The Vici syndrome protein EPG5 regulates intracellular nucleic acid trafficking linking autophagy to innate and adaptive immunity.

Vici syndrome is a human inherited multi-system disorder caused by recessive mutations in EPG5, encoding the EPG5 protein that mediates the fusion of autophagosomes with lysosomes. Immunodeficiency characterized by lack of memory B cells and increased susceptibility to infection is an integral part of the condition, but the role of EPG5 in the immune system remains unknown. Here we show that EPG5 is indispensable for the transport of the TLR9 ligand CpG to the late endosomal-lysosomal compartment, and for TLR9-initiated signaling, a step essential for the survival of human memory B cells and their ultimate differentiation into plasma cells. Moreover, the predicted structure of EPG5 includes a membrane remodeling domain and a karyopherin-like domain, thus explaining its function as a carrier between separate vesicular compartments. Our findings indicate that EPG5, by controlling nucleic acids intracellular trafficking, links macroautophagy/autophagy to innate and adaptive immunity.

Hyperinsulinism reduction associated with icodextrin treatment in continuous ambulatory peritoneal dialysis patients.

Glucose absorption from peritoneal dialysis solutions causes a chronic stimulation of insulin secretion, which leads to hyperinsulinism. The use of solutions without glucose should correct this metabolic derangement together with the associated cardiovascular risk. To verify this hypothesis, we studied the entire non diabetic continuous ambulatory peritoneal dialysis (CAPD) population of our center: 27 patients with a mean age of 62 +/- 15 years, and a median 17 months on treatment. Morning fasting serum insulin was 32.8 +/- 9.3 microU/mL; glucose, 104.4 +/- 21.8 mg/dL; triglycerides, 162.4 +/- 125.7 mg/dL; cholesterol, 221.9 +/- 54.7 mg/dL; intact parathyroid hormone (iPTH), 212 +/- 189 pg/mL; fibrinogen, 519 +/- 112 mg/dL; body mass index, 24.1 +/- 4.1; and daily erythropoietin subcutaneous therapy dose, 17 +/- 6 U/kg. Insulin sensitivity, measured as ISI-HOMA (insulin sensitivity index, derived from the homeostasis model assessment) was 2.4 +/- 0.7. Daily glucose load, calculated from dialytic schedules, was 135 +/- 38 g. Of the 27 patients, 12 were treated with standard glucose solutions during the day and with one icodextrin dwell during the night for a median of 9 months (range: 1-28). The remaining 15 patients were treated with standard glucose solutions. The icodextrin group showed significantly lower serum insulin levels (28.6 +/- 6.0 microU/mL vs 36.1 +/- 10.2 microU/mL, p = 0.021) and significantly higher ISI-HOMA values (2.7 +/- 0.5 vs 2.2 +/- 0.7, p = 0.041) than the control group. The two groups showed no significant differences for glucose, triglycerides, cholesterol, iPTH, fibrinogen, body mass index, or erythropoietin therapy dose. Daily glucose load was lower in the icodextrin group, but without reaching statistical significance (128 +/- 31 g vs 142 +/- 43 g). This study shows, in a preliminary way, that the chronic use of icodextrin in the long nighttime dwell can reduce serum insulin levels and increase insulin sensitivity in CAPD patients.

[Vulvar lesions caused by HPV]. / Lesioni vulvari da HPV.

Human papillomavirus subclinical lesions are well known on the cervix and are identified by colposcopy after acetic acid staining. The transfer of this technique from the cervix to the vulva has led to the identification of areas of white epithelial changes which have been defined by similarity as vulvar subclinical HPV (VSHPV) lesions. A critical revision of the different clinical VSHPV lesions classifications, the vulvar diagnostic role of acetic acid staining, the natural history of HPV infection and the histological-biomolecular diagnostic techniques has the authors to the conclusions that the majority of the "so called" VSHPV lesions should not be considered a real disease. The presence of HPV-DNA in these subclinical lesions should be considered causal and not causal. To avoid overtreatments in women with proven HPV-DNA positivity without macroscopic clinical lesions, the authors recommend to abandon the acetic acid staining on the vulva and invite to consider the VSHPV lesions a faked diagnosis and not a clinical entity.

A proposed glossary of terminology related to the surgical treatment of vulvar carcinoma.

BACKGROUND: The authors' objective was to provide a glossary of terminology related to the surgical treatment of invasive vulvar carcinoma. There is currently no consensus in the literature regarding the names of the surgical procedures used to treat this disease. METHODS: A surgical glossary should be supported by clear definitions and acceptance of notions related to topographic anatomy that are specific to the surgical practice. A critical review of the classic, chiefly used Italian, French, German, and English textbooks of anatomy revealed some discrepancies and lack of uniformity in descriptions of vulvar and inguinal fascial structures and lymph nodes, which represent the principal landmarks of surgical treatment. In the proposed glossary, the descriptions of these anatomic landmarks integrate classic anatomic knowledge, data from recent gynecologic studies of inguinal anatomy, and the clinical experiences of the authors. RESULTS: The glossary is composed of 16 surgical definitions, which are divided into 3 main sections of terminology describing the surgical treatment of the: 1) vulva, 2) inguinal lymph nodes, and 3) pelvic lymph nodes. The fundamental objective behind the glossary is to describe the area and the depth of the surgical procedure. Three determinants of the area (local, partial, and total) and three determinants of the depth of surgery (superficial, simple, and deep) were used to arrive at the fully articulated definitions in the glossary. CONCLUSIONS: The authors are aware that the proposed glossary should not be considered a definitive one; however, it could serve as a good basis for further debate. The terms employed in the glossary are accompanied by anatomic and descriptive references to help avoid confusion and promote better understanding among gynecologic oncologists who are involved in the treatment of vulvar carcinoma.

Clinical validation of PD Adequest software: modeling error assessment.

OBJECTIVE: PD ADEQUEST software (Baxter Healthcare, Deerfield, IL, U.S.A.) is used in peritoneal dialysis for calculating the indices of dialysis efficiency and for the mathematical simulation of the results of various dialysis regimens. The aim of our study was to quantify the modeling errors and find the methods which give best results. DESIGN: Nonrandomized, repeated measurement, clinical validation study. PATIENTS: The study included 78 patients on continuous ambulatory peritoneal dialysis (PD), daytime ambulatory PD, and automated PD. MEASUREMENTS: We used 207 collections of dialysate and urine associated with peritoneal equilibration tests (PETs) performed with different glucose concentrations (1.36%, 2.27%, 3.86%). The measured urea Kt/V, creatinine clearance (CRCL) and ultrafiltration (UF) were compared with the same data simulated mathematically using the PD ADEQUEST software version 1.4. RESULTS: The Kt/V, CRCL, and UF measured values were significantly correlated and in agreement with modeled data [concordance correlation (rc) was 0.849, 0.839, 0.625 respectively]. The errors (modeled - measured) were: Kt/V = -0.04 +/- 0.27 (p = ns), CRCL = 2.1 +/- 7.7 L (p < 0.001), UF = -121 +/- 711 mL (p = 0.016). Applying ANOVA to both the peritoneal transport data calculated by PD ADEQUEST (mass transfer area coefficient of the solutes, fluid reabsorption, and hydraulic permeability) and the modeling errors, significant differences were found in relation to the PET glucose concentrations. CONCLUSION: PD ADEQUEST proves to be a useful instrument in peritoneal dialysis, although there is undoubtedly still room for improvement in its prediction efficacy, which is influenced by the glucose concentration used in the PET.

Continuous tidal peritoneal dialysis (CTPD) prescription and adequacy targets.

NKF-DOQI guidelines suggest a Kt/V value of 2.1 and a creatinine clearance (CRCL) value of 63 L/1.73 m2 of body surface area per week as minimum targets in continuous cycling peritoneal dialysis (CCPD). Those targets are obtained by adapting the CAPD guidelines. The aim of our study was to verify the possibility of reaching the suggested targets with continuous tidal peritoneal dialysis (CTPD) and to check target modification in this automated treatment. Eight anuric patients underwent four consecutive CTPD sessions with increasing total prescribed volumes (17 L, 22 L, 27 L, and 32 L; night 9 h; fill 2.2 L; tidal 75%, day 2 dwells). The Kt/V increase was significant (P = 0.012), unlike that of CRCL, with larger volumes. Two patients did not reach target Kt/V, and four did not reach target CRCL. The volume normalized for 1.73 m2 corresponding to DOQI targets was 19.6 +/- 2.6 L for Kt/V and 20.2 +/- 2.4 for CRCL. The overall Kt/V was 2.29 +/- 0.66 and CRCL was 57.3 +/- 16.5 L/1.73 m2. CRCL/Kt/V overall ratio was 25.6 +/- 4.7 and significantly different from the target ratio (63/2.1 = 30, P < 0.001). The CRCL/Kt/V ratio showed a significant decrease with larger volumes (P = 0.001, linear trend P < 0.001). Adequacy targets can be reached only in some patients on CTPD even with high dialysis volumes. The changes in the CRCL/Kt/V ratio in relation to dialysis volume can be considered for adaptation and evaluation of adequacy targets in automated treatments.

[Comparative study of diagnostic hysteroscopy and transvaginal ultrasonography in patients with abnormal uterine hemorrhage during the peri- and post-menopausal period]. / Studio comparativo tra isteroscopia diagnostica ed ecografia transvaginale in pazienti con sanguinamento uterino anomalo in epoca peri- e postmenopausale.

BACKGROUND: The aim of this study was to determine the diagnostic value of hysteroscopy and transvaginal ultrasonography in patients with abnormal uterine bleeding (AUB) in the peri and postmenopausal period. METHODS: 302 patients with AUB, underwent hysteroscopy and in 86 cases, also a transvaginal ultrasonography before hysteroscopy was performed. Results were compared with the histological diagnosis. RESULTS: The diagnostic accuracy of hysteroscopy was very high in the cases of endometrial carcinoma (sensibility 100%, specificity 99%), and lower in the cases of endometrial hyperplasia (sensibility 69%, specificity 72%) and endometrial atrophy (sensibility 29% and specificity 97%). Sonography proved to be less reliable in the diagnosis of endometrial pathology (carcinoma: sensibility 57%, specificity 100%, hyperplasia: sensibility 62.5% specificity 63%). The results of this study show that sonography may be used as a first choice diagnostic test in the investigation of women with AUB. CONCLUSIONS: Hysteroscopy represent a second diagnostic step for achieving a proper histologic diagnosis.

Total clearance and extracellular volume with 125I-iothalamate in peritoneal dialysis.

To assess treatment adequacy by calculating total clearance (CL) in patients on peritoneal dialysis (PD), fluids must be collected over 24 hours, a laborious procedure and prone to inaccuracy. CL calculation from the plasma disappearance curve of an injected tracer has none of the above inconveniences. We therefore compared creatinine clearance CR-CL with CL calculated from the plasma disappearance curve of 125I-iothalamate (IO) injected in a single intravenous bolus. Twelve patients aged 63 (44-80) years and on PD for four (1-44) months were studied in hospital. Nine plasma samples were taken for IO-CL after a bolus of 21 kBq/kg of tracer. The least-squares biexponential fitting according to Gauss-Newton-Raphson was then carried out: [Aexp(-at) + Bexp(-bt)], and clearance was calculated by the formula, IO-CL = dose/AUC, where AUC = A/a + B/b. Both CLs were normalized for 1.73 m2 of body surface. Agreement (r = 0.746, p = 0.005) for the CR-CL (6.8 +/- 1.9 mL/min) and IO-CL (7.6 +/- 1.9 mL/min) was good, with a difference of 0.9 +/- 1.4 mL/min (t = 2.182, p = 0.052). Extracellular volume (ECV), calculated from the IO plasma disappearance curve with the formula, ECV = dose/ bAUC, and including the endoperitoneal fluid, was 19.8 +/- 2.9 L (29.5 +/- 6.2% body weight).

Calcium lactate interference in measuring creatinine in peritoneal dialysis fluids by the Jaffé kinetic method.

Creatinine measurements in peritoneal dialysis fluids using the Jaffé method have poor specificity due to interfering substances. We have checked to see if calcium lactate, in addition to glucose, interferes with the Jaffé kinetic measurement. Eight samples were prepared with increasing concentrations of glucose (960-3890 mg/dL) and eight were prepared with the same glucose content plus 7 mg/dL of calcium lactate, all without creatinine; in addition, 96 samples with increasing concentrations of glucose (1500-4000 mg/dL), calcium lactate (3-7.5 mg/dL), and creatinine (0.75-4.5 mg/dL) were prepared. There was a 0.31 +/- 0.13 mg/dL glucose interference on the Jaffé kinetic measurement in the first series, with an exponential trend. Interference was greater with calcium lactate and glucose: 0.50 +/- 0.16 mg/dL with the same trend. Data from the second series confirm the overestimation: 0.54 +/- 0.05 mg/dL (32.6%) with an exponential trend. The interference of glucose, creatinine, and calcium lactate on the Jaffé kinetic measurement was obtained by multi-variate regression. The single effects of glucose2 and glucose are predominant, but both creatinine and calcium lactate have a significant effect. Our study highlights the nonlinear glucose interference on creatinine measurement with the Jaffé kinetic method and the linear interference of both calcium lactate and creatinine.

Compliance study in peritoneal dialysis using PD Adequest software.

Poor compliance in peritoneal dialysis (PD) is a significant cause of dropout and morbidity. PD Adequest software, which, through a mathematical model, predicts the effect of the dialysis prescription on the basis of the peritoneal transport, may be used to identify the noncompliant patient. Fifty patients from two dialysis centers, aged 65.9 +/- 1.5 years and on PD for 28.6 +/- 4.7 months, were studied. A peritoneal equilibration test (PET) was carried out and 24-hour urine and dialysate were collected. Total weekly creatinine clearance (CrCl, L/week/1.73 m2) was calculated, as well as the glomerular filtration rate [(GFR), mL/min, mean CrCl and urea nitrogen clearance (UNCI)]. The dialytic schedules used were then introduced into the program and the parameters were recalculated using the software model. Nine patients considered noncompliant from their case histories were used to assess the differences of reference between expected and measured values. The control group was significantly different from the noncompliant group in the percentage of the CrCl and the serum creatinine (sCR) differences. The noncompliance threshold value was calculated from the mean of the lower 95% confidence interval of the compliant group and the higher one of the noncompliant group (-5.3%) for CrCl and vice versa for sCR (+10%), which behaved to the contrary. Reassessing the patients, 11 (22%) were identified as probably noncompliant.

Correction of glucose concentration interference on Jaffé kinetic creatinine assay in peritoneal dialysis.

Overestimation of creatinine measurement using the Jaffé kinetic method in peritoneal dialysis solutions, due to glucose interference, has been quantified and corrected through the elaboration of linear formulas obtained from 110 recovery and 301 biological tests. The added pure powdered creatinine and enzymatic method were considered as references after proven accuracy. Considering creatinine as well as glucose concentration interference, we obtained correction formulas from multiple regression application. All the computed formulas gave satisfactory corrections but different accuracy levels. The best model in biological samples was: Corrected CR = K1JafféCr + K2Glucose (all values in mg/dl) where K1 = 0.973 and K2 = -0.00035 (Rsq = 0.987, F ratio = 10,945, p = 0.00001). Applying formulas to biological samples there was a drop in accuracy, possibly explained by the presence of numerous unidentified substances in peritoneal dialysis biological samples that can amplify scatter. Every laboratory can reduce the error of the Jaffé kinetic assay by calculating their own correction formula in relation to the method and instrument used, because Jaffé kinetic assay gives different results with different kinetic windows. So, especially when applied to peritoneal dialysis fluid measurements, if a creatinine assay reference method is not available, the correction formula can be applied directly as given. Otherwise the method we have described can be followed with a well-structured creatinine recovery fest to identify and quantify assay interferences.

Low sodium concentration solution in normohydrated CAPD patients.

The aim of this study was to examine the possibility of increasing sodium and water removal with peritoneal dialysis. Ten patients aged 67.3 +/- 6.2 years, on continuous ambulatory peritoneal dialysis (CAPD) for 28.1 +/- 13.9 months, with no episodes of peritonitis for at least 2 months and clinically normohydrated, gave their informed consent to undergo two consecutive peritoneal equilibration tests (PETs) with dialysis solution at a sodium concentration of 126 mEq/L (low sodium) and 132 mEq/L (normal sodium), both with 2.5% glucose. Net ultrafiltration and sodium mass transfer were 319.4 +/- 178.5 and 443.2 +/- 234.4 mL (p = 0.0346) and 27.7 +/- 24.5 and 28.2 +/- 27.1 mEq (p = NS), respectively. There were no variations in natremia or the transport indices of the studied solutes or in the arterial pressure or heart rate. All patients showed drowsiness or torpor during the low sodium PET and one had cramps. The 126 mEq/L sodium dialysis solution showed no advantages compared to the more common solution, 132 mEq/L. However, further study is necessary to check the potentiality of solutions with different sodium and glucose compositions for both acute and chronic use.

Fungal peritonitis in peritoneal dialysis: critical review of six cases.

Fungal peritonitis (FP) is uncommon in patients on peritoneal dialysis (PD); it is difficult to treat and has a high mortality rate. We report 6 cases of fungal peritonitis observed between 1980 and 1992 in our center. The etiologic agents were: Candida spp., C. guilliermondi, C. parapsilosis, C. albicans, and Verticillium spp. All 6 patients had suffered at least one episode of bacterial peritonitis in the two months before the fungal infection appeared and were all treated by intraperitoneal administration of antibiotics. The catheter was removed early in 3 patients followed by antimycotic therapy, while the remaining 3 patients received antimycotic therapy, with removal of the catheter in a later stage. The result in the first group was that they all switched permanently to hemodialysis, while in the second group there were 2 deaths and 1 transfer to hemodialysis. In the light of these 6 cases, we analyzed 22 published reports to assess risk factors, therapy, and outcome of this pathology. The major predisposing factors were intraperitoneal antibiotics and bacterial peritonitis, and the best results were obtained by continuing PD plus intraperitoneal and systemic antifungal agents.

Verticillium peritonitis in a patient on peritoneal dialysis.

We describe a case of peritonitis due to Verticillium spp. in a 33-year-old farmer on continuous ambulatory peritoneal dialysis (CAPD) for 3 months for end-stage renal failure due to chronic pyelonephritis. The etiologic agent was a hyaline hyphomycete which we report as a new human opportunistic pathogen. The fungus was isolated from the peritoneal fluid culture and from the tip of the catheter; identification was made on the basis of macroscopic and microscopic features. The patient had previously been admitted to our hospital for peritonitis caused by mixed enteric flora and treated for 8 days with intraperitoneal broad-spectrum antibiotic therapy. Five days after discharge he was readmitted for severe abdominal pain and cloudy drainage fluid. Two days of intraperitoneal broad-spectrum antimicrobial therapy produced no clinical improvement. Intravenous fluconazole and oral flucytosine were administered upon identifying the fungus. After another 2 days without improvement, peritoneal dialysis was discontinued and the catheter removed. Antimycotic therapy was continued for 4 days with complete resolution of the peritonitis. The patient chose to start hemodialysis and was discharged in good clinical condition.

Comparison of fast peritoneal equilibration tests with 1.36 and 3.86% dialysis solutions.

At present dialysis solutions with different glucose concentrations are used for the peritoneal equilibration test (PET) and Fast-PET in peritoneal dialysis (PD). We compared the results of two Fast-PETs, using 1.36 and 3.86% solutions sequentially in 30 patients on PD treatment, to obtain information on peritoneal transport (D/P-4 h) and ultrafiltration rates. Creatinine, phosphorus and urea D/P-4 h in the two Fast-PETs were not statistically different, unlike those for potassium, beta 2-microglobulin and glucose. The creatinine and phosphorus D/P-4 h values in particular proved to be uninfluenced by the different dialysis solutions. The lack of correlation between the two Fast-PET ultrafiltration values confirmed the difficulty in interpreting this parameter, above all in the case of non-homologous Fast-PETs. We obtained useful indications for comparing different Fast-PET results, but were unable to reach a decisive conclusion regarding the best of the two dialysis solutions for this test.

Serum beta-2-microglobulin level and residual renal function in peritoneal dialysis.

In 32 noncirrhotic patients on peritoneal dialysis, mean serum beta 2-microglobulin (s beta 2M) was 26.58 +/- 12.32 mg/l (9.7-63.5). We found a significant correlation between s beta 2M and serum creatinine (sCr; r = 0.760), blood urea nitrogen (BUN; r = 0.573), total creatinine and BUN clearance (r = 0.623 and 0.599, respectively), 24-hour Kt/V (r = 0.638), glomerular filtration rate (r = 0.623), 24-hour urine output (r = 0.669), serum total protein (r = 0.584) (p < 0.01 for all the above r values); beta 2M peritoneal clearance and mass transfer (r = 0.414 and 0.427, respectively; p < 0.05). Our data demonstrate and confirm the contribution of residual renal function in determining s beta 2M levels and it is seemingly more important than beta 2M peritoneal clearance.