Nummular keratopathy in a patient with Hyper-IgD Syndrome

<p>Abstract</p> <p>Purpose</p> <p>To report a case of recurrent nummular keratitis in a pediatric patient with Hyperimmunoglobulinemia D syndrome.</p> <p>Methods</p> <p>A retrospective chart review.</p> <p>Results</p> <p>A 14-year-old boy with Hyperimmunoglobulinemia D syndrome (HIDS) presented with photophobia and ocular irritation concomitant with disease exacerbation. He was found on exam to have significant nummular keratitis, which responded to a short course of topical steroids. Despite acute response to local immunosuppression, the patient had several recurrent attacks and eventually developed a large corneal scar and decreased vision. After initiation of infliximab therapy his ocular sequelae improved dramatically and his vision returned to 20/20.</p> <p>Conclusion</p> <p>One possible form of end-organ damage associated with HIDS is vision threatening nummular keratopathy.</p

Impact of Preoperative Chemotherapy Features on Patient Outcomes after Hepatectomy for Initially Unresectable Colorectal Cancer Liver Metastases: A LiverMetSurvey Analysis

Background: Prognostic factors have been extensively reported after resection of colorectal liver metastases (CLM); however, specific analyses of the impact of preoperative systemic anticancer therapy (PO-SACT) features on outcomes is lacking. Methods: For this real-world evidence study, we used prospectively collected data within the international surgical LiverMetSurvey database from all patients with initially-irresectable CLM. The main outcome was Overall Survival (OS) after surgery. Disease-free (DFS) and hepatic-specific relapse-free survival (HS-RFS) were secondary outcomes. PO-SACT features included duration (cumulative number of cycles), choice of the cytotoxic backbone (oxaliplatin- or irinotecan-based), fluoropyrimidine (infusional or oral) and addition or not of targeted monoclonal antibodies (anti-EGFR or anti-VEGF). Results: A total of 2793 patients in the database had received PO-SACT for initially irresectable diseases. Short (<7 or <13 cycles in 1st or 2nd line) PO-SACT duration was independently associated with longer OS (HR: 0.85 p = 0.046), DFS (HR: 0.81; p = 0.016) and HS-RFS (HR: 0.80; p = 0.05). All other PO-SACT features yielded basically comparable results. Conclusions: In this international cohort, provided that PO-SACT allowed conversion to resectability in initially irresectable CLM, surgery performed as soon as technically feasible resulted in the best outcomes. When resection was achieved, our findings indicate that the choice of PO-SACT regimen had a marginal if any, impact on outcomes.info:eu-repo/semantics/publishedVersio

Cryptosporidium parvum, a potential cause of colic adenocarcinoma

<p>Abstract</p> <p>Background</p> <p>Cryptosporidiosis represents a major public health problem. This infection has been reported worldwide as a frequent cause of diarrhoea. Particularly, it remains a clinically significant opportunistic infection among immunocompromised patients, causing potentially life-threatening diarrhoea in HIV-infected persons. However, the understanding about different aspects of this infection such as invasion, transmission and pathogenesis is problematic. Additionally, it has been difficult to find suitable animal models for propagation of this parasite. Efforts are needed to develop reproducible animal models allowing both the routine passage of different species and approaching unclear aspects of <it>Cryptosporidium </it>infection, especially in the pathophysiology field.</p> <p>Results</p> <p>We developed a model using adult severe combined immunodeficiency (SCID) mice inoculated with <it>Cryptosporidium parvum </it>or <it>Cryptosporidium muris </it>while treated or not with Dexamethasone (Dex) in order to investigate divergences in prepatent period, oocyst shedding or clinical and histopathological manifestations. <it>C. muris</it>-infected mice showed high levels of oocysts excretion, whatever the chemical immunosuppression status. Pre-patent periods were 11 days and 9.7 days in average in Dex treated and untreated mice, respectively. Parasite infection was restricted to the stomach, and had a clear preferential colonization for fundic area in both groups. Among <it>C. parvum</it>-infected mice, Dex-treated SCID mice became chronic shedders with a prepatent period of 6.2 days in average. <it>C. parvum</it>-inoculated mice treated with Dex developed glandular cystic polyps with areas of intraepithelial neoplasia, and also with the presence of intramucosal adenocarcinoma.</p> <p>Conclusion</p> <p>For the first time <it>C. parvum </it>is associated with the formation of polyps and adenocarcinoma lesions in the gut of Dex-treated SCID mice. Additionally, we have developed a model to compare chronic <it>muris </it>and <it>parvum </it>cryptosporidiosis using SCID mice treated with corticoids. This reproducible model has facilitated the evaluation of clinical signs, oocyst shedding, location of the infection, pathogenicity, and histopathological changes in the gastrointestinal tract, indicating divergent effects of Dex according to <it>Cryptosporidium </it>species causing infection.</p

Pediatr Nephrol

BACKGROUND: Distal renal tubular acidosis (dRTA), due to impaired acid secretion in the urine, can lead to severe long-term consequences. Standard of care (SoC) oral alkalizers, requiring several daily intakes, are currently used to restore normal plasma bicarbonate levels. A new prolonged-release formulation, ADV7103, has been developed to achieve a sustained effect with an improved dosing scheme. METHODS: In a multicenter, open-label, non-inferiority trial (n = 37), patients with dRTA were switched from SoC to ADV7103. Mean plasma bicarbonate values and proportion of responders during steady state therapy with both treatments were compared, as were other blood and urine parameters, as well as acceptability, tolerability, and safety. RESULTS: When switching from SoC to ADV7103, the number of daily intakes was reduced from a median of three to twice daily. Mean plasma bicarbonate was increased and non-inferiority of ADV7103 was demonstrated (p < 0.0001, per protocol), as was statistical superiority (p = 0.0008, intention to treat [ITT]), and the response rate increased from 43 to 90% with ADV7103 (p < 0.001, ITT). Urine calcium/citrate ratio was reduced below the threshold for risk of lithogenesis with ADV7103 in 56% of previously non-responders with SoC (p = 0.021, ITT). Palatability was improved (difference [95% CI] of 25 [10.7, 39.2] mm) and gastrointestinal discomfort was reduced (difference [95% CI] of - 14.2 [- 25.9, - 2.6] mm) with ADV7103. CONCLUSIONS: Plasma bicarbonate levels and response rate were significantly higher with ADV7103 than with SoC. Urine calcium/citrate ratio, palatability, and gastrointestinal safety were significantly improved, supporting the use of ADV7103 as first-line treatment for dRTA. TRIAL REGISTRATION: Registered as EudraCT 2013-002988-25 on the 1st July 2013 Graphical abstract

Normalised intrinsic mortality risk in liver transplantation: European Liver Transplant Registry study

Background No model exists for liver transplantation to estimate the mortality risk in a given patient, and no standard by which to assess performance in different centres. We investigated the intrinsic mortality risk in the absence of known mortality risk factors, Methods We identified mortality risk factors and risk ratios quantified in data from the European Liver Transplant Registry (22 089 patients at 102 centres in 18 countries) registered from 1988 to 1997. To develop a model of the intrinsic risk and the risk ratios for specific factors, univariate and multivariate analyses were done separately for the overall population, for adults, and for children younger than 15 years, and the number of deaths were estimated, We validated the model by comparing mortality in patients without risk factors with the model-adjusted mortality in patients with risk factors. Findings Overall 5-year and 8-year actuarial survival was 66% (95% CI 65-66) and 61% (60-62). 65% of deaths occurred within 6 months, Retransplantation, transplantation for cancer, acute liver failure, fewer than 20 split-liver grafts per year, and a centre workload of fewer than 25 transplants per year were the main risk factors of 12 identified factors, 1-year and 5-year death rates among adults with no risk factors were similar to model estimates (15 [13-16] vs 14% [13-15], and 22 (20-24) vs 23% [21-24]). Corresponding data for paediatric transplants were 9% (7-12) compared with 11% (9-12) and 13% (10-17) compared with 14% (11-16). The reduction of mortality risk in high-volume centres was even greater in patients without risk factors (48 vs 23%, p<0.001). Interpretation The normalised intrinsic mortality risk can be combined with the relative risk ratios of known risk factors to better estimate the mortality risk of a given procedure in a given patient. Centres can assess performance by removing potential bias of donor and recipient selection

QM/MM calculations with deMon2k

The density functional code deMon2k employs a fitted density throughout (Auxiliary Density Functional Theory), which offers a great speed advantage without sacrificing necessary accuracy. Powerful Quantum Mechanical/Molecular Mechanical (QM/MM) approaches are reviewed. Following an overview of the basic features of deMon2k that make it efficient while retaining accuracy, three QM/MM implementations are compared and contrasted. In the first, deMon2k is interfaced with the CHARMM MM code (CHARMM-deMon2k); in the second MM is coded directly within the deMon2k software; and in the third the Chemistry in Ruby (Cuby) wrapper is used to drive the calculations. Cuby is also used in the context of constrained-DFT/MM calculations. Each of these implementations is described briefly; pros and cons are discussed and a few recent applications are described briefly. Applications include solvated ions and biomolecules, polyglutamine peptides important in polyQ neurodegenerative diseases, copper monooxygenases and ultra-rapid electron transfer in cryptochromes

C5 nephritic factors drive the biological phenotype of C3 glomerulopathies

C3 Glomerulopathies, which include Dense Deposit Disease and C3 Glomerulonephritis, are associated with genetic and acquired dysregulation of the C3 convertase alternative pathway of complement. The potential role of the activation of the C5 convertase has not been studied extensively. Here we analyzed IgG samples from patients with C3 Glomerulopathies to identify circulating autoantibodies that stabilize the C3 alternative pathway (C3 Nephritic Factors) as well as C5 convertases (C5 Nephritic Factors), thus preventing decay of these enzyme complexes. Rare variants in alternative pathway genes were found in 28 of 120 tested patients. C3 and C5 Nephritic Factors were found in 76 of 101 (75%) and 29 of 59 (49%) of the patients, respectively. Therefore, we compared the results of the assays for the C3 and C5 nephritic factors functional activity: 29% were positive for C3 Nephritic Factors alone, 39% were positive for both C3 and C5 Nephritic Factors, and 10% were positive for C5 Nephritic Factors alone. We found that the addition of properdin-enhanced stabilization of C3 convertase in the presence of IgG doubly positive for both Nephritic Factors, while it did not modify the stabilization mediated by IgG solely positive for C3 Nephritic Factors. Both C3 and C5 Nephritic Factors correlated with C3 consumption, while only C5 Nephritic Factors correlated with sC5b9 levels. C5 Nephritic Factors-positive patients were more likely to have C3 Glomerulonephritis than Dense Deposit Disease. Thus, dysregulation of the C5 convertase contributes to C3 Glomerulopathies inter-disease differences and may have direct therapeutic implications