Parenting a child with phenylketonuria or galactosemia: implications for health-related quality of life

Parents of children with chronic disorders have an impaired health-related quality of life (HRQoL) compared to parents of healthy children. Remarkably, parents of children with a metabolic disorder reported an even lower HRQoL than parents of children with other chronic disorders. Possibly, the uncertainty about the course of the disease and the limited life expectancy in many metabolic disorders are important factors in the low parental HRQoL. Therefore, we performed a cross-sectional study in parents of children with phenylketonuria (PKU, OMIM #261600) and galactosemia (OMIM #230400), metabolic disorders not affecting life expectancy, in order to investigate their HRQoL compared to parents of healthy children and to parents of children with other metabolic disorders. A total of 185 parents of children with PKU and galactosemia aged 1-19 years completed two questionnaires. Parents of children with PKU or galactosemia reported a HRQoL comparable to parents of healthy children and a significantly better HRQoL than parents of children with other metabolic disorders. Important predictors for parental mental HRQoL were the psychosocial factors emotional support and loss of friendship. As parental mental functioning influences the health, development and adjustment of their children, it is important that treating physicians also pay attention to the wellbeing of the parents. The insight that emotional support and loss of friendship influence the HRQoL of the parents enables treating physicians to provide better support for these parents

Methodological standards in non-inferiority AIDS trials: moving from adherence to compliance

BACKGROUND: The interpretation of the results of active-control trials regarding the efficacy and safety of a new drug is important for drug registration and following clinical use. It has been suggested that non-inferiority and equivalence studies are not reported with the same quantitative rigor as superiority studies. METHODS: Standard methodological criteria for non-inferiority and equivalence trials including design, analysis and interpretation issues were applied to 18 recently conducted large non-inferiority (15) and equivalence (3) randomized trials in the field of AIDS antiretroviral therapy. We used the continuity-corrected non-inferiority chi-square to test 95% confidence interval treatment difference against the predefined non-inferiority margin. RESULTS: The pre-specified non-inferiority margin ranged from 10% to 15%. Only 4 studies provided justification for their choice. 39% of the studies (7/18) reported only intent-to-treat (ITT) analysis for the primary endpoint. When on-treatment (OT) and ITT statistical analyses were provided, ITT was favoured over OT for results interpretation for all but one study, inappropriately in this statistical context. All but two of the studies concluded there was "similar" efficacy of the experimental group. However, 9/18 had inconclusive results for non-inferiority. CONCLUSION: Conclusions about non-inferiority should be drawn on the basis of the confidence interval analysis of an appropriate primary endpoint, using the predefined criteria for non-inferiority, in both OT and ITT, in compliance with the non-inferiority and equivalence CONSORT statement. We suggest that the use of the non-inferiority chi-square test may provide additional useful information

Genes in S and T Subgenomes Are Responsible for Hybrid Lethality in Interspecific Hybrids between Nicotiana tabacum and Nicotiana occidentalis

Many species of Nicotiana section Suaveolentes produce inviable F(1) hybrids after crossing with Nicotiana tabacum (genome constitution SSTT), a phenomenon that is often called hybrid lethality. Through crosses with monosomic lines of N. tabacum lacking a Q chromosome, we previously determined that hybrid lethality is caused by interaction between gene(s) on the Q chromosome belonging to the S subgenome of N. tabacum and gene(s) in Suaveolentes species. Here, we examined if hybrid seedlings from the cross N. occidentalis (section Suaveolentes)×N. tabacum are inviable despite a lack of the Q chromosome.Hybrid lethality in the cross of N. occidentalis×N. tabacum was characterized by shoots with fading color. This symptom differed from what has been previously observed in lethal crosses between many species in section Suaveolentes and N. tabacum. In crosses of monosomic N. tabacum plants lacking the Q chromosome with N. occidentalis, hybrid lethality was observed in hybrid seedlings either lacking or possessing the Q chromosome. N. occidentalis was then crossed with two progenitors of N. tabacum, N. sylvestris (SS) and N. tomentosiformis (TT), to reveal which subgenome of N. tabacum contains gene(s) responsible for hybrid lethality. Hybrid seedlings from the crosses N. occidentalis×N. tomentosiformis and N. occidentalis×N. sylvestris were inviable.Although the specific symptoms of hybrid lethality in the cross N. occidentalis×N. tabacum were similar to those appearing in hybrids from the cross N. occidentalis×N. tomentosiformis, genes in both the S and T subgenomes of N. tabacum appear responsible for hybrid lethality in crosses with N. occidentalis

HIV Tropism and Decreased Risk of Breast Cancer

During the first two decades of the U.S. AIDS epidemic, and unlike some malignancies, breast cancer risk was significantly lower for women with human immunodeficiency virus (HIV) infection compared to the general population. This deficit in HIV-associated breast cancer could not be attributed to differences in survival, immune deficiency, childbearing or other breast cancer risk factors. HIV infects mononuclear immune cells by binding to the CD4 molecule and to CCR5 or CXCR4 chemokine coreceptors. Neoplastic breast cells commonly express CXCR4 but not CCR5. In vitro, binding HIV envelope protein to CXCR4 has been shown to induce apoptosis of neoplastic breast cells. Based on these observations, we hypothesized that breast cancer risk would be lower among women with CXCR4-tropic HIV infection.We conducted a breast cancer nested case-control study among women who participated in the WIHS and HERS HIV cohort studies with longitudinally collected risk factor data and plasma. Cases were HIV-infected women (mean age 46 years) who had stored plasma collected within 24 months of breast cancer diagnosis and an HIV viral load≥500 copies/mL. Three HIV-infected control women, without breast cancer, were matched to each case based on age and plasma collection date. CXCR4-tropism was determined by a phenotypic tropism assay. Odds ratios (OR) and 95% confidence intervals (CI) for breast cancer were estimated by exact conditional logistic regression. Two (9%) of 23 breast cancer cases had CXCR4-tropic HIV, compared to 19 (28%) of 69 matched controls. Breast cancer risk was significantly and independently reduced with CXCR4 tropism (adjusted odds ratio, 0.10, 95% CI 0.002-0.84) and with menopause (adjusted odds ratio, 0.08, 95% CI 0.001-0.83). Adjustment for CD4+ cell count, HIV viral load, and use of antiretroviral therapy did not attenuate the association between infection with CXCR4-tropic HIV and breast cancer.Low breast cancer risk with HIV is specifically linked to CXCR4-using variants of HIV. These variants are thought to exclusively bind to and signal through a receptor that is commonly expressed on hyperplastic and neoplastic breast duct cells. Additional studies are needed to confirm these observations and to understand how CXCR4 might reduce breast cancer risk

Complex Deleterious Interactions Associated with Malic Enzyme May Contribute to Reproductive Isolation in the Copepod Tigriopus californicus

Dobzhansky-Muller incompatibilities can result from the interactions of more than a single pair of interacting genes and there are several different models of how such complex interactions can be structured. Previous empirical work has identified complex conspecific epistasis as a form of complex interaction that has contributed to postzygotic reproductive isolation between taxa, but other forms of complexity are also possible. Here, I probe the genetic basis of reproductive isolation in crosses of the intertidal copepod Tigriopus californicus by looking at the impact of markers in genes encoding metabolic enzymes in F2 hybrids. The region of the genome associated with the locus ME2 is shown to have strong, repeatable impacts on the fitness of hybrids in crosses and epistatic interactions with another chromosomal region marked by the GOT2 locus in one set of crosses. In a cross between one of these populations and a third population, these two regions do not appear to interact despite the continuation of a large effect of the ME2 region itself in both crosses. The combined results suggest that the ME2 chromosomal region is involved in incompatibilities with several unique partners. If these deleterious interactions all stem from the same factor in this region, that would suggest a different form of complexity from complex conspecific epistasis, namely, multiple independent deleterious interactions stemming from the same factor. Confirmation of this idea will require more fine-scale mapping of the interactions of the ME2 region of the genome

Selection against Spurious Promoter Motifs Correlates with Translational Efficiency across Bacteria

Because binding of RNAP to misplaced sites could compromise the efficiency of transcription, natural selection for the optimization of gene expression should regulate the distribution of DNA motifs capable of RNAP-binding across the genome. Here we analyze the distribution of the −10 promoter motifs that bind the σ70 subunit of RNAP in 42 bacterial genomes. We show that selection on these motifs operates across the genome, maintaining an over-representation of −10 motifs in regulatory sequences while eliminating them from the nonfunctional and, in most cases, from the protein coding regions. In some genomes, however, −10 sites are over-represented in the coding sequences; these sites could induce pauses effecting regulatory roles throughout the length of a transcriptional unit. For nonfunctional sequences, the extent of motif under-representation varies across genomes in a manner that broadly correlates with the number of tRNA genes, a good indicator of translational speed and growth rate. This suggests that minimizing the time invested in gene transcription is an important selective pressure against spurious binding. However, selection against spurious binding is detectable in the reduced genomes of host-restricted bacteria that grow at slow rates, indicating that components of efficiency other than speed may also be important. Minimizing the number of RNAP molecules per cell required for transcription, and the corresponding energetic expense, may be most relevant in slow growers. These results indicate that genome-level properties affecting the efficiency of transcription and translation can respond in an integrated manner to optimize gene expression. The detection of selection against promoter motifs in nonfunctional regions also confirms previous results indicating that no sequence may evolve free of selective constraints, at least in the relatively small and unstructured genomes of bacteria

Extension of the core map of common bean with EST-SSR, RGA, AFLP, and putative functional markers

Microsatellites and gene-derived markers are still underrepresented in the core molecular linkage map of common bean compared to other types of markers. In order to increase the density of the core map, a set of new markers were developed and mapped onto the RIL population derived from the ‘BAT93’ × ‘Jalo EEP558’ cross. The EST-SSR markers were first characterized using a set of 24 bean inbred lines. On average, the polymorphism information content was 0.40 and the mean number of alleles per locus was 2.7. In addition, AFLP and RGA markers based on the NBS-profiling method were developed and a subset of the mapped RGA was sequenced. With the integration of 282 new markers into the common bean core map, we were able to place markers with putative known function in some existing gaps including regions with QTL for resistance to anthracnose and rust. The distribution of the markers over 11 linkage groups is discussed and a newer version of the common bean core linkage map is proposed