[Bio-ecological control of chronic liver disease and encephalopathy]. / Controllo bio-ecologico della cirrosi epatica e dell'encefalopatia.

Minimal encephalopathy was originally associated with chronic liver disease but is increasingly associated with most other chronic diseases and particularly with diabetes and also chronic disorders in other organs: kidneys, lungs, thyroid and with obesity. It is increasingly with dramatically increased and more or less permanent increase in systemic inflammation, most likely a result of Western lifestyle. Frequent physical exercise and intake of foods rich in vitamins, antioxidants, fibres, lactic acid bacteria etc in combination with reduction in intake of refined and processed foods is known to reduce systemic inflammation and prevent chronic diseases. Some lactic acid bacteria, especially Lb paracasei, lb plantarum and pediococcus pentosaceus have proven effective to reduce inflammation and eliminate encephalopathy. Significant reduction in blood ammonia levels and endotoxin levels were reported in parallel to improvement of liver disease. Subsequent studies with other lactic acid bacteria seem to demonstrate suppression of inflammation and one study also provides evidence of clinical improvement.

Fatal hemorrhage in two renal graft recipients with multi-drug resistant Pseudomonas aeruginosa infection.

Pseudomonas aeruginosa (PA) infections occurring after renal transplantation (RT) represent a potentially life-threatening complication. We present 2 cases of early death following RT in which PA was transmitted, possibly from the donor to the recipients, despite preoperative cultures that were negative. The donor had developed PA-related bilateral pneumonia while in the intensive care unit. However, after appropriate antibiotic therapy, no signs of infection were present at the time of organ retrieval and cultures were negative. Both recipients received a renal graft from the same donor and developed multi-drug resistant (MDR)-PA infections with bacterial phenotypes and resistances similar to the donor. The first recipient died 9 days after RT from rupture of a false aneurysm of the external iliac artery, caused by a fully thickened PA-related arteritis. The second recipient died postoperatively on day 10 after rupture of an aneurysm in the right vertebral artery. Our experience shows that MDR-PA infection early after RT may be a catastrophic event. Specific anti-PA antibiotic therapy in RT patients during the perioperative period is recommended in the case of PA infection in the donor, even after apparent successful therapy with negative cultures.

Two recombinant human interferon-beta 1a pharmaceutical preparations produce a similar transcriptional response determined using whole genome microarray analysis.

OBJECTIVES: Recombinant human interferon-beta (IFN-b) is a well-established treatment for multiple sclerosis (MS). The regulatory process for marketing authorization of biosimilars is currently under debate in certain countries. In the EU, EMEA has clearly defined the process including overarching and product-specific guidelines, which includes clinical testing. Biosimilarity needs to be based on comparability criteria, including at least molecular characterization, biological activity relevant for the therapeutic effect and relative bioavailability ("bioequivalence"). In the case of such complex diseases as MS, where the effect of treatment is not so directly measurable, in vitro tools can provide additional data to support comparability. Genomic microarrays assays might be useful to compare multisource biopharmaceuticals. The aim of the present study was to compare the pharmacodynamic genomic effects (in terms of transcriptional regulation) of two recombinant human IFN-I(2)1a preparations on lymphocytes of multiple sclerosis patients using a whole genome microarray assay. METHODS: We performed an ex vivo whole genome expression profiling of the effect of two preparations of IFN-I(2)1a on non-adherent mononuclears from five relapsing-remitting MS patients analyzing microarrays (CodeLink Human Whole Genome). Patients blood was drawn, PBMCs isolated and cultured in three different conditions: culture medium (control), 1,000 U/ml of IFN-I(2)1a (BLA- (STOFERON, Bio Sidus) and 1,000 U/ml of IFN-I(2)1a (REBIF, Serono) RNA was purified from non-adherent cells (mostly lymphocytes), amplified and hybridized. Raw data were generated by CodeLink proprietary software. Data normalization, quality control and analysis of differential gene expression between treatments were done using linear model for microarray data. Functional annotation analysis of IFN-I(2)1a MS treatment transcription was done using DAVID. RESULTS: Out of the approximately 45,000 human sequences examined, no evidence of differential regulation was found when both treatments were compared (minimum adjusted p-value > 0.999). The IFN-I(2)1a effect differentially regulated the expression of 868 genes. The expression of standard markers such as GTP cyclohidrolase, MxA, and OAS isoenzymes A and B changed as a consequence of the action of IFN-I(2)1a. CONCLUSIONS: This exhaustive and highly sensitive assay did not show differences in the genomic expression profile of these two products under the assayed experimental conditions. These results suggest that this technology might be useful for the initial comparison of biosimilars, being part of a comprehensive comparability program that includes clinical testing.

Clinical operational tolerance after kidney transplantation: a short literature review.

The clinical era of solid organ transplantation started with a renal transplantation (RT) performed between identical twins in Boston in 1954. The patient did not receive any immunosuppression, thus representing the very first case of operational tolerance (Tol). However, more than half a century later, we must admit the inadequacy of our knowledge regarding such a fundamental aspect of transplant immunology, as demonstrated by the fact that Tol has never been achieved in an intention-to-treat protocol. Herein we aim to shortly review the worldwide experience on clinical operational Tol after RT. Thus far, reports on successful cases of Tol after RT have been anecdotal: the largest series included no more than 10 individuals. We will understand that Tol can develop even in the presence of either HLA mismatches or blood group incompatibility at baseline, in the presence of anti-HLA antibodies during follow-up, as well as in patients having experienced acute rejection. Despite the lack of robust evidence, the fact that Tol is often accidentally discovered by transplant physicians during follow-up in noncompliant patients justifies the hypothesis that the real number of Tol cases might be much higher than currently reported.

Incidence of urinary tract infections caused by germs resistant to antibiotics commonly used after renal transplantation.

BACKGROUND: The inadequate utilization of antibiotics is responsible for the development of urinary tract infections (UTI) after renal transplantation (RT), through the induction of resistance to the antibiotics themselves. The purpose of this study was to evaluate the incidence of resistance to cefotaxime (CEF) and trimethoprim/sulfamethoxazole (TMP-SMX), routinely used for surgical perioperative prophylaxis and prevention of Pneumocystis carinii, respectively. MATERIALS AND METHODS: We enrolled all adult patients having received an RT from 2001 to 2006 and having a minimum follow-up of 6 months. Urine cultures (UC) were routinely performed at every outpatient clinic control and whenever required by the onset of significant clinical signs/symptoms. UTI was diagnosed by the presence of a positive UC. The endpoint of the study was the emergence of bacterial strains resistant to either CEF or TMP/SMX. RESULTS: We recorded 169 UTI in 76 patients (38 men/38 women, 33%) over a mean follow-up of 779.9+/-523.3 days. Thirty-nine patients (51%) developed more than 1 UTI episode. When gram-negative bacteria were considered, 102/144 (70.8%) tests showed resistance to TMP/SMX, while data were available in about only 7 gram-positive infections (5/7, 71%). CEF was tested less frequently with 21/43 (49%) germs resistant to this molecule. CONCLUSIONS: The onset of bacterial resistance to either TMP/SMX or CEF is frequent after RT. A wiser stricter utilization of antibiotics is mandatory. Standard antibiotic protocols should be revised.

De novo autoimmune hepatitis following liver transplantation: a case report.

De novo autoimmune hepatitis (AIH), a rare disorder first described in 1998, appears in patients with liver transplants due to autoimmune and nonautoimmune etiologies. De novo AIH occurs in 2.5% to 3.4% of allografts; children seem to have a predilection for this syndrome. We have present herein a case of a liver allograft recipient who developed chronic hepatitis associated with autoimmune features outlining the clinical course, liver histology, and response to treatment.

The registry of brain deaths in quality control program: evaluation of potentiality of each hospital in Abruzzo and Molise regions.

Quality control procedures in donation and transplantation of organ and tissue, which were started in 2001, are aspects of the activity of Regional Centre for Transplantation. Over the years there has been a significant increase in the number of diagnosed brain deaths that is close to the figure reported in the international literature of 50/60 per million inhabitants (p.m.i). Misidentification of brain death is still the most important cause of loss of organs for transplantation; in fact in Italy, there are some regions that overcome this value, but there are other regions in which the number of brain death identified is still low. Abruzzo and Molise in 2003 achieved the highest registered brain deaths (61 p.m.i.); in 2004, 51; in 2005, 43; and the projection for 2006 is about around 50. For this study we collected data from five hospitals with a neurosurgical unit, which were representative of procurement activity in two regions, because they had identified the most brain deaths, 53/65 in 2005. The data were compared among hospitals and with the Spanish country data (1999-2003), which was avant-garde for the processing of organ donation and transplantation in Europe. Some useful indices to define the theoretical capacity of donation for each hospital (ability to identify brain death, the cause of donor loss) were evaluated for determining the efficacy of the procedure in organ procurement.

The role of liver transplantation in the treatment of hereditary hemorrhagic telangiectasia: a short literature review.

The liver is involved in up to 73% of patients suffering from hereditary hemorrhagic telangiectasia (HHT), but only some of them become symptomatic. Although management is often conservative, sometimes a more aggressive approach is required. The role of surgery is still undefined. Open ligation, banding, or closure of the arteriovenous malformation feeding artery have been proposed but rejected, as they are followed by an unacceptably high incidence of complications, derived from ischemia of the biliary tree. Orthotopic liver transplantation (OLT) has been successfully attempted in 28 patients with cardiac, biliary, or portal hypertension as well as mixed clinical presentations. Twenty-four were alive at time of data collection. Cardiovascular and pulmonary functions have improved after the operation in most cases. Intrahepatic relapse of the hallmark lesion of the disease (telangiectasia and arterovenous malformation) has been recently described in two cases. OLT represents a valuable therapeutic option for hepatic-based HHT, provided early diagnosis and referral to a specialized unit.

Organ donation quality control in Abruzzo region (Italy).

Abruzzo is a region in central Italy with a population of 1,262,392. Within this region there are 13 hospitals with intensive care units, four of which have neurosurgical units. The Regional Centre for Transplants in L'Aquila is notified of encephalic deaths in hospitals in Abruzzo and Molise and coordinates organ retrieval and transplantation. Organ donation is a process that involves a whole series of professionals who, operating in a sequential manner in each hospital, make possible the use of a cadaveric organ to give life to a person or improve the quality of life of a patient on a waiting list. Quality control procedures were introduced in 2001 and involve all of the hospitals in the region with intensive care units. The system for quality control was computerized in 2004 and is used in the four hospitals with neurosurgical units (type A hospitals) and in the 13 hospitals without (type B hospitals); the different types of deaths (cause of death, age, etc) are also analyzed with this system. One of the aims of this system is to discover the theoretical donation capacity, taking as benchmark values those resulting from the regional average and those published in international literature, and noting any shortcomings. It has emerged that donor identification is well organized and efficient and this is thanks to a concerted effort that has been made to overcome technical and organizational problems connected to donor detection and donor maintenance during the 6 hours of legal observation. The high percentage of opposition to organ removal, despite the fall registered in the first half of this year (2005), is still above the national average and still remains a critical point in the organ donation process.

Risk factors that can influence kidney transplant outcome.

The survival and function of a kidney transplant are influenced by numerous immunological and nonimmunological factors. The aim of this study was to evaluate the role of a number of cadaveric donor parameters on transplanted kidney function, and in particular on the occurrence of delayed graft function (DGF) since DGF is one of the most important factors in long-term organ survival. This study looked at 143 patients who underwent kidney transplant of whom 32 displayed DGF. The creatinine levels in organ recipients, which were evaluated during a follow-up that ranged between 6 months and 4 years, were significantly higher among recipients who developed DGF after transplant (1.8 +/- 0.7 vs 1.4 +/- 0.4; P = .02). The following donor parameters were taken into consideration: history of diabetes and hypertension; creatinine levels; inotropie therapy; problems relating to hemodynamics (hypotension and/or cardiac arrest); and cold ischemia time. We observed that a donor history of hypertension (46.8% DGF vs 23.27% no DGF; P = .01) and high levels of donor creatinine prior to organ removal (1.9 +/- 1.2 mg/dL DGF vs 1.2 +/- 0.9 mg/dL no DGF; P = .007) were significant risk factors for DGF among kidney recipients. No significant differences were found for others factors between recipients with versus without DGF.

Kidney Transplantation, Polymorphisms of IL-18, and Other Pro-Inflammatory Genes and Late Post-Transplant Outcome.

BACKGROUND: Functional polymorphisms of molecules involved in immune-mediated mechanisms of allograft rejection could be predictive of increased risk for early and late post-transplant complications. In the past years, the challenge for long-term graft survival in kidney recipients is the implementation of personalized approaches. In this study, effects of interleukin (IL)-18-137G/C (rs187238), -607C/A (rs1946518), and other pro-inflammatory cytokine gene polymorphisms (tumor necrosis factor [TNF]-α-308G/A, rs1800629, IL-6-174G/C, rs1800795, and interferon [IFN]-γ+874A/T, rs2430561) on the main post-transplant risk parameters and diseases (metabolic, cardiovascular, infective, and chronic allograft rejection) were assessed in kidney-transplanted patients. METHODS: One hundred seventy-nine transplanted patients were retrospectively analyzed for clinical and biochemical parameters and onset of post-transplant complications. Taqman allelic discrimination and PCR-SSP (polymerase chain reaction-sequence specific primers) techniques were used for genotyping. RESULTS: No predictive effects of allele and genotypes of IL-18-607C/A, TNF-α-308G/A, IL-6-174G/C, and IFN-γ+874A/T gene polymorphisms and onset of risk factors and late complications were evidenced. However, Kaplan-Meier analysis evidenced a weak effect of IL-18-137G/C genotypes on graft survival. CONCLUSIONS: Analyzing associations between some pro-inflammatory cytokine gene polymorphisms and onset of the most relevant risk factors and late complications of kidney transplant, results suggested a possible impact of IL-18-137G/C genotypes on graft survival, which deserves further studies.

Cutaneous manifestations in Italian kidney transplant recipients.

Several cutaneous disorders may occur in organ transplant recipients. We examined the incidence and the clinical spectrum of cutaneous manifestations among kidney transplant recipients. One hundred nine patients (70 males and 39 females), aged 19 to 69 years (mean: 42.5 years), were consecutively examined as outpatients between June 2000 and August 2004. The mean interval after kidney transplantation was 61 months (range: 2 to 120 months). The immunosuppressive regimen consisted of combinations including cyclosporine, systemic corticosteroids, azathioprine, tacrolimus, mycophenolate mofetil, antivirals, and antibiotics. Ninety-one cutaneous manifestations were identified in 60 of 109 (55.0%) kidney transplant patients over a 4-year period. Sixteen (17.5%) cutaneous viral infections identified in 11 patients (10.0%) included verruca vulgaris (n = 9), herpes zoster (n = 5) and herpes simplex (n = 2). Thirteen (11.9%) patients showed 19 (20.8%) superficial fungal infections, consisting of dermatophytosis (n = 6), onycomycosis (n = 6), pityriasis versicolor (n = 5) and mucocutaneous candidiasis (n = 2). Twenty (22%) nonmelanoma skin cancers were identified in seven (6.4%) patients, six basal cell carcinomas (BCC) in four patients, two squamous cell carcinomas (SCC) in two patients, and 11 BCCs in addition to one SCC in one patient. Twenty-six (23.8%) patients developed 32 (35.4%) drug-related manifestations, including acneiform eruption (n = 14), gingival hypertrophy (n = 6), hypertrichosis (n = 6), ecchymosis (n = 3), and plantar hyperkeratosis (n = 3). In addition, psoriasis and seborrheic dermatitis, which had been diagnosed before kidney transplantation, were observed in five and three patients, respectively. Our results emphasize the importance of dermatologic examinations and monitoring kidney transplant recipients to obtain an early diagnosis and treatment of cutaneous manifestations.

Waiting list for kidney transplants.

Medical and technological progress have made kidney transplants an effective, alternative therapy to dialysis for patients suffering from chronic kidney failure. Transplantation improves the quality of life of these patients significantly; however, waiting lists are long and this is because of the attitude of the general public to organ donation, not a lack of medical expertise. In fact, the only limiting factor in kidney transplant is the opposition to donation expressed by the deceased or family members. Herein we outline the distribution of patients on the kidney transplant waiting list in the Regional Transplant Centre for Abruzzo and Molise in L'Aquila, Italy, and highlight the reasons why patients are withdrawn from the list, the main reason being a deterioration in patient condition after long periods of dialysis.

Anti-HLA antibodies in kidney transplanted patients.

Anti-human leukocyte antibodies (HLA) play a central role in graft survival, particularly in kidney transplantation. The presence of preformed donor specific anti-HLA antibodies is always excluded before transplantation by performing crossmatches using current and historic recipient serum samples. Several recent studies have observed a correlation between HLA antibodies and graft rejection. It has been suggested that these antibodies should be monitored routinely after kidney transplant to predict graft failure. Here in report the results of a study of on serum samples from 111 kidney transplant recipients that were monitored for anti-HLA antibodies using flow cytometry. Anti-HLA antibodies were only detected in four pre-immunized patients and showed the same HLA specificity that was present before the transplantation (in two cases against previous graft antigens). Furthermore, only two patients with functioning grafts developed anti-HLA antibodies, at 1 month and 1 year after the transplantation. However, they were not donor specific, but probably related to posttransplant transfusions. In our study, none of the patients who suffered an adverse event during the first year (including two with histologically documented acute rejection) developed anti-HLA antibodies. These results are probably related to the use of mycophenolate mofetil, which may reduce the incidence of HLA antibodies. We cannot exclude the possibility that antibodies produced by some patients may not be detectable because they are attached to the graft.

Infectious complications in the renal transplant recipient.

The aim of this study was to estimate the incidence of infectious diseases in a group of patients who underwent kidney transplantation from January 1, 2004 to September 30, 2004, including 121 operations, with 119 from cadaveric and 2 from living donors. The protocol sought herpes viruses (CMV, VZV, and EBV), hepatitis viruses, human immunodeficiency virus, T. gondii, M. tubercolosis, and T. pallidum. Therapy for CMV was used both as prophylaxis in immunoglobulin (Ig)G-negative recipients from IgG-positive donors and preemptive therapy, that is, before the appearance of clinical symptoms, but after viremia reached borderline levels. For VZV infections, the treatment started after the appearance of papulo-vesicular cutaneous eruptions and antibody positivity. The treatment for pneumonia consisted of empirical therapy after radiography; for pyelonephritis, antibiotic therapy was based on the results of kidney echography, blood culture, and urine culture. Infectious complications appeared in 25 patients (20.7%), 3 of the which were polymicrobic: 12 CMV infections, 9 VZV infections, 3 pneumoniae, 4 pyelonephritis, and 1 salmonellosis. The most frequent infection was CMV, which occurred in the first 3 months after transplantation in 9 of 12 cases. This study showed that a knowledge of infection prevalence can help the physician to establish a more specific, efficacious antimicrobial therapy, despite the laboratory response not being available in a short time.

Urologic complications in kidney transplantation.

Urologic complications in kidney transplantation have an incidence ranging from 3% to 20%, representing an important cause of organ loss. From January 2001 to September 2004, 123 renal transplantations were performed using an immunosuppressive protocol including basiliximab, mycophenolate mofetil, calcineurin inhibitors, and steroids. The surgical technique was vascular anastomoses to external iliac vessels, and ureteral anastomosis according to Lich Gregoire technique using a JJ ureteral stent. We report 5 renal complications (4.2%) and 4 extrarenal complications (3.5%), the majority of which required corrective surgery. The surgical strategy uses the clinical condition of the donor and the recipient; the anatomic anomalies of the graft, and a reduced cold ischemia time. Moreover, a reduction in acute rejection episodes and immediate renal function has been fundamental to reduce urologic complications. In fact, the main cause of urologic complications is ureteral ischemia, linked both to backtable surgery and to rejection episodes. Another important factor in the reduction of early urologic complications has been the routine use of a JJ stent, which allowed us a conservative approach in this setting.

Malignancies after kidney transplantation.

The most effective treatment of end-stage renal disease is renal transplantation; its superiority to prolong the longevity of patients is well established. Patient and graft survivals have improved with more potent immunosuppression but this advance has been associated with an increased incidence of cancer. The aim of this study was to assess the prevalence of cancer among 265 kidney transplant recipients engrafted between 1968 and October 2004. The overall prevalence of de novo malignancies was 3%. The mean age at diagnosis was 53.3 years (range, 28-63 years) and the duration of the transplant was 11.6 years (range, 0.3-33 years). One patient among 127 (0.8%) who had a history of less than 3 years under immunosuppression, developed a posttransplantation lymphoproliferative disorder (PTLD). Among the 138 patients who had more than 3 years immunosuppression, 7 (5%) developed neoplasms of vulva, colon, native kidneys, prostatic gland, and ovary. One patient was affected by de novo carcinoma in the transplanted kidney. Compared with other published studies, our early cancer prevalence is low, possibly due to a careful history before grafting, good HLA matching, and abstinence from anti-T-cell therapy for treatment of acute rejection episodes. The low level of immunosuppression may account for the low prevalence of neoplasia. The risk of developing a malignancy increases with long-term immunosuppression, comparable with most reports.

Comparative study of pentoxifylline vs antiaggregants in patients with transient ischaemic attacks.

Out of 235 patients with recent cerebral transient ischaemic attacks, 208 subjects were available for final evaluation after 6 months' randomised treatment with either pentoxifylline (PTX 1200 mg/day) or a combination (ASAD) of acetylsalicylic acid (ASA, 1050 mg/day) and dipyridamole (D, 150 mg/day). Prevention of TIA, stroke or death attributable to previous events were endpoint criteria. The pentoxifylline group (n = 100) exhibited no recurrent episodes in 86 patients (86%). TIA occurred in 9 patients, stroke in 5 patients and there was 1 death. In the ASAD group (n = 108) no recurrence of ischaemic episodes was recorded in 82 cases (75.9%). TIA occurred in 20 patients, stroke in 6 patients and there were 3 deaths of vascular origin. Side effects were recorded in 4 ASAD and 1 PTX patients. The total rate of recurrence was 14% with PTX as compared to 24.1% with ASAD treatment.

Peripheral markers and diagnostic criteria in Alzheimer's disease: critical evaluations.

This review analyzes recent developments in diagnostic criteria and peripheral markers used clinically in the definitive diagnosis of Alzheimer's disease (AD), comparing past and current views, together with a discussion of their shortcoming and difficulties of implementation. Consideration is given to studies on the presence of amyloid substances outside the central nervous system: in cerebrospinal fluid, in plasma, in primary cultures, and in continuous cultures of cell lines of neuronal and glial origin. We discuss alterations of cholinesterases and noradrenaline in red blood cells (RBC) in AD and, with relation to the infectious theory, the presence of spirochaetes in patients. The activities of the enzymes leading to the formation of amyloid substances and those reflecting more general alterations of metabolic processes are considered, both in respect to their role in the pathogenesis of the neurodegenerative disorders of AD and of their potential use as markers. Enzymatic changes have been studied comparing AD patients with non AD controls as well as with AD relatives: proteases and their inhibitors; plasminogen activators; transketolases; increases in the activity of Cu-Zn superoxide dismutase in AD patients' RBC, serum, fibroblasts and cortical neurons, pointing to alterations in oxidative processes; and apolipoprotein E epsilon 4 allele, linked to late-onset AD and familial cases. This review presents reasons why the involvement of peripheral markers in AD should advance from hypothesis to accepted fact.

Copper-zinc superoxide dismutase activity in red blood cells and serum in demented patients and in aging.

The activity of the enzyme copper-zinc superoxide dismutase (Cu-Zn SOD) has been investigated in serum and red blood cells (RBC) homogenate obtained from demented patients with associated vascular lesions (VD), demented patients with probable Alzheimer's disease (DAT) and healthy controls (CG) of the same age. The increase in SOD activity was statistically significant (P < 0.01) in RBCs homogenate of DAT and VD patients, when compared to controls, but no differences appear between the two diseases groups. Additionally, a statistically significant increase in SOD activity (P < 0.01) in DAT patients above 70 years as compared to those 50-70 years old, and a relation between SOD and age were found. No changes in SOD activity with age in healthy controls nor in vascular dementia group were detected. A statistically significant increase in Circulating SOD activity (P < 0.01) was observed in vascular patients compared to controls. The observed increase in DAT Circulating SOD activity (against CG) was not significant. The increased levels of Cu-Zn SOD, probably represent a general alteration of the oxidative processes characteristic of these dementias and suggest that the enzyme might be used as a marker.