► Evolution of BChE, in particular, subfunctionalisation of a duplicated gene. ► BChE-like activity has arisen a number of times, suggesting convergent evolution. ► Subfunctionalisation of BChE in ...the nervous system and in detoxification. ► Analysis of natural mutations in human BCHE in relation to BChE structure.
While acetylcholinesterase (EC 3.1.1.7) has a clearly defined role in neurotransmission, the functions of its sister enzyme butyrylcholinesterase (EC 3.1.1.8) are more obscure. Numerous mutations, many inactivating, are observed in the human butyrylcholinesterase gene, and the butyrylcholinesterase knockout mouse has an essentially normal phenotype, suggesting that the enzyme may be redundant. Yet the gene has survived for many millions of years since the duplication of an ancestral acetylcholinesterase early in vertebrate evolution. In this paper, we ask the questions: why has butyrylcholinesterase been retained, and why are inactivating mutations apparently tolerated? Butyrylcholinesterase has diverged both structurally and in terms of tissue and cellular expression patterns from acetylcholinesterase. Butyrylcholinesterase-like activity and enzymes have arisen a number of times in the animal kingdom, suggesting the usefulness of such enzymes. Analysis of the published literature suggests that butyrylcholinesterase has specific roles in detoxification as well as in neurotransmission, both in the brain, where it appears to control certain areas and functions, and in the neuromuscular junction, where its function appears to complement that of acetylcholinesterase. An analysis of the mutations in human butyrylcholinesterase and their relation to the enzyme’s structure is shown. In conclusion, it appears that the structure of butyrylcholinesterase’s catalytic apparatus is a compromise between the apparently conflicting selective demands of a more generalised detoxifier and the necessity for maintaining high catalytic efficiency. It is also possible that the tolerance of mutation in human butyrylcholinesterase is a consequence of the detoxification function. Butyrylcholinesterase appears to be a good example of a gene that has survived by subfunctionalisation.
Total colonic aganglionosis (TCA) is a relatively uncommon form of Hirschsprung disease (HSCR), occurring in approximately 2%-13% of cases. It can probably be classified as TCA (defined as ...aganglionosis extending from the anus to at least the ileocecal valve, but not >50 cm proximal to the ileocecal valve) and total colonic and small bowel aganglionosis, which may involve a very long segment of aganglionosis. It is not yet clear whether TCA merely represents a long form of HSCR or a different expression of the disease. There are many differences between TCA and other forms of HSCR, which require explanation if its ubiquitous clinical features are to be understood. Clinically, TCA appears to represent a different spectrum of disease in terms of presentation and difficulties that may be experienced in diagnosis, suggesting a different pathophysiology from the more common forms of HSCR. There is also some evidence suggesting that instead of being purely congenital, it may represent certain different pathophysiologic mechanisms. This study, in addition to reviewing current understanding and differences between TCA and the more frequently encountered rectosigmoid (or short-segment) expression, correlates them with what is currently known about the genetic and molecular biological background. Moreover, it reviews current outcomes to find consensus on management.
Hirschsprung disease is a functional obstruction of the gastrointestinal tract due to the congenital absence of ganglion cells in the intermyenteric plexuses of the distal bowel. Gastrointestinal ...motility requires intact muscular layers as well as neural network connection to function properly. The Actin G2 gene is the main gene encoding actin gamma 2; a smooth muscle actin found in enteric tissues.
This study of the Actin G2 gene in patients with Hirschsprung disease explores a possible molecular basis abnormal muscle function and post-surgical pseudo-obstruction in a group of patients. As far as the authors are aware, this is the first report confirming structural muscle deficits in Hirschsprung disease.
Ethical permission and informed consent were obtained. DNA was extracted from whole blood samples in 10 patients with histologically proven HSCR patients. PCR amplification of the ACTG2 gene, were subjected to semi-automated bi-directional sequencing analysis. Sequencing results were analyzed using FinchTV Sequence Alignment Software (http:/en.biosoft.net) to read chromatogram files. Further predicting bioinformatic investigation was obtained by PolyPhen 2 software to evaluate the significance of the observed amino acid changes.
Ten new patients with similar HSCR phenotypes were prospectively investigated for variation in the Actin G2 gamma gene (ACTG2) variations. The results of ACTG2 gene analysis showing variation in exons 5, 8 and 10 of the ACTG2 gene in 7 of them (64%). The c.109C > G S345 L was the most frequent occurring in 6 of the 10 patients (54%), the c.171 A > A K119E in 2 and the significant c.108 T > G W357G variation in exon 10 (1 patient) Four patients had a combination of different variants in different exons which were less significant. Allele frequency on a control sample of the South African population showed no comparable pathology link scores (http://gnomad.broadinstitute.org/). Bioinformatic in silico modeling showed that the residue replacements in both variants (Lys to Glu and Trp to Gly) are highly non-conservative and variation can alter interactions within the protein conformation.
The Actin smooth muscle gene showed variation in 64% of samples, indicating a reason for abnormal functioning muscle in many HSCR patients. Hirschsprung disease is part of a complex spectrum which also includes smooth muscle.
VI
Young Man With Shortness of Breath Hodson, Daniel Z.; Reinhardt, Samuel W.; Moore, Christopher L.
Annals of emergency medicine,
05/2021, Letnik:
77, Številka:
5
Journal Article
Objectives
To develop a consensus statement on current best practice of active surveillance (AS) in the UK, informed by patients and clinical experts.
Subjects and Methods
A consensus statement was ...drafted on the basis of three sources of data: systematic literature search of national and international guidelines; data arising from a Freedom of Information Act request to UK urology departments regarding their current practice of AS; and survey and interview responses from men with localized prostate cancer regarding their experiences and views of AS. The Prostate Cancer UK Expert Reference Group (ERG) on AS was then convened to discuss and refine the statement.
Results
Guidelines and protocols for AS varied significantly in terms of risk stratification, criteria for offering AS, and protocols for AS between and within countries. Patients and healthcare professionals identified clinical, emotional and process needs for AS to be effective. Men with prostate cancer wanted more information and psychological support at the time of discussing AS with the treating team and in the first 2 years of AS, and a named healthcare professional to discuss any questions or concerns they had. The ERG agreed 30 consensus statements regarding best practice for AS. Statements were grouped under headings: ‘Inclusion/Exclusion Criteria’; ‘AS follow‐up protocol’ and ‘When to stop AS’.
Conclusion
Significant variation currently exists in the practice of AS in the UK and internationally. Men have clear views on the level of involvement in treatment decisions and support from their treating professionals when receiving AS. The Prostate Cancer UK AS ERG has developed a set of consensus statements for best practice in AS. Evidence for best practice in AS, and the use of multiparametric magnetic resonance imaging in AS, is still evolving, and further studies are needed to determine how to optimize AS outcomes.
Active surveillance (AS) is a management option for men diagnosed with lower risk prostate cancer. There is wide variation in all aspects of AS internationally, from patient selection to ...investigations and follow-up intervals, and a lack of clear evidence on the optimal approach to AS. This study aimed to provide guidance for clinicians from an international panel of prostate cancer experts.
A modified Delphi approach was undertaken, utilising two rounds of online questionnaires followed by a face-to-face workshop. Participants indicated their level of agreement with statements relating to patient selection for AS via online questionnaires on a 7-point Likert scale. Factors not achieving agreement were iteratively developed between the two rounds of questionnaires. Draft statements were presented at the face-to-face workshop for discussion and consensus building.
12 prostate cancer experts (9 urologists, 2 academics, 1 radiation oncologist) participated in this study from a range of geographical regions (4 USA, 4 Europe, 4 Australia). Complete agreement on statements presented to the participants was 29.4% after Round One and 69.0% after Round Two. Following robust discussions at the face-to-face workshop, agreement was reached on the remaining statements. PSA, PSA density, Multiparametric MRI, and systematic biopsy (with or without targeted biopsy) were identified as minimum diagnostic tests required upon which to select patients to recommend AS as a treatment option for prostate cancer. Patient factors and clinical parameters that identified patients appropriate to potentially receive AS were agreed. Genetic and genomic testing was not recommended for use in clinical decision-making regarding AS.
The lack of consistency in the practice of AS for men with lower risk prostate cancer between and within countries was reflected in this modified Delphi study. There are, however, areas of common practice and agreement from which clinicians practicing in the current environment can use to inform their clinical practice to achieve the best outcomes for patients.
Broadly neutralizing antibodies (bnAbs) against HIV-1 are an effective means of preventing transmission. To better understand the mechanisms by which HIV-specific bnAbs naturally develop, we ...investigated blood and lymphoid tissue in pediatric infection, since potent bnAbs develop with greater frequency in children than adults. As in adults, the frequency of circulating effector T-follicular helper cells (T
) in HIV infected, treatment naïve children correlates with neutralization breadth. However, major differences between children and adults were also observed both in circulation, and in a small number of tonsil samples. In children, T
cells are significantly more abundant, both in blood and in lymphoid tissue germinal centers, than in adults. Second, HIV-specific T
cells are more frequent in pediatric than in adult lymphoid tissue and secrete the signature cytokine IL-21, which HIV-infected adults do not. Third, the enrichment of IL-21-secreting HIV-specific T
in pediatric lymphoid tissue is accompanied by increased T
regulation via more abundant regulatory follicular T-cells and HIV-specific CXCR5+ CD8 T-cells compared to adults. The relationship between regulation and neutralization breadth is also observed in the pediatric PBMC samples and correlates with neutralization breadth. Matching neutralization data from lymphoid tissue samples is not available. However, the distinction between infected children and adults in the magnitude, quality and regulation of HIV-specific T
responses is consistent with the superior ability of children to develop high-frequency, potent bnAbs. These findings suggest the possibility that the optimal timing for next generation vaccine strategies designed to induce high-frequency, potent bnAbs to prevent HIV infection in adults would be in childhood.
Abstract Background Clinical association between Hirschsprung disease (HD) and Down syndrome (DS) is well established. RET promoter and intron 1 variations have been shown to interfere with RET ...function, increasing the risk of HD pathogenesis. The intronic single-nucleotide polymorphism 2 (SNP2 rs2435357) has been associated with DS-associated HD (DS-HD). This study focuses on variations of specific RET intron, 1 SNPs (viz, SNP1 rs2506004 and SNP2 rs2435357) in DS-HD. Patients and Methods DNA was extracted from paraffin-embedded tissue samples and whole blood in 14 patients with DS with histologically proven HD. Polymerase chain reaction products of RET intron 1 were screened for genetic variation and matched to DS and controls from the general population. Results Thirty-seven blood and/or tissue from 14 patients with DS-HD were investigated. RET intronic variations (SNP1 rs2506004 or SNP2 rs2435357) were detected in all patients. SNP1 was detected in all patients, was heterozygous in 9, and homozygous in 5 samples (all aganglionic and 1 total colonic aganglionosis). SNP2 was absent in 6 patients, heterozygous in 6, and homozygous in 3. Three DS controls had a heterozygous SNP1. Homozygous intronic SNP RET variations were related to aganglionic tissue but not normally ganglionated or transitional zone from the same individual. Conclusions Potential disease-related RET mutations were identified in the intron region in 80% of patients with DS-HD investigated, suggesting a causal relationship. The presence of a homozygous form in the aganglionic tissue probably represents a somatic mutation, which suggests local microenvironmental factors in HD pathogenesis.
Accurate and rapid diagnosis of extrapulmonary nodal tuberculosis in children is of paramount importance. This retrospective study performed at Tygerberg Hospital using data from the laboratory ...records between January 1, 2004 and June 30, 2014 demonstrates how since the introduction laboratory-run FNAB service; fine needle aspiration biopsy has become an acceptable and routine diagnostic procedure for triage of pediatric lymphadenopathy.
This research used a stress-coping conceptual framework to examine intimate partner violence (IPV) among men who are fathers. The current study examined how perceived stress explained associations ...between stressors (e.g., employment status, psychological and physical female-to-male partner violence FMPV, substance use, criminal justice system involvement) and male-perpetrated physical and psychological IPV. Participants were 1,971 low-income, ethnically diverse fathers involved in a statewide fatherhood program. Findings indicated that, across African American, White, and Hispanic/Latino men, male-reported FMPV and criminal justice involvement were associated with psychological and/or physical IPV via perceived stress. Employment status and alcohol use were associated with psychological IPV via perceived stress among African American men only. Implications for community-based fatherhood programs are discussed.
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