deprivation. Unlike in adult rodents, expression levels of Nanos2 and Pdk4 were increased, and those of Pgpep1, Ndp, Brms1l, Mett10d, and Snx1 were decreased after neonatal deprivation. In addition, we compared hypothalamic gene expression profiles at postnatal days 5 and 13 and observed significant developmental changes. Notably, the gene expression profiles of Snord116del deletion mice and wild-type littermates were very similar at all time points and conditions, arguing against a role of Snord116 in feeding regulation in the neonatal period.     

Optimization of affinity, specificity and function of designed influenza inhibitors using deep sequencing

We show that comprehensive sequence-function maps obtained by deep sequencing can be used to reprogram interaction specificity and to leapfrog over bottlenecks in affinity maturation by combining many individually small contributions not detectable in conventional approaches. We use this approach to optimize two computationally designed inhibitors against H1N1 influenza hemagglutinin and, in both cases, obtain variants with subnanomolar binding affinity. The most potent of these, a 51-residue protein, is broadly cross-reactive against all influenza group 1 hemagglutinins, including human H2, and neutralizes H1N1 viruses with a potency that rivals that of several human monoclonal antibodies, demonstrating that computational design followed by comprehensive energy landscape mapping can generate proteins with potential therapeutic utility.     

Amphipoda (crustacea) from palau, micronesia: families ampeliscidae, ampithoidae, aoridae, colomastigidae and cyproideidae

12 species of amphipod in 5 families, collected from shallow reefs in Palau by S. DeGrave during 2002, are reported here. Of these, five species are new to science and Microdeutopus tridens Schellenberg (1938) is redescribed and transferred to the genus Bemlos Shoemaker (1925). The collection included several additional species in the genera Amphilochus Bate, 1862, Ampithoe Leach (1814), Bemlos, Byblis Boeck (1871), Colomastix Grube (1861) and Notopoma Lowry & Berents (1996), that were either incomplete or juvenile and could therefore not adequately be described. In addition, two new species of Plumithoe Barnard & Karaman (1991) are erected from the literature. Other families collected in Palau will be considered in later contributions.     

A role for the neural cell adhesion molecule, NCAM, in myoblast interaction during myogenesis

The Ca2(+)-independent neural cell adhesion molecule, NCAM, is expressed by both nerve and muscle cells and has been shown to mediate both nerve-nerve and nerve-muscle cell interaction. A role for NCAM in muscle-muscle cell interaction has been proposed but not demonstrated. Here we report evidence that NCAM is expressed by embryonic chick muscle cells during in vitro development and functions together with Ca2(+)-dependent adhesion molecules in mediating myoblast interaction during the formation of multinucleate cells.