Surgical repair of large hiatal hernias is associated with a high recurrence rate when the repair is made by simple cruroplasty. The use of a mesh goes from a reinforcement of a simple cruroplasty to ...a tension-free repair. We discuss the evolution of this approach and evaluate the outcomes of 27 patients with type II (n = 9), type III (n = 16), and type IV (n = 2) hiatal hernias treated laparoscopically.
Between November 1999 and October 2003, 27 patients (18 women and 9 men) received laparoscopic repair of large hiatal hernias by means of an A-shaped polypropylene-polytetrafluoroethylene mesh. A total or a partial fundoplication was associated in all cases. The mean age was 60.1 years (range, 36-76 years). The patients presented with symptoms of 2 months to 10 years in duration. Preoperative assessment included an upper gastrointestinal endoscopy, esophageal manometry, 24 hour pH monitoring, and barium swallow. Concomitant esophagitis was found in 16 patients and impaired esophageal peristalsis in 2 patients. Four patients had concomitant gallbladder disease treated at the same time.
No conversions occurred in our series. There was no perioperative mortality, and morbidity was low. Follow-up averaged 27 months (range, 6-46 months). There has been 1 recurrence (3.7%), prolonged dysphagia in 4 cases, and no mesh erosion.
Early results confirm the feasibility of the tension-free repair of large hiatal hernias and the effectiveness of the composite A-shaped mesh. Long-term follow-up for all patients is necessary to determine the real incidence of recurrence.
Summary
Delayed graft function (DGF) is a frequent complication of kidney transplantation (KT) that may affect both short‐ and long‐term graft outcome. It has been reported that pretransplantation ...peritoneal dialysis was correlated with a better recovery of graft function than hemodialysis in adult kidney recipients. However, the effect of pretransplantation dialysis mode (PDM) seemed to be unclear on the early outcome of KT in pediatric recipients. In this study, the potential impact of PDM on early graft function was evaluated in 174 pediatric patients who underwent KT by using cadaveric donors. The primary outcome parameter was the time to reach a serum creatinine (SCr) level 50% of the pretransplantation value T1/2(SCr), while DGF was defined as a T1/2(SCr) >3 days after KT (n = 40). By stratifying kidney recipients for normal function graft or DGF, this latter group showed a significantly higher body weight (BW) on the day of KT (P = 0.014), body surface area (BSA) (P = 0.005), warm ischemia time (WIT) (P = 0.022), early SCr on the day 1 after KT (P < 0.001), and T1/2(SCr) (P < 0.001), whereas lower urine volume (UV) collected in the first 24 h after KT (P < 0.001) and fluid load (P < 0.001) occurred. Univariate exponential correlation that was carried out between T1/2(SCr) and all the other variables had shown a better value than the linear correlation for BW (R2 = 0.28 vs. R2 = 0.04), BSA (R2 = 0.29 vs. R2 = 0.03), and SCr (R2 = 0.51 vs. R2 = 0.28). In a multivariate regression analysis performed by entering T1/2(SCr) as dependent variable and following a forward stepwise method, cold ischemia time (CIT) (P = 0.027) but not PDM (P = 0.195) reached significance. In a Cox regression analysis carried out with T1/2(SCr) as dependent variable, neither CIT nor PDM gained significance. This study suggests that PDM does not affect early graft function in pediatric kidney recipients.
Conspectus Intron removal from premature-mRNA (pre-mRNA splicing) is an essential part of gene expression and regulation that is required for the production of mature, protein-coding mRNA. The ...spliceosome (SPL), a majestic machine composed of five small nuclear RNAs and hundreds of proteins, behaves as an eminent transcriptome tailor, efficiently performing splicing as a protein-directed metallo-ribozyme. To select and excise long and diverse intronic sequences with single-nucleotide precision, the SPL undergoes a continuous compositional and conformational remodeling, forming eight distinct complexes throughout each splicing cycle. Splicing fidelity is of paramount importance to preserve the integrity of the proteome. Mutations in splicing factors can severely compromise the accuracy of this machinery, leading to aberrant splicing and altered gene expression. Decades of biochemical and genetic studies have provided insights into the SPL’s composition and function, but its complexity and plasticity have prevented an in-depth mechanistic understanding. Single-particle cryogenic electron microscopy techniques have ushered in a new era for comprehending eukaryotic gene regulation, providing several near-atomic resolution structures of the SPL from yeast and humans. Nevertheless, these structures represent isolated snapshots of the splicing process and are insufficient to exhaustively assess the function of each SPL component and to unravel particular facets of the splicing mechanism in a dynamic environment. In this Account, building upon our contributions in this field, we discuss the role of biomolecular simulations in uncovering the mechanistic intricacies of eukaryotic splicing in health and disease. Specifically, we showcase previous applications to illustrate the role of atomic-level simulations in elucidating the function of specific proteins involved in the architectural reorganization of the SPL along the splicing cycle. Moreover, molecular dynamics applications have uniquely contributed to decrypting the channels of communication required for critical functional transitions of the SPL assemblies. They have also shed light on the role of carcinogenic mutations in the faithful selection of key intronic regions and the molecular mechanism of splicing modulators. Additionally, we emphasize the role of quantum-classical molecular dynamics in unraveling the chemical details of pre-mRNA cleavage in the SPL and in its evolutionary ancestors, group II intron ribozymes. We discuss methodological pitfalls of multiscale calculations currently used to dissect the splicing mechanism, presenting future challenges in this field. The results highlight how atomic-level simulations can enrich the interpretation of experimental results. We envision that the synergy between computational and experimental approaches will aid in developing innovative therapeutic strategies and revolutionary gene modulation tools to fight the over 200 human diseases associated with splicing misregulation, including cancer and neurodegeneration.
The spliceosome accurately promotes precursor messenger-RNA splicing by recognizing specific noncoding intronic tracts including the branch point sequence (BPS) and the 3'-splice-site (3'SS). ...Mutations of Hsh155 (yeast)/SF3B1 (human), which is a protein of the SF3b factor involved in BPS recognition and induces altered BPS binding and 3'SS selection, lead to mis-spliced mRNA transcripts. Although these mutations recur in hematologic malignancies, the mechanism by which they change gene expression remains unclear. In this study, multi-microsecond-long molecular-dynamics simulations of eighth distinct ∼700,000 atom models of the spliceosome Bact complex, and gene sequencing of SF3B1, disclose that these carcinogenic isoforms destabilize intron binding and/or affect the functional dynamics of Hsh155/SF3B1 only when binding non-consensus BPSs, as opposed to the non-pathogenic variants newly annotated here. This pinpoints a cross-talk between the distal Hsh155 mutation and BPS recognition sites. Our outcomes unprecedentedly contribute to elucidating the principles of pre-mRNA recognition, which provides critical insights on the mechanism underlying constitutive/alternative/aberrant splicing.
Summary
The CCR5 gene encodes a cell‐surface chemokine receptor molecule that serves as a co‐receptor for macrophage‐tropic strains of human immunodeficiency virus type 1 (HIV‐1). A mutation in this ...gene may alter the expression or the function of the protein product, thereby altering chemokine binding and/or signalling or HIV‐1 infection of cells that normally express CCR5 protein. Individuals homozygous for a 32‐bp deletion allele of CCR5 (CCR5 Δ32), heritable as a Mendelian trait, are relatively resistant to HIV‐1 infection. The CCR5 Δ32 mutation is present in the Caucasian population at different frequencies. The aim of this study was to investigate the frequency of truncated alleles of the CCR5 Δ32 gene in a Sicilian population, as the interpopulation variation in CCR5 Δ32 frequency may be a significant factor in the prediction of AIDS endemicity in future studies. We examined 901 healthy individuals from several Sicilian provinces. We found a mean (± standard deviation) Δ32 allele frequency (fr) of 0.04 ± 0.012. The highest value was observed in the province of Messina, with a mean Δ32 allele frequency of 0.06 ± 0.024, where we collected samples from a cohort of 114 HIV‐1‐infected individuals. The observed frequency amongst these patients was quite low (fr = 0.03 ± 0.031) compared to the healthy population, although the difference was not statistically significant.
The CCR5 gene encodes a cell-surface chemokine receptor molecule that serves as a co-receptor for macrophage-tropic strains of human immunodeficiency virus type 1 (HIV-1). A mutation in this gene may ...alter the expression or the function of the protein product, thereby altering chemokine binding and/or signalling or HIV-1 infection of cells that normally express CCR5 protein. Individuals homozygous for a 32-bp deletion allele of CCR5 (CCR5 delta32), heritable as a Mendelian trait, are relatively resistant to HIV-1 infection. The CCR5 delta32 mutation is present in the Caucasian population at different frequencies. The aim of this study was to investigate the frequency of truncated alleles of the CCR5 delta32 gene in a Sicilian population, as the interpopulation variation in CCR5 delta32 frequency may be a significant factor in the prediction of AIDS endemicity in future studies. We examined 901 healthy individuals from several Sicilian provinces. We found a mean (+/- standard deviation) delta32 allele frequency (fr) of 0.04 +/- 0.012. The highest value was observed in the province of Messina, with a mean delta32 allele frequency of 0.06 +/- 0.024, where we collected samples from a cohort of 114 HIV-1-infected individuals. The observed frequency amongst these patients was quite low (fr = 0.03 +/- 0.031) compared to the healthy population, although the difference was not statistically significant.
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