Publications

Background We investigated differences in breast cancer mortality between younger (younger than 40 years of age) and older (40 years of age and older) women by stage at diagnosis to identify patient and tumor characteristics accounting for disparities. Study Design We conducted a retrospective study of women diagnosed with breast cancer in the 1988 to 2003 Surveillance, Epidemiology, and End Results Program data. Multivariate Cox regression models calculated adjusted hazard ratios (aHR) and 95% confidence intervals to compare overall and stage-specific breast cancer mortality in women younger than 40 years old and women 40 years and older, controlling for potential confounding variables identified in univariate tests. Results Of 243,012 breast cancer patients, 6.4% were younger than 40 years old, and 93.6% were 40 years of age or older. Compared with older women, younger women were more likely to be African American, single, diagnosed at later stages, and treated by mastectomy. Younger women had tumors that were more likely to be higher grade, larger size, estrogen receptor/progesterone receptor–negative, and lymph-node positive (p < 0.001). Younger women were more likely to die from breast cancer compared with older women (crude HR = 1.39; CI, 1.34 to 1.45). Controlling for confounders, younger women were more likely to die compared with older women if diagnosed with stage I (aHR = 1.44; CI, 1.27 to 1.64) or stage II (aHR = 1.09; CI, 1.03 to 1.15) disease and less likely to die if diagnosed with stage IV disease (aHR = 0.85; CI, 0.76 to 0.95). Conclusions Higher breast cancer mortality in younger women was attributed to poorer outcomes with early-stage disease. Additional studies should focus on specific tumor biology contributing to the increased mortality of younger women with early-stage breast cancer.

Penicillium marneffei is a major cause of opportunistic infection in patients with AIDS in north and northeastern Thailand. A method for the quantitation of P. marneffei antigen in urine was developed by using fluorescein isothiocyanate-labelled purified rabbit hyperimmune immunoglobulin G in an enzyme-linked immunosorbent assay. This method was evaluated with 33 patients with culture-proven penicilliosis and 300 controls (52 healthy subjects, 248 hospitalized patients without penicilliosis) from the same area in which penicilliosis is endemic. Urinary antigen was found in all 33 (100%) patients with penicilliosis, with a median titer of 1:20,480. With undiluted samples, 67 (27%) of 248 hospital patients and 3 (6%) of 52 healthy controls were reactive. At a cutoff titer of 1:40, the urine antigen detection assay had a diagnostic sensitivity of 97% and specificity of 98% (positive predictive value, 84%; negative predictive value, 99.7%). This test offers a valuable and rapid method for the diagnosis of penicilliosis in patients with AIDS and could be a useful addition to conventional diagnostic methods in areas in which penicilliosis is endemic.

Quinine (n = 246) was used to treat uncomplicated Plasmodium falciparum and chloroquine (n = 130) was used to treat P. vivax, in a total of 376 episodes of malaria in the first trimester of pregnancy, in 300 Karen women (Thailand 1995–2000). Parasites were still present on day 6 or 7 in 4·7% (11/234) of episodes treated with quinine. The overall 28 day parasite reappearance rate following quinine was 28·7% (60/209) for primary treatments and 44% (11/25) for re-treatments. Quinine treatment resulted in a high rate of gametocyte carriage: person-gametocyte-weeks = 42·5 (95% CI 27·8–62·1) per 1000 woman-weeks. For P. vivax, the reappearance rate for all episodes by day 28 was 4·5% (5/111). Significantly more women complained of tinnitus following quinine treatment compared to on admission: 64·5% (78/121) vs 31·6% (59/187), P < 0·001. Using survival analysis, the community rate of spontaneous abortion in women who never had malaria in pregnancy, 17·8% (16·5–19·0), did not differ significantly from rates in women treated with quinine: 22·9% (95% CI 15·5–30·3), or chloroquine: 18·3% (95% CI 9·3–27·3), P = 0·42. Pregnancies exposed to quinine or chloroquine and carried to term did not have increased rates of congenital abnormality, stillbirth or low birthweight. These results suggest that therapeutic doses of quinine and chloroquine are safe to use in the first trimester of pregnancy.

In many endemic areas, Plasmodium vivax malaria is predominantly a disease of young adults and children. International recommendations for radical cure recommend fixed target doses of 0.25 or 0.5 mg/kg/day of primaquine for 14 days in glucose-6-phosphate dehydrogenase normal patients of all ages. However, for many anti-malarial drugs, including primaquine, there is evidence that children have lower exposures than adults for the same weight-adjusted dose. The aim of the study was to develop 14-day weight-based and age-based primaquine regimens against high-frequency relapsing tropical P. vivax.

The aim of this study was to identify and compare factors associated with Plasmodium falciparum gametocyte carriage in three regions of differing malaria endemicity. Retrospective data from Thailand, The Gambia and Tanzania were used. The data came from large prospective field-based clinical trials, which investigated gametocyte carriage after different anti-malarial drug treatments. Gametocytaemia was detected during the observation period in 12% of patients (931 out of 7548) in Thailand, 34% (683 out of 2020) in The Gambia, and 31% (430 out of 1400) in Tanzania (p < 0.001). Approximately one third (33%, 680/2044) of the patients with gametocytaemia during the observation period, already had patent gametocytaemia at enrolment (day 0 or day 1): 35% (318/931) in Thailand, 37% (250/683) in The Gambia, 26% (112/430) in Tanzania. Maximum gametocytaemia was usually observed on or before the seventh day after starting treatment (93% in Thailand, 70% in Tanzania and 78% in The Gambia). Lowest gametocyte carriage rates were observed following treatment with artemisinin derivatives, while sulphadoxine-pyrimethamine (SP) was associated with significantly greater development of gametocytaemia than other drug treatments (p < 0.001). The duration of gametocyte carriage was shorter in Thailand by 86% and Tanzania by 65% than in The Gambia. Gametocyte carriage was 27% longer among people presenting with anaemia, and was shorter in duration among patients who received artemisinin derivatives, by 27% in Thailand and by 71% in Tanzania and The Gambia. This study confirms the independent association of gametocytaemia with anaemia, and the significantly lower prevalence and duration of gametocyte carriage following treatment with an artemisinin derivative. The large differences in gametocyte carriage rates between regions with different levels of malaria transmission suggest that drug interventions to prevent transmission will have different effects in different places.

Historically seen as a benign disease, it is now becoming clear that Plasmodium vivax can cause significant morbidity. Effective control strategies targeting P. vivax malaria is hindered by our limited understanding of vivax biology. Here we established the P. vivax transcriptome of the Intraerythrocytic Developmental Cycle (IDC) of two clinical isolates in high resolution by Illumina HiSeq platform. The detailed map of transcriptome generates new insights into regulatory mechanisms of individual genes and reveals their intimate relationship with specific biological functions. A transcriptional hotspot of vir genes observed on chromosome 2 suggests a potential active site modulating immune evasion of the Plasmodium parasite across patients. Compared to other eukaryotes, P. vivax genes tend to have unusually long 5' untranslated regions and also present multiple transcription start sites. In contrast, alternative splicing is rare in P. vivax but its association with the late schizont stage suggests some of its significance for gene function. The newly identified transcripts, including up to 179 vir like genes and 3018 noncoding RNAs suggest an important role of these gene/transcript classes in strain specific transcriptional regulation.

Ceftriaxone, a third generation cephalosporin, has a wide antibacterial spectrum that has good CNS penetration, which makes it potentially suitable for initial treatment of severe neonatal pediatric infections providing suitable formulation. We evaluated its physicochemical and technical characteristics to assess its potential for development as a non-parenteral dosage form. As ceftriaxone is marked only for injectable use, these data are not available. Using HPLC and Karl Fischer titration, sensitivity of ceftriaxone to water, feasibility and impact of pharmaceutical processes and compatibility with common pharmaceutical excipients were assessed. X-ray diffraction studies gave deeper insight into the mechanisms involved in degradation. Chemometrical analysis of near infrared spectra enabled classification of ceftriaxone powder according to exposure conditions or processes applied. The results showed that ceftriaxone was not highly hygroscopic, could be processed in all climatic zones, but should be packaged protected against humidity. Controlling water presence in formulation was shown critical, as ceftriaxone degraded in the presence of water content above 2.4% w/w. To improve flowability, a critical parameter for dry dosage form development, granulation (wet and dry techniques, providing complete drying and moderate force compaction respectively) was shown feasible. Compression with moderate forces was possible, but grinding and high compression forces significantly affected long term ceftriaxone stability and should be avoided. Based on these results, development of ceftriaxone non-parenteral solid or liquid non-aqueous forms appears feasible.

No abstract is provided for this article.

For highly social species, population dynamics depend on hierarchical demography that links local processes, group dynamics, and population growth. Here, we describe a stage-structured matrix model of hierarchical demography, which provides a framework for understanding social influences on population change. Our approach accounts for dispersal and affords insight into population dynamics at multiple scales. The method has close parallels to integral projection models but focuses on a discrete characteristic (group size). Using detailed long-term records for meerkats (Suricata suricatta), we apply our model to explore patterns of local density dependence and implications of group size for group and population growth. Taking into account dispersers, the model predicts a per capita growth rate for social groups that declines with group size. It predicts that larger social groups should produce a greater number of new breeding groups; thus, dominant breeding females (responsible for most reproduction) are likely to be more productive in larger groups. Considering the potential for future population growth, larger groups have the highest reproductive value, but per capita reproductive value is maximized for individuals in smaller groups. Across a plausible range of dispersal conditions, meerkats' long-run population growth rate is maximized when individuals form groups of intermediate size.

Molecular techniques have enabled behavioural ecologists to reassess mating systems from a genetic perspective. Studies of paternity frequently reveal that mating behaviour does not always reflect parentage, and may bring to light alternative mating tactics. Here we present a comparison of behavioural and genetic measures of male reproductive success in a mammalian mating system in which both sexes are highly promiscuous. Rather than having a stable harem social structure, Soay rams (Ovis aries) on the island of Hirta, St Kilda, UK usually consort with individual oestrous ewes sequentially. Not all matings occur between consort pairs, however, and ewes have been seen to mate with up to 10 different rams on the same day. Using locus-specific polymorphism at five protein and 10 microsatellite DNA loci, we determined paternity for 236 lambs born into three cohorts, and compared paternity with estimates of mating success derived from more than one census of rutting behaviour. The correlation between the number of ewes with which each ram was witnessed in consort and the number of paternities assigned was positive and statistically significant, and rams that were observed in consort with a ewe were 18 times more likely to have sired her offspring than other candidate rams. However, most lambs (73%) were not sired by a ram seen in consort with the oestrous mother. Many juveniles, yearlings and some adult rams were rarely seen in consort with ewes, yet were assigned a significant number of paternities. These results suggest that mating tactics differ between age groups, and that alternative mating strategies among adults that do not involve forming consorts with many females also confer mating success. For these reasons, census-based observations of consort associations between individuals cannot be used to accurately estimate individual male reproductive success in this population.

Serial audiometry was performed in ten patients receiving quinine treatment for acute falciparum malaria. Quinine reduced high tone auditory acuity in all patients, resulting in flattening of the audiograms. The effect was rapid in onset, usually unnoticed (although tinnitus was reported in seven patients), and resolved completely after treatment was completed.

Long-distance dispersal in microbial eukaryotes has been shown to result in the establishment of populations on continental and global scales. Such "ubiquitous dispersal" has been claimed to be a general feature of microbial eukaryotes, homogenising populations over large scales. However, the unprecedented sampling of opportunistic infectious pathogens created by the global AIDS pandemic has revealed that a number of important species exhibit geographic endemicity despite long-distance migration via aerially dispersed spores. One mechanism that might tend to drive such endemicity in the face of aerial dispersal is the evolution of niche-adapted genotypes when sexual reproduction is rare. Dispersal of such asexual physiological "species" will be restricted when natural habitats are heterogeneous, as a consequence of reduced adaptive variation. Using the HIV-associated endemic fungus Penicillium marneffei as our model, we measured the distribution of genetic variation over a variety of spatial scales in two host species, humans and bamboo rats. Our results show that, despite widespread aerial dispersal, isolates of P. marneffei show extensive spatial genetic structure in both host species at local and country-wide scales. We show that the evolution of the P. marneffei genome is overwhelmingly clonal, and that this is perhaps the most asexual fungus yet found. We show that clusters of genotypes are specific to discrete ecological zones and argue that asexuality has led to the evolution of niche-adapted genotypes, and is driving endemicity, by reducing this pathogen's potential to diversify in nature.