Dent��s disease: clinical features and molecular basis

Dent’s disease is an X-linked recessive renal tubulopathy characterized by low-molecular-weight proteinuria (LMWP), hypercalciuria, nephrocalcinosis, nephrolithiasis, and progressive renal failure. LMWP is the most constant feature, while the other clinical manifestations show wide variability. Patients also present variable manifestations of proximal tubule dysfunctions, such as aminoaciduria, glucosuria, hyperphosphaturia, kaliuresis, and uricosuria, consistent with renal Fanconi syndrome. Dent’s disease affects mainly male children, and female carriers are generally asymptomatic. In two-thirds of patients, the disease is caused by mutations in the CLCN5 gene, which encodes the electrogenic chloride/proton exchanger ClC-5. A few patients have mutations in OCRL1, the gene associated with the oculocerebrorenal syndrome of Lowe, which encodes a phosphatidylinositol-4,5-biphosphate-5-phosphatase (OCRL1). Both ClC-5 and OCRL1 are involved in the endocytic pathway for reabsorption of LMW proteins in the proximal tubule. This review will provide an overview of the important phenotypic characteristics of Dent’s disease and summarize the molecular data that have significantly increased our comprehension of the mechanisms causing this disease.     

Long-Term Effects of Neridronate and its Discontinuation in Patients with Primary Hyperparathyroidism

In patients with primary hyperparathyroidism (PHPT) not suitable for surgical correction, a skeletal protection with bisphosphonates is considered a reasonable option, but the long-term effects after treatment discontinuation are not well known. Sixty postmenopausal women with PHPT were given 400–600 IU vitamin D₃ daily and 100 mg neridronate IV every 2 months for 2 years with 2 additional years of follow-up without antiresorptive therapies. Bone mineral density (BMD) progressively rose by 6.7 ± 7.6% (SD) and by 2.9 ± 4.5% at the spine and femoral neck, respectively. During follow-up, mean BMD progressively fell, but after 2 years it was still 3.9 ± 5.5% higher than baseline values at the spine. Bone alkaline phosphatase and serum C-telopeptide of type I collagen decreased significantly within 6 months (28 and 49% versus baseline, respectively) and rose to baseline values within 6–12 months during follow-up. Serum PTH significantly rose from baseline during treatment, but it remained significantly higher than baseline during follow-up. The PTH changes were significantly correlated with serum 25-hydroxyvitamin D (25OHD) levels. In conclusion, in this study we observed that in patients with mild PHPT treatment with bisphosphonates is associated with the expected changes in bone-turnover markers and that the significant increases of both hip and spine BMD are partially maintained for at least 2 years after treatment discontinuation at the vertebral site. The marked increases in serum PTH levels, particularly in subjects with low 25OHD levels, persist after treatment discontinuation and this raises the suspicion that this might reflect a worsening of PHPT.     

Vasculature-targeted tumor necrosis factor-alpha increases the therapeutic index of doxorubicin against prostate cancer

BACKGROUND: Poor penetration and uneven distribution of doxorubicin in tumors limits the efficacy of this drug in patients with prostate cancer (PC). Aim of the study was to investigate whether pre-treatment with NGR-TNF, a tumor necrosis factor-alpha derivative able to target tumor vessels and alter vessel permeability, increases the penetration and the efficacy of doxorubicin in pre-clinical models of PC. METHODS: Wild type C57BL/6 mice bearing androgen-independent TRAMP-C1 PC and transgenic adenocarcinoma of the mouse prostate (TRAMP) mice, which spontaneously develop PC and metastasis, were treated with repeated cycles of doxorubicin, administered either alone or following NGR-TNF. Tumor growth and drug uptake by cancer cells was evaluated. RESULTS: Doxorubicin as a single agent blocked the growth of TRAMP-C1 cells in vitro but not in vivo. Pre-treatment of mice bearing subcutaneous TRAMP-C1 tumors with NGR-TNF favored doxorubicin penetration into the tumor mass, and in both TRAMP-C1 and TRAMP models significantly delayed tumor growth without increasing drug-related toxicity. CONCLUSIONS: Pre-treatment with NGR-TNF significantly expanded the therapeutic index of doxorubicin in mouse models of hormone-dependent and -independent PC.     

Clinical usefulness of FDG-PET/CT scan imaging in the management of posttransplant lymphoproliferative disease

BACKGROUND: Posttransplant lymphoproliferative disease (PTLD) is, aside skin cancer, the most common malignancy occurring after solid organ transplant in adults. Fluorodeoxyglucose (FDG) positron emission tomography (PET) has proved useful in the management of lymphomas. METHODS: We report our experience with the use of FDG-PET inline with computed tomography (CT) scanning in the management of four transplant recipients with histologically confirmed PTLD, including three monomorphic PTLDs and one polymorphic PTLD. RESULTS: FDG-PET/CT scan at diagnosis showed increased FDG uptake in all examined PTLD lesions, and the disease was upstaged on the basis of FDG-PET/CT scan results over conventional CT scanning in one patient. At the end of treatment, PET/CT scans no longer demonstrated FDG uptake in the original PTLD lesions in all patients. Complete remission of disease persisted for at least 1 year after diagnosis in all. CONCLUSIONS: Our results strongly support that FDG-PET scanning is highly specific for diagnosis and follow-up of PTLD. The clinical relevance of including FDG-PET/CT scanning in the management of PTLD should be evaluated in a larger prospective cohort study.     

Octanediol treatment of glutaraldehyde fixed bovine pericardium: evidence of anticalcification efficacy in the subcutaneous rat model

OBJECTIVE: Anticalcification strategies of glutaraldehyde-fixed xenograft tissue aim to extract lipids or to neutralize toxic aldehyde residuals. The purpose of this study was to evaluate the efficacy of octanediol compared to standard treatments of glutaraldehyde-fixed bovine pericardium in the subdermal rat model. Octanediol treatment is an ethanolic solution (40%) containing a long chain aliphatic alcohol (5% 1,2-octanediol) that removes lipids without diminishing the stability of collagen. METHODS: Octanediol and standard glutaraldehyde fixed bovine pericardium were both implanted in 24 Sprague-Dawley rats, explanted after 30-75 days (12 animals each) and submitted to X-ray (score 0-4), histology, electron microscopy and elemental analysis by spectroscopy (Ca and P content). Unimplanted octanediol and standard glutaraldehyde fixed pericardium served as control. RESULTS: At 30 days octanediol-treated pericardium showed calcium content of 0.20+/-0.1 vs 20.07+/-36.79 mg/g dry weight for standard pericardium. The difference was also evident at 75 days: calcium content of 2.36+/-7.38 mg/g dry weight for octanediol vs 165.61+/-23.35 mg/g dry weight for standard (p<0.0001). Differences were also detected at X-ray (mean score 0.7+/-0.6 octanediol vs 3.8+/-0.4 standard at 75 days). Equally, mean P content was 11.69+/-21.33 mg/g dry weight for standard vs 0.60+/-1.45 mg/g dry weight for octanediol samples at 30 days, and 90.90+/-12.61 mg/g dry weight for standard vs 1.42+/-4.34 mg/g dry weight for octanediol at 75 days (p<0.0001). At electron microscopy collagen appeared well preserved regardless of the type of treatment; in octanediol treated pericardium cell membranes almost disappeared and only few profiles of endoplasmic reticulum and rare mitochondria were visible. CONCLUSIONS: Treatment with octanediol strongly prevents calcification of glutaraldehyde fixed bovine pericardium in rat subdermal model, even in the long-term. Evidence of octanediol efficacy may entail important implications for new generation bioprosthetic valves.     

Pregnant woman presenting with a gross retroperitoneal mass: surgical treatment with caval replacement

A 40-year-old woman in the twenty-fifth week of pregnancy presented with a gross retroperitoneal mass. At the end of the pregnancy, the patient was submitted to surgery, and the gross infiltration of the inferior vena cava wall required the resection of the vena cava with its prosthetic substitution. The histopathological examination demonstrated the presence of a leiomyosarcoma of the inferior vena cava. An electronic video supplement showing the most important intraoperative passages is available online at doi:10.1016/j.eururo.2008.06.074.     

Radiological and Pathological Assessment of Hepatocellular Carcinoma Response to Radiofrequency. A Study on Removed Liver after Transplantation

BACKGROUND: The real efficacy of radiofrequency ablation (RFA) in destroying hepatocellular carcinoma is not completely known, nor is the ability of computed tomography (CT) to precisely assess response. Our aims were to analyze pathological response, tumor size influence, and CT response evaluation. MATERIALS AND METHODS: This was a retrospective study of 30 hepatocellular carcinoma nodules treated by RFA before liver transplant (LT) in 28 patients. Pathological study of the whole removed liver was then performed and the tumor response was classified as complete, incomplete, or absent. The biggest nodule diameter was estimated by CT or ultrasound. The procedure was carried out percutaneously in all but 3 patients, and in those 3 it was done surgically. RESULTS: The pathological response was complete in 14 nodules (46.7%) and incomplete in 16 (53.3%). The differences in mean preoperative diameter between cases with complete and incomplete response were not significant (p = 0.3). We found that small tumors were not always completely destroyed, whereas bigger tumors could be successfully deleted. There was no clear association between any location and better or poorer response. The detection of RFA incomplete response by means of CT scan had 50% sensitivity and 100% specificity. CONCLUSIONS: In our experience, RFA can achieve some degree of tumor destruction in every treated case of hepatocellular carcinoma, the complete response rate being slightly lower than half. We have not found any association of response with tumor size or interval RFA-transplant. Second, CT had not enough sensitivity to assess RFA response of hepatocellular carcinoma.     

Peroperative fractures in uncemented total hip arthrography: results with a single design of stem implant

The incidence of intraoperative femoral fractures with a single design of stem implant, the Meridian (Stryker-Howmedica, Rutherford, N.J.), has been assessed in a study of 117 implants in patients treated consecutively between 1996 and 2001. The aim of the study was to evaluate the risk factors for suffering an intraoperative fracture and to determine, based on a short-term follow-up, if there were radiographic signs of early loosening. The following variables were analysed: demographic factors of the patient, morphology of the femur, intraoperative factors and postoperative radiographic factors. The radiographic stability of the implant and the presence of early signs of loosening were evaluated 2 years after surgery. The incidence of femoral fractures was 11% (13 cases in 117 implants), which is higher that reported in earlier published studies, and there was an increased number of fractures when the proximal filling of the femoral canal was higher. Although there was no statistically significant relation between the variables studied and the appearance of an intraoperative fracture, we conclude that the appearance of a femoral intraoperative fracture did not affect the radiographic stability of the implant during the short-term follow-up of our study cohort.     

Rapamycin enhances the number of alloantigen-induced human CD103+CD8+ regulatory T cells in vitro

BACKGROUND: Regulatory T cells (T(reg) cells) may be operational in both the induction and maintenance of transplantation tolerance. We recently showed that alloantigen-induced CD103+ CD8+ T cells strongly suppressed T-cell proliferation in mixed lymphocyte culture (MLC) via a contact-dependent mechanism. CD103 directs T lymphocytes to their ligand E-cadherin, which is expressed on renal tubular epithelial cells, and CD103+ CD8+ T cells have been described to be present in late renal allograft rejection. METHODS: We studied the influence of prednisolone, cyclosporin, tacrolimus, CD25 monoclonal antibodies, rapamycin, and mycophenolate mofetil (MMF) on the development and functional activity of alloantigen-activated CD103+ CD8+ T cells in MLC. RESULTS: Calcineurin inhibitors, MMF, and CD25mAb did not influence the number of CD103 expressing CD8+ T cells. In contrast, corticosteroids diminished CD103 expression on alloactivated CD8+ T cells, which appeared to be caused by their inhibitory action on myeloid dendritic cells. Addition of rapamycin to allocultures led to an increased percentage of CD103+ CD8+ alloreactive T cells. Moreover, in the presence of rapamycin, these cells tended to show higher suppressive capacity. CONCLUSIONS: Alloreactive CD103+ CD8+ T(reg) cells may expand and exert their suppressive function during immunosuppressive treatment with rapamycin. These data are relevant in the design of immunosuppressive drug regimens intended to induce and/or maintain transplantation tolerance.     

Computed tomographic diagnosis of obturator hernia and its surgical management: a case series

The obturator hernia is a rare type of hernia which usually presents in thin, elderly women. The preoperative diagnosis is typically difficult, with non-specific signs and symptoms which result in a delay in the diagnosis. It can also be an incidental finding at exploratory laparotomy for a patient with intestinal obstruction. The treatment is surgical. A series of four females with obturator hernia is presented. All patients presented with a history of intestinal obstruction and the hernia was diagnosed preoperatively by computed tomography. All patients underwent a preperitoneal mesh repair with a favourable outcome. The diagnosis and the surgical approach are discussed.