Long-Term Outcomes of Pre-emptive Valganciclovir Compared with Valacyclovir Prophylaxis for Prevention of Cytomegalovirus in Renal Transplantation

Prevention of cytomegalovirus (CMV) is essential in organ transplantation. The two main strategies are pre-emptive therapy, in which one screens for and treats asymptomatic CMV viremia, and universal antiviral prophylaxis. We compared these strategies and examined long-term outcomes in a randomized, open-label, single-center trial. We randomly assigned 70 renal transplant recipients (CMV-seropositive recipient or donor) to 3-month prophylaxis with valacyclovir (n=34) or pre-emptive valganciclovir for significant CMV viremia detected at predefined assessments through month 12 (n=36). Among the 55 patients who had a protocol biopsy specimen available at 3 years to allow assessment of the primary outcome, 9 (38%) of 24 patients in the prophylaxis group and 6 (19%) of 31 patients in the pre-emptive therapy group had moderate to severe interstitial fibrosis and tubular atrophy (odds ratio, 2.50; 95% confidence interval, 0.74-8.43; P=0.22). The prophylaxis group had significantly higher intrarenal mRNA expression of genes involved in fibrogenesis. The occurrence of CMV disease was similar in both groups, but pre-emptive therapy improved 4-year graft survival (92% versus 74%; P=0.049) as a result of worse outcomes in patients with late-onset CMV viremia. In conclusion, compared with valacyclovir prophylaxis, pre-emptive valganciclovir therapy may lead to less severe interstitial fibrosis and tubular atrophy and to significantly better graft survival.     

Leukotrienes B4, C4, D4 and E4 in the Exhaled Breath Condensate (EBC), Blood and Urine in Patients with Pneumoconiosis

Leukotrienes (LTs) are involved in the pathogenesis of lung fibrosis and were increased in exhaled breath condensate (EBC) of the patients with pneumoconiosis. However the possible influence of extra-pulmonary disorders on the EBC markers is not known. Therefore in parallel with EBC, LTs' levels in the plasma and urine were measured in patients with pneumoconiosis (45 × asbestos exposure, 37 × silica exposure) and in 27 controls. Individual LTs B4, C4, D4 and E4 were measured by liquid chromatography - electrospray ionization - tandem mass spectrometry (LC-ESI-MS/MS). In EBC, LT D4 and LT E4 were increased in both groups of patients (p<0.001 and p<0.05), comparing with the controls. Both LT B4 and cysteinyl LTs were elevated in asbestos-exposed subjects (p<0.05). Asbestosis with more severe radiological signs (s1/s2-t3/u2) and lung functions impairment has shown higher cysteinyl LTs and LT C4 in the EBC (p<0.05) than mild asbestosis (s1/s0-s1/s1). In addition, in the subjects with asbestosis, cysteinyl LTs in EBC correlated with TLC (-0.313, p<0.05) and TLCO/Hb (-0.307, p<0.05), and LT C4 with TLC (-0.358, p<0.05). In pneumoconioses, EBC appears the most useful from the 3 fluids studied.     

Comparison of 3 Fusion Techniques in the Treatment of the Degenerative Cervical Spine Disease. Is Stand-Alone Autograft Really the "Gold Standard?": Prospective Study With 2-Year Follow-up

STUDY DESIGN.: A prospective study. OBJECTIVE.: The aim of this study was to compare the 3 different methods of interbody fusion of the cervical spine-autograft in stand-alone technique, autograft with anterior plate, and polyetheretherketone cage supported by anterior plate. The clinical and radiological data obtained were analyzed and discussed. SUMMARY OF BACKGROUND DATA.: Although degenerative cervical spine disease has been treated by an anterior approach for more than 50 years, there is not one generally accepted operative approach. There is a very low-quality evidence of little or no difference in pain relief between each of the techniques. Iliac crest autograft still seems to be the "gold standard" for interbody fusion. METHODS.: Prospective study collecting clinical and radiological data of 81 patients undergoing anterior cervical interbody fusion, in which the interbody fusion of 1 or 2 motion segments from C3 to C7 was done by any of the 3 techniques--stand-alone insertion of autograft (group 1: 28 patients), autograft and anterior plate (group 2: 18 patients), and polyetheretherketone cage filled with beta-tricalcium phosphate and plate (group 3: 29 patients). Patients were followed for 2 years after surgery. RESULTS.: Significant interaction of relative height in the segment and time was found (P < 0.001). The values of the relative height of stand-alone autograft dropped below 95% of initial height and the values of the other 2 groups remained above 105%. Significant interaction of time and group was found for Cobb S angles (P < 0.001). Values of group 1 decreased substantially and remained significantly lower than values of other 2 groups. Fusion rate was 100% in all groups. Neck Disability Index group and time interaction was found (P = 0.023). During postoperative follow-up, group 1 scored in all controls higher than the other 2 groups, but differences were not significant. Visual analogue scale showed effect of time (P < 0.001). This was due to a smaller improvement of patients in group 1 during the whole follow-up in comparison with the other 2 groups. Highest proportion of unsatisfied patients was in group 1 compared with the other 2 groups after 2 years (P = 0.034). CONCLUSION.: Significantly worse radiological and clinical results after 2 years of follow-up were achieved using stand-alone autograft technique in comparison with autograft supported by anterior plating similarly as in comparison with cage implant and anterior plating. Using artificial fusion substrate together with plate and cage can offer the same clinical and radiological results such as iliac autograft and plating. Anterior plating seems to be an important factor influencing the postoperative cervical spine alignment and also the clinical outcome.     

Ascent of the testis in children

Among 460 children who had an orchiopexy (ORP), we identified 72 children who had attended our institution 1–12 years earlier and in whom the testicular position had been specified. Of the 72 boys 19 were had ascended testes (26%). The age at ORP of the children with ascent of the testes was 7.0 years (1.8–14.0 years). Light and electron microscopy of 13 testicular biopsies taken at ORP, showed alterations of germ cells and sertoli cells, similar but less pronounced than alterations seen in congenital undescended testes.Conclusion A normally positioned testis may ascend into the inguinal region or upper scrotum and remain there fixed. This secondary cryptorchidism does not usually respond to human chorionic gonadotropin treatment and must be corrected by orchiopexy.     

HPMA based macromolecular therapeutics: internalization, intracellular pathway and cell death depend on the character of covalent bond between the drug and the peptidic spacer and also on spacer composition

Polymeric conjugates based on N-(2-hydroxypropyl)methacrylamide (HPMA) have been tested as potential carrier for anticancer drug - doxorubicin (Dox). Two types of conjugates were synthesized: (a) conjugates containing Dox bound through an amidic bond to an oligopeptidic side-chain (usually GFLG) and (b) hydrolytically cleavable conjugates wherein Dox is bound to the polymeric carrier through a pH sensitive bond. The mechanism of action of both conjugates is different and reflects the diverse way and intensity of their intracellular accumulation. All conjugates containing doxorubicin bound via an amidic bond directly penetrate the plasma membrane and are detectable in all associated cellular membranes, i.e. membranes of the endocytic compartment, a nuclear membrane as well as membranes of Golgi and endoplasmic reticulum. We have never been able to detect released doxorubicin inside the nuclei of the treated cells. The cytotoxicity of these conjugates seems to be primarily caused by the damage of cellular membranes. Necrosis is the main mechanism of the cell death. Conjugates containing hydrolytically bound doxorubicin are internalized by endocytosis and fluid phase pinocytosis and doxorubicin is cleaved from the polymeric carrier at low pH in late endosomes and lysosomes. An apoptosis is the main mechanism of the cell death. The spacer influences the rate of the intracellular release of the drug rather than the rate of internalization.     

TEL/AML1 and immunoreceptor gene rearrangements-which comes first?

TEL/AML1 fusion gene is present in 20-25% of childhood acute lymphoblastic leukaemias. In order to unravel at which stage of B-cell precursor development the fusion is originated, we analysed frequency and pattern of immunoreceptor (immunoglobulin and T-cell receptor) gene rearrangements in 47 TEL/AML1-positive and 43 TEL/AML1-negative cases of the same CD10+ immunophenotype. Moreover, we compared corresponding immunoreceptor gene rearrangements in 11 cases of TEL/AML1-positive leukaemia at diagnosis and relapse. More mature immunogenotype of TEL/AML1-positive cases and changes in 37% of rearrangements between diagnosis and relapse suggest that in most cases the TEL/AML1 fusion is formed during immunoreceptor gene rearrangement process.