Posterior shoulder instability following anatomic total shoulder arthroplasty: A case report and review of management

We report a case of posterior shoulder instability following anatomic total shoulder arthroplasty (TSA). In addition, we present guidelines to aid in the management of posterior instability after TSA. A 50-year-old male underwent anatomic TSA for glenohumeral osteoarthritis. Postoperatively, the patient developed posterior instability secondary to glenoid retroversion. He did not improve despite conservative treatment. He underwent an arthroscopic posterior bone block procedure, 4-month after his index arthroplasty. At 14-month follow-up, the patient had regained near full motion and strength, and radiographs demonstrated osseous integration with no evidence of component loosening. Posterior instability following TSA is a relatively rare complication and challenging to manage. The posterior, arthroscopic iliac crest bone block grafting procedure represents a treatment option for posterior instability in the setting of a stable glenoid prosthesis following TSA.     

Hypermethylation of the CDKN2/p16 promoter during neoplastic progression in Barrett's esophagus

Background & Aims: Inactivation of the CDKN2/p16^INK4A tumor-suppressor gene is one of the most frequent genetic alterations in human malignancies. In esophageal adenocarcinomas, mutations of the p16 gene or homozygous deletions of the gene locus 9p21 are rare. This study investigated whether p16 promoter hypermethylation is an alternative mechanism for p16 gene inactivation during neoplastic progression in Barrett's esophagus. Methods: A methylation-specific polymerase chain reaction protocol was applied. A total of 95 specimens from 14 patients with Barrett's esophagus were analyzed longitudinally. The p16 promoter status was compared with histomorphological findings. Results: p16 promoter hypermethylation was detected in 9 of the 10 patients who had displayed dysplasia at some time during surveillance, whereas none of the patients who had not displayed dysplasia during surveillance had p16 promoter hypermethylation. p16 promoter hypermethylation was detected in 3% (2 of 67) of the samples without dysplasia, 60% (3 of 5) of the samples with lesions indefinite for dysplasia, 55.6% (10 of 18) of the specimens with low-grade dysplasia, and 75% (3 of 4) of the specimens with high-grade dysplasia. Conclusions: These data suggest that p16 promoter hypermethylation is a common mechanism of p16 gene inactivation during neoplastic progression in Barrett's esophagus.GASTROENTEROLOGY 1998;115:1381-1386     

Wound healing and all‐cause mortality in 958 wound patients treated in home care

Skin wounds are associated with significant morbidity and mortality. Data are, however, not readily available for benchmarking, to allow prognostic evaluation, and to suggest when involvement of wound‐healing experts is indicated. We, therefore, conducted an observational cohort study to investigate wound healing and all‐cause mortality associated with different types of skin wounds. Consecutive skin wound patients who received wound care by home‐care nurses from January 2010 to December 2011 in a district in Eastern Denmark were included in this study. Patients were followed until wound healing, death, or the end of follow‐up on December 2012. In total, 958 consecutive patients received wound care by home‐care nurses, corresponding to a 1‐year prevalence of 1.2% of the total population in the district. During the study, wound healing was achieved in 511 (53.3%), whereas 90 (9.4%) died. During the first 3 weeks of therapy, healing was most likely to occur in surgical wounds (surgical vs. other wounds: adjusted hazard ratio [AHR] 2.21, 95% confidence interval 1.50–3.23), while from 3 weeks to 3 months of therapy, cancer wounds, and pressure ulcers were least likely to heal (cancer vs. other wounds: AHR 0.12, 0.03–0.50; pressure vs. other wounds: AHR 0.44, 0.27–0.74). Cancer wounds and pressure ulcers were further associated with a three times increased probability of mortality compared with other wounds (cancer vs. other wounds: AHR 3.19, 1.35–7.50; pressure vs. other wounds: AHR 2.91, 1.56–5.42). In summary, the wound type was found to be a significant predictor of healing and mortality with cancer wounds and pressure ulcers being associated with poor prognosis.     

Negative selection on human genes underlying inborn errors depends on disease outcome and both the mode and mechanism of inheritance

Genetic variants underlying life-threatening diseases, being unlikely to be transmitted to the next generation, are gradually and selectively eliminated from the population through negative selection. We study the determinants of this evolutionary process in human genes underlying monogenic diseases by comparing various negative selection scores and an integrative approach, CoNeS, at 366 loci underlying inborn errors of immunity (IEI). We find that genes underlying autosomal dominant (AD) or X-linked IEI have stronger negative selection scores than those underlying autosomal recessive (AR) IEI, whose scores are not different from those of genes not known to be disease causing. Nevertheless, genes underlying AR IEI that are lethal before reproductive maturity with complete penetrance have stronger negative selection scores than other genes underlying AR IEI. We also show that genes underlying AD IEI by loss of function have stronger negative selection scores than genes underlying AD IEI by gain of function, while genes underlying AD IEI by haploinsufficiency are under stronger negative selection than other genes underlying AD IEI. These results are replicated in 1,140 genes underlying inborn errors of neurodevelopment. Finally, we propose a supervised classifier, SCoNeS, which predicts better than state-of-the-art approaches whether a gene is more likely to underlie an AD or AR disease. The clinical outcomes of monogenic inborn errors, together with their mode and mechanisms of inheritance, determine the levels of negative selection at their corresponding loci. Integrating scores of negative selection may facilitate the prioritization of candidate genes and variants in patients suspected to carry an inborn error.

Negative (or purifying) selection is the natural process by which deleterious alleles are selectively purged from the population (1). In diploid species, the strength of negative selection at a given locus is predicted to increase with decreasing fitness and increasing dominance of the genetic variants controlling traits: Variation causing early death in the heterozygous state are the least likely to be transmitted to the next generation, as their carriers have fewer offspring than noncarriers (2). Human genetic variants that cause severe diseases are, thus, expected to be the primary targets of negative selection, particularly for diseases affecting heterozygous individuals. In humans, several studies have ranked protein-coding genes according to their levels of negative selection (3–5). Nevertheless, the extent to which negative selection affects human disease-causing genes, and the factors determining its strength, remain largely unknown, particularly because our knowledge of the severity, mode, and mechanism of inheritance of the corresponding human diseases remains incomplete (3, 6–8).The strength of negative selection at a given gene has been traditionally approximated by comparing the coding sequence of the gene in a given species with that of one or several closely related species; it depends on the proportion of amino acid changes that have accumulated during evolution (9–11). With the advent of high-throughput sequencing, intraspecies metrics have been developed, based on the comparison of the probability of predicted loss-of-function (pLOF) mutations for a gene under a random model with the frequency of pLOF mutations observed in population databases (5, 12, 13), which capture the species-specific evolution of genes. Using an interspecies-based method and a hand-curated version of the Online Mendelian Inheritance in Man (hOMIM) database, a previous study elegantly showed that most human genes for which mutations cause highly penetrant diseases, including autosomal dominant (AD) diseases in particular, evolve under stronger negative selection than genes associated with complex disorders (6). However, other studies based on OMIM genes have reported conflicting results (3, 14–17), probably due to the incompleteness and heterogeneity of the datasets used. Moreover, no study has yet addressed this problem with intraspecies metrics, even though it has been suggested that the choice of the reference species for interspecies metrics contributes to discrepancies across studies (6).We aimed to improve the identification of the drivers of negative selection acting on human disease-causing genes, by developing a negative selection score combining several informative intraspecies and interspecies statistics, focusing on inborn errors of immunity (IEI). IEI, previously known as primary immunodeficiencies (18), are genetic diseases that disrupt the development or function of human immunity. They form a large and expanding group of genetic diseases that has been widely studied, and they are well characterized physiologically (immunologically) and phenotypically (clinically) (19–21). IEI are often symptomatic in early childhood, and at least until the turn of the 20th century and the introduction of antibiotics, most individuals with IEI probably died before reaching reproductive maturity. Accordingly, IEI genes have probably been under strong negative selection from the dawn of humankind until very recently. In this study, we investigated whether the severity of IEI and their mode and mechanism of inheritance have left signatures of negative selection of various intensities in the corresponding human genes. Furthermore, we validated our model on genes underlying inborn errors of neurodevelopment (IEND), another group of well-characterized severe genetic diseases.     

Immune response to capsular polysaccharide and surface proteins of Streptococcus pneumoniae in patients with invasive pneumococcal disease

The immune response to pneumococcal capsular polysaccharides (CPSs) and to the pneumococcal surface proteins cell wall-associated serine proteinase A (PrtA), pneumococcal surface protein A (PspA), and Streptococcus pneumoniae pullulanase A was evaluated in 45 patients with invasive pneumococcal disease compared with healthy adults. In serum from patients with meningitis and pneumonia, CPS antibody levels were low, compared with healthy adults; antibody levels did not differ between groups and did not change between phases. Levels of immunoglobulin G directed against the investigated pneumococcal surface proteins in patients with invasive pneumococcal disease were in the same range as in healthy adults. However, median PrtA and PspA antibody levels tended to increase during early convalescent phase. Low levels of CPS antibody, rather than of antibodies directed against the pneumococcal surface proteins, may predispose to invasive pneumococcal infection.     

Targeting Notch signaling in autoimmune and lymphoproliferative disease

Patients with autoimmune lymphoproliferative syndrome (ALPS) and systemic lupus erythematosis (SLE) have T-cell dysregulation and produce abnormal, activated T lymphocytes and an atypical peripheral T-cell population, termed double negative T cells (DNTs). T-cell functions, including DNT transition in T-cell development and T-cell activation, are critically dependent on Notch signaling. We hypothesized that inhibiting Notch signaling would be effective in ALPS and SLE by reducing the production of abnormal DNTs and by blocking aberrant T-cell activation. We tested this hypothesis using murine models of ALPS and SLE. Mice were randomized to treatment with the notch pathway inhibitor (gamma-secretase inhibitor), N-S-phenyl-glycine-t-butyl ester (DAPT), or vehicle control. Response to treatment was assessed by measurement of DNTs in blood and lymphoid tissue, by monitoring lymph node and spleen size with ultrasound, by quantifying cytokines by bead-array, by ELISA for total IgG and anti-double-stranded DNA (dsDNA) specific antibodies, and by histopathologic assessment for nephritis. We found a profound and statistically significant decrease in all disease parameters, comparing DAPT-treated mice to controls. Using a novel dosing schema, we avoided the reported toxicities of gamma-secretase inhibitors. Inhibiting the Notch signaling pathway may thus present an effective, novel, and well-tolerated treatment for autoimmune and lymphoproliferative diseases.