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Background: Lynch syndrome is a hereditary disorder, with a very high risk of developing colorectal carcinoma (CRC) and a predilection to develop other cancers, including upper tract urothelial carcinoma (UTUC). We aimed to assess the prevalence of UTUC in a Lynch syndrome cohort undergoing screening for CRC, to determine the need for a UTUC screening programme.Methods: Lynch syndrome patients were screened with urine dipstick for microscopic haematuria. Patients with confirmed microhaematuria were offered urine cytology, microscopy and culture, ultrasound (US) of their upper tracts and flexible cystoscopy.Results: Of the 89 patients screened, 86 had an MLH1 mutation and two had an MSH2 mutation. Eleven of the 12 patients who had microscopic haematuria were female. Ten patients had urinary tract infections. One patient had follicular cystitis and another had a simple renal cyst. No patients had hydronephrosis on ultrasound. All urine cytology specimens were negative for malignancy.Conclusion: No cases of UTUC were detected in our cohort during this study. A more rational screening protocol in this group may be to screen patients for UTUC with known MSH2 mutations at an earlier age (over 35).

Background: Flexible ureteroscopy (FURS) and laser lithotripsy for ureteric and renal calculi requires adequate irrigation for visualisation. This study aimed to evaluate how bolus administration of irrigant fluid impacts intrarenal pressure (IRP) during FURS. We also investigated how ureteral access sheaths (UAS) of varying sizes mitigate elevated IRP. Methods: Using a porcine cadaveric model, IRP was evaluated using an arterial invasive pressure measurement system. Given a fluid column height (driving force) of 80 cm H2O, and varying bolus administration (1, 2, 3, 5, 10 ml), IRP was studied with and without a UAS. An IRP of < 40 mmHg was considered the cut off for “safe” FURS. The flow (drainage capacity) of UAS was also evaluated. At varying fluid column heights, three sizes of UAS were used, 10/12 French size (Fr), 11/13 Fr and 12/14 Fr, all 36 cm long. Results: Bolus administration with a UAS of < 5 ml with a starting fluid column height of 80 cm H2O was “safe” (< 40 mmHg). In contrast, where no UAS was used, bolus sizes as small as 2 ml produced “unsafe” peak pressures. The flow through a 10/12 Fr UAS was poor but improved greatly with larger UAS diameters. Conclusion: This study suggests that 10/12 Fr UAS may be inadequate to maintain drainage from the kidney at acceptable pressures. Bolus fluid administration produces “unsafe” (> 40 mmHg) elevated IRP in the absence of a UAS. When a UAS is used, a fluid bolus of < 5 ml is likely “safe”.

Background: Idiopathic hyperoxaluria is a risk factor for developing calcium oxalate nephrolithiasis. Dietary oxalate’s effect on urinary oxalate is not well studied. The aim of this study is to assess the effect of advice focused on reducing dietary oxalate in a cohort of idiopathic hyperoxaluric patients. Methods: Patients referred to the Groote Schuur Hospital Stone Clinic from 2015 to 2017 were considered eligible, if they were an idiopathic hyperoxaluric stone former, excreting > 40 mg/d of urinary oxalate on a pre-intervention 24-hour stone study urinalysis. Patients were asked to adhere to a diet sheet which included general stone prevention advice (low salt diet, increased fluid intake and moderate protein intake) and specific low oxalate diet advice. A post-intervention 24-hour urinalysis was performed at six weeks. Results: Nineteen patients had hyperoxaluria (eight men and 11 women) with a mean age of 49 years (range 25–76 years). The mean BMI of the group was 28.4 kg/m2 (17.4–50). All patients had mean number of 1.9 range prior stone episodes (range 1–6 stone episodes). Fourteen (14/19) patients completed the study. The mean pre-dietary advice urinary oxalate was 53.2 mg/24 hours (n = 14), SD while the post-intervention was 29.6 mg/24 hours SD (p = 0.0002). Only 3/14 patients who completed the assessment failed to normalise their urinary oxalate on the diet. Conclusion: In the stone clinic setting, general advice of low salt diet, increased water intake, moderate protein intake and specific oxalate restriction can significantly reduce oxalate excretion in hyperoxaluric stone formers. Sustained reduction of oxalate excretion and longitudinal clinical benefit are worthy of study in larger cohorts.

Altres ajuts: This work was generated within the European Reference Network on Rare Hematological Diseases (ERN-EuroBloodNet) - FPA No. 739541 Hereditary spherocytosis (HS) originates from defective anchoring of the cytoskeletal network to the transmembrane protein complexes of the red blood cell (RBC). Red cells in HS are characterized by membrane instability and reduced deformability and there is marked heterogeneity in disease severity among patients. To unravel this variability in disease severity, we analyzed blood samples from 21 HS patients with defects in ankyrin, band 3, á-spectrin or β-spectrin using red cell indices, eosin-5- maleimide binding, microscopy, the osmotic fragility test, Percoll density gradients, vesiculation and ektacytometry to assess cell membrane stability, cellular density and deformability. Reticulocyte counts, CD71 abundance, band 4.1 a:b ratio, and glycated hemoglobin were used as markers of RBC turnover. We observed that patients with moderate/severe spherocytosis have short-living erythrocytes of low density and abnormally high intercellular heterogeneity. These cells show a prominent decrease in membrane stability and deformability and, as a consequence, are quickly removed from the circulation by the spleen. In contrast, in mild spherocytosis less pronounced reduction in deformability results in prolonged RBC lifespan and, hence, cells are subject to progressive loss of membrane. RBC from patients with mild spherocytosis thus become denser before they are taken up by the spleen. Based on our findings, we conclude that RBC membrane loss, cellular heterogeneity and density are strong markers of clinical severity in spherocytosis.

Summary CD81 is a major receptor for Hepatitis C Virus (HCV). It belongs to the tetraspanin family whose members form dynamic clusters with numerous partner proteins and with one another, forming tetraspanin‐enriched areas in the plasma membrane. In our study, we combined single‐molecule microscopy and biochemistry experiments to investigate the clustering and membrane behaviour of CD81 in the context of cells expressing EWI‐2wint, a natural inhibitor of HCV entry. Interestingly, we found that EWI‐2wint reduces the global diffusion of CD81 molecules due to a decrease of the diffusion rate of mobile CD81molecules and an increase in the proportion of confined molecules. Indeed, we demonstrated that EWI‐2wint promotes CD81 clustering and confinement in CD81‐enriched areas. In addition, we showed that EWI‐2wint influences the colocalization of CD81 with Claudin‐1 – a co‐receptor required for HCV entry. Together, our results indicate that a change in membrane partitioning of CD81 occurs in the presence of EWI‐2wint. This study gives new insights on the mechanism by which HCV enters into its target cells, namely by exploiting the dynamic properties of CD81.