Repeat Transanal Advancement Flap Repair: Impact on the Overall Healing Rate of High Transsphincteric Fistulas and on Fecal Continence

PURPOSE: Transanal advancement flap repair (TAFR) has been advocated as the treatment of choice for transsphincteric fistulas passing through the upper or middle third of the external anal sphincter. It is not clear whether previous attempts at repair adversely affect the outcome of TAFR. The purpose of the present study was to evaluate the success rate of a repeat TAFR and to assess the impact of such a second procedure on the overall healing rate of high transsphincteric fistulas and on fecal continence. METHODS: Between January 2001 and January 2005, a consecutive series of 87 patients (62 males; median age, 49 (range, 27-73) years) underwent TAFR. Median follow-up was 15 (range, 2-50) months. Patients in whom the initial operation failed were offered two further treatment options: a second flap repair or a long-term indwelling seton drainage. Twenty-six patients (male:female ratio, 5:2; median age, 51 (range, 31-72) years) preferred a repeat repair. Continence status was evaluated before and after the procedures by using the Rockwood Faecal Incontinence Severity Index (RFISI). RESULTS: The healing rate after the first TAFR was 67 percent. Of the 29 patients in whom the initial procedure failed, 26 underwent a repeat TAFR. The healing rate after this second procedure was 69 percent, resulting in an overall success rate of 90 percent. Both before and after the first attempt of TAFR, the median RFISI was 7 (range, 0-34). In patients who underwent a second TAFR, the median RFISI before and after this procedure was 9 (range, 0-34) and 8 (range, 0-34), respectively. None of these changes were statistically significant. CONCLUSIONS: Repeat TAFR increases the overall healing rate of high transsphincteric fistulas from 67 percent after one attempt to 90 percent after two attempts without a deteriorating effect on fecal continence

Structure-Based Analysis of Five Novel Disease-Causing Mutations in 21-Hydroxylase-Deficient Patients

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is the most frequent inborn error of metabolism, and accounts for 90–95% of CAH cases. The affected enzyme, P450C21, is encoded by the CYP21A2 gene, located together with a 98% nucleotide sequence identity CYP21A1P pseudogene, on chromosome 6p21.3. Even though most patients carry CYP21A1P-derived mutations, an increasing number of novel and rare mutations in disease causing alleles were found in the last years. In the present work, we describe five CYP21A2 novel mutations, p.R132C, p.149C, p.M283V, p.E431K and a frameshift g.2511_2512delGG, in four non-classical and one salt wasting patients from Argentina. All novel point mutations are located in CYP21 protein residues that are conserved throughout mammalian species, and none of them were found in control individuals. The putative pathogenic mechanisms of the novel variants were analyzed in silico. A three-dimensional CYP21 structure was generated by homology modeling and the protein design algorithm FoldX was used to calculate changes in stability of CYP21A2 protein. Our analysis revealed changes in protein stability or in the surface charge of the mutant enzymes, which could be related to the clinical manifestation found in patients

No selection for change in polyandry under experimental evolution

What drives mating system variation is a major question in evolutionary biology. Female multiple mating (polyandry) has diverse evolutionary consequences, and there are many potential benefits and costs of polyandry. However, our understanding of its evolution is biased towards studies enforcing monandry in polyandrous species. What drives and maintains variation in polyandry between individuals, genotypes, populations and species remains poorly understood. Genetic variation in polyandry may be actively maintained by selection, or arise by chance if polyandry is selectively neutral. In Drosophila pseudoobscura, there is genetic variation in polyandry between and within populations. We used isofemale lines to found replicate populations with high or low initial levels of polyandry and tracked polyandry under experimental evolution over seven generations. Polyandry remained relatively stable, reflecting the starting frequencies of the experimental populations. There were no clear fitness differences between high versus low polyandry genotypes, and there was no signature of balancing selection. We confirmed these patterns in direct comparisons between evolved and ancestral females and found no consequences of polyandry for female fecundity. The absence of differential selection even when initiating populations with major differences in polyandry casts some doubt on the importance of polyandry for female fitness

The Effect of Diet Quality and Wing Morph on Male and Female Reproductive Investment in a Nuptial Feeding Ground Cricket

A common approach in the study of life-history trade-off evolution is to manipulate the nutrient content of diets during the life of an individual in order observe how the acquisition of resources influences the relationship between reproduction, lifespan and other life-history parameters such as dispersal. Here, we manipulate the quality of diet that replicate laboratory populations received as a thorough test of how diet quality influences the life-history trade-offs associated with reproductive investment in a nuptial feeding Australian ground cricket (Pteronemobius sp.). In this species, both males and females make significant contributions to the production of offspring, as males provide a nuptial gift by allowing females to chew on a modified tibial spur during copulation and feed directing on their haemolymph. Individuals also have two distinct wing morphs, a short-winged flightless morph and a long-winged morph that has the ability to disperse. By manipulating the quality of diet over seven generations, we found that the reproductive investment of males and females were affected differently by the diet quality treatment and wing morph of the individual. We discuss the broader implications of these findings including the differences in how males and females balance current and future reproductive effort in nuptial feeding insects, the changing nature of sexual selection when diets vary, and how the life-history trade-offs associated with the ability to disperse are expected to differ among populations

Consensus recommendations for the diagnosis, treatment and follow-up of inherited methylation disorders

Inherited methylation disorders are a group of rarely reported, probably largely underdiagnosed disorders affecting transmethylation processes in the metabolic pathway between methionine and homocysteine. These are methionine adenosyltransferase I/III, glycine N-methyltransferase, S-adenosylhomocysteine hydrolase and adenosine kinase deficiencies. This paper provides the first consensus recommendations for the diagnosis and management of methylation disorders. Following search of the literature and evaluation according to the SIGN-methodology of all reported patients with methylation defects, graded recommendations are provided in a structured way comprising diagnosis (clinical presentation, biochemical abnormalities, differential diagnosis, newborn screening, prenatal diagnosis), therapy and follow-up. Methylation disorders predominantly affect the liver, central nervous system and muscles, but clinical presentation can vary considerably between and within disorders. Although isolated hypermethioninemia is the biochemical hallmark of this group of disorders, it is not always present, especially in early infancy. Plasma S-adenosylmethionine and S-adenosylhomocysteine are key metabolites for the biochemical clarification of isolated hypermethioninemia. Mild hyperhomocysteinemia can be present in all methylation disorders. Methylation disorders do not qualify as primary targets of newborn screening. A low-methionine diet can be beneficial in patients with methionine adenosyltransferase I/III deficiency if plasma methionine concentrations exceed 800 μmol/L. There is some evidence that this diet may also be beneficial in patients with S-adenosylhomocysteine hydrolase and adenosine kinase deficiencies. S-adenosylmethionine supplementation may be useful in patients with methionine adenosyltransferase I/III deficiency. Recommendations given in this article are based on general principles and in practice should be adjusted individually according to patient's age, severity of the disease, clinical and laboratory findings

Female responses to experimental removal of sexual selection components in Drosophila melanogaster

Despite the common assumption that multiple mating should in general be favored in males, but not in females, to date there is no consensus on the general impact of multiple mating on female fitness. Notably, very little is known about the genetic and physiological features underlying the female response to sexual selection pressures. By combining an experimental evolution approach with genomic techniques, we investigated the effects of single and multiple matings on female fecundity and gene expression. We experimentally manipulated the opportunity for mating in replicate populations of Drosophila melanogaster by removing components of sexual selection, with the aim of testing differences in short term post-mating effects of females evolved under different mating strategies