Andrological findings in infertile men with two (biallelic) CFTR mutations: results of a multicentre study in Germany and Austria comprising 71 patients.

STUDY QUESTION: When should cystic fibrosis transmembrane conductance regulator (CFTR) mutation analysis be recommended in infertile men based on andrological findings? SUMMARY ANSWER: CFTR mutation analysis is recommended in all men with unexplained azoospermia in the presence of normal gonadotropin levels. WHAT IS KNOWN ALREADY: While 80-97% of men with congenital bilateral absence of the vas deferens (CBAVD) are thought to carry CFTR mutations, there is uncertainty about the spectrum of clinical and andrological abnormalities in infertile men with bilallelic CFTR mutations. This information is relevant for evidence-based recommendations to couples requesting assisted reproduction. STUDY DESIGN, SIZE, DURATION: We studied the andrological findings of patients with two CFTR mutations who were examined in one of the cooperating fertility centres in Germany and Austria. In the period of January till July 2019, the completed and anonymized data sheets of 78 adult male patients were returned to and analysed by the project leader at the Institute of Human Genetics in Innsbruck, Austria. PARTICIPANTS/MATERIALS, SETTING, METHODS: Minimum study entry criteria were the presence of two (biallelic) CFTR mutations and results of at least one semen analysis. Andrological assessments were undertaken by standardized data sheets and compared with normal reference values. Seventy-one patients were eligible for the study (n = 30, 42% from Germany, n = 26, 37% from Austria, n = 15, 21% other nations). MAIN RESULTS AND THE ROLE OF CHANCE: Gonadotropin levels (FSH, LH) were normal, 22% of patients had reduced testosterone values. Mean right testis volume was 23.38 ml (SD 8.77), mean left testis volume was 22.59 ml (SD 8.68) and thereby statistically increased compared to normal (P < 0.01). although the means remained in the reference range of 12-25 ml. Semen analysis revealed azoospermia in 70 of 71 (99%) patients and severe oligozoospermia <0.1 × 106/ml in one patient. Four semen parameters, i.e. ejaculate volume, pH, α-glucosidase and fructose values, were significantly reduced (P < 0.01). Only 18% of patients had a palpatory and sonographically diagnosed CBAVD, while in 31% the diagnosis of CBAVD was uncertain, in 12% patients, the vas deferens was present but hypoplastic, and in 39% the vas deferens was normally present bilaterally. Seminal vesicles were not detectable in 37% and only unilaterally present in 37% of patients. Apart from total testes volume, clinical findings were similar in patients with two confirmed pathogenic CFTR mutations (Group I) compared with patients who carried one pathogenic mutation and one CFTR variant of unknown significance (Group II). LIMITATIONS, REASONS FOR CAUTION: We could not formally confirm the in trans position of genetic variants in most patients as no family members were available for segregation studies. Nonetheless, considering that most mutations in our study have been previously described without other rare variants in cis, and in view of the compatible andrological phenotype, it is reasonable to assume that the biallelic genotypes are correct. WIDER IMPLICATIONS OF THE FINDINGS: Our study reveals that CFTR mutation analysis has a broader indication than just the absence of the vas deferens. We recommend to completely sequence the CFTR gene if there is a suspicion of obstructive azoospermia, and to extend this analysis to all patients with unexplained azoospermia in the presence of normal gonadotropin levels. STUDY FUNDING/COMPETING INTEREST(S): German Research Foundation Clinical Research Unit 'Male Germ Cells: from Genes to Function' (DFG CRU326, grants to F.T.). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

When and how do patients with cardiac amyloidosis die?

BACKGROUND: Cardiac amyloidosis (CA) is an underappreciated cause of morbidity and mortality. Light-chain (AL) and transthyretin (ATTR) amyloidosis have different disease trajectories. No data are available on subtype-specific modes of death (MOD) in patients with CA. METHODS AND RESULTS: We retrospectively investigated 66 with AL and 48 with wild-type ATTR amyloidosis (ATTRwt) from 2000 to 2018. ATTRwt differed from AL by age (74.6 ± 5.4 years vs. 63 ± 10.8 years), posterior wall thickness (16.8 ± 3.3 mm vs. 14.3 ± 2.2 mm), left ventricular mass index (180.7 ± 63.2 g/m2 vs. 133.5 ± 42.2 g/m2), and the proportions of male gender (91.7% vs. 59.1%), atrial enlargement (92% vs. 68.2%) and atrial fibrillation (50% vs. 12.1%). In AL NYHA Functional Class and proteinuria (72.7% vs. 39.6%) were greater; mean arterial pressure (84.4 ± 13.5 mmHg vs. 90.0 ± 11.3 mmHg) was lower. Unadjusted 5-year mortality rate was 65% in AL-CA vs. 44% in the ATTRwt group. Individuals with AL-CA were 2.28 times ([95%CI 1.27-4.10]; p = 0.006) more likely to die than were individuals with ATTRwt-CA. Information on MOD was available in 56 (94.9%) of 59 deceased patients. MOD was cardiovascular in 40 (66.8%) and non-cardiovascular in 16 (27.1%) patients. Cardiovascular [28 (68.3%) vs. 13 (80%)] death events were distributed equally between AL and ATTRwt (p = 0.51). CONCLUSION: Our data indicate no differences in MOD between patients with AL and ATTRwt cardiac amyloidosis despite significant differences in clinical presentation and disease progression. Cardiovascular events account for more than two-thirds of fatal casualties in both groups.

Klotho is upregulated in human cardiomyopathy independently of circulating Klotho levels.

Klotho is an antiaging protein which exerts known cardioprotection. In kidney, trans-membrane Klotho acts as essential co-receptor of fibroblast growth factor 23 (FGF23). In the heart, soluble Klotho (sKlotho) protects from systolic dysfunction independently of FGF23. Here, we analyzed the association of FGF23 and sKlotho upon progression of chronic heart failure (CHF) and analyzed Klotho expression in human hearts. Serum levels of sKlotho and FGF23 were measured in 287 patients with cardiomyopathy (CMP). Tissue samples from CMP (n = 10) and healthy control hearts (n = 10) were analyzed for Klotho mRNA and protein expression. Individuals in the first FGF23 tertile were 4.1 times more likely of freedom from death, heart transplantation or assist device implantation compared to third tertile. No relationship was found between sKlotho and the combined endpoint. Instead, Klotho mRNA encoding the full-length form was upregulated in human CMP hearts. Immunoblotting confirmed upregulation of sKlotho associated with increased expression of proteases involved in cleavage of Klotho suggesting rather local effects of Klotho in the heart. Therefore, we conclude that in contrast to FGF23, serum sKlotho is not associated with disease severity or progression in CHF. Instead, Klotho is expressed and upregulated in diseased hearts, suggesting local paracrine effects.

Dynamic Behavior of Engineered Lattice Materials.

Additive manufacturing (AM) is enabling the fabrication of materials with engineered lattice structures at the micron scale. These mesoscopic structures fall between the length scale associated with the organization of atoms and the scale at which macroscopic structures are constructed. Dynamic compression experiments were performed to study the emergence of behavior owing to the lattice periodicity in AM materials on length scales that approach a single unit cell. For the lattice structures, both bend and stretch dominated, elastic deflection of the structure was observed ahead of the compaction of the lattice, while no elastic deformation was observed to precede the compaction in a stochastic, random structure. The material showed lattice characteristics in the elastic response of the material, while the compaction was consistent with a model for compression of porous media. The experimental observations made on arrays of 4 × 4 × 6 lattice unit cells show excellent agreement with elastic wave velocity calculations for an infinite periodic lattice, as determined by Bloch wave analysis, and finite element simulations.

Solubility and permeability of steroids in water in the presence of potassium halides.

Water forms a network of hydrogen bonded water molecules that gives liquid water unique physicochemical properties. Ions that affect the network structure, e.g. potassium halides, are known to either increase or decrease aqueous solubilities of drugs. Most biological membranes consist of hydrophilic exterior and a lipophilic interior. Mathematically they can be treated as two-layer membranes, i.e. a hydrophilic water layer that is referred to as unstirred water layer (UWL) and a lipophilic membrane. The purpose of this study was to investigate if and then how ions affect drug permeation through the UWL. The effects of potassium halides on the solubility and permeability of dexamethasone and hydrocortisone was investigated. The potassium halides had either increasing or decreasing effect on their aqueous solubility but did not have any effect on their permeability through UWL.

Identification of lysophosphatidylcholine-chlorohydrin in human atherosclerotic lesions.

Lysophosphatidylcholine (LysoPtdCho) levels are elevated in sera in patients with atherosclerosis and in atherosclerotic tissue. Previous studies have shown that reactive chlorinating species attack plasmalogens in human coronary artery endothelial cells (HCAEC), forming lysoPtdCho and lysoPtdCho-chlorohydrin (lysoPtdCho-ClOH). The results herein demonstrate for the first time that lysoPtdCho-ClOH is elevated over 60-fold in human atherosclerotic lesions. In cultured HCAEC, 18:0 lysoPtdCho-ClOH led to a statistically significant increase in P-selectin cell-surface expression, but unlike 18:1 lysoPtdCho did not lead to cyclooxygenase-2 protein expression. These data show that 18:0 lysoPtdCho-ClOH is elevated in atherosclerotic tissue and may have unique pro-atherogenic properties compared to lysoPtdCho.

The superficial cervical plexus block for postoperative pain therapy in carotid artery surgery. A prospective randomised controlled trial.

OBJECTIVES: Rapid and reliable neurological evaluation soon after carotid artery surgery is feasible with modern methods of general anesthesia, but postoperative pain therapy remains a challenge. Use of opioids can mask neurological deficits. We investigated whether superficial cervical plexus block reduced postoperative opioid consumption after carotid endarterectomy. DESIGN: Prospective, randomised, double-blinded, placebo controlled trial. METHODS: 46 patients undergoing unilateral carotid endarterectomy under general anesthesia were randomized to either superficial cervical block with ropivacaine (n=23) or placebo (n=23). A patient controlled analgesia device (PCA) delivering morphine was provided for all patients. Subjective pain levels (visual analog scale, VAS) were recorded. The primary outcome was total morphine consumption on discharge from the recovery room. Secondary outcomes included arterial pCO2 (as an indicator of central nervous effects of morphine) and patient satisfaction. RESULTS: No adverse effects of the superficial cervical plexus block were reported. Four patients in the placebo group were excluded because of other drug use post-operatively. Per protocol analysis compared 23 patients in ropivacaine group and 19 patients in the placebo group. The ropivacaine group had a significant reduction in morphine consumption (3.8+/-2.0 versus 12.9+/-4.0, p<0.001), lower maximal pain scores (2.6+/-2.0 versus 5.8+/-1.6, p<0.001), and paCO2 levels (39.0+/-2.6 versus 41.9+/-3.4, p=0.008) at discharge from the recovery room. Patient satisfaction (1=very good to 6=insufficient) was substantially higher in the ropivacaine group (1.7+/-0.7 versus 3.1+/-1.2, p<00.01). CONCLUSION: The significant and clinically relevant lower morphine consumption and pain score, as well as the substantially higher patient satisfaction demonstrate that superficial cervical plexus block provides effective pain relief for patients undergoing carotid endarterectomy.

C4d: a marker for hepatic transplant rejection.

BACKGROUND: Acute rejection is still a common complication of hepatic transplantation. The diagnosis, based on the histological examination of the graft, may be difficult to confirm in the setting of combined hepatitis C virus infection. The presence of C4d in the portal capillaries could facilitate differentiation between acute rejection and relapsed hepatitis C. The deposit of C4d provides evidence of activation of humoral immunity. To attempt to confirm this hypothesis, we searched for the presence of C4d in posttransplant hepatic biopsies. METHODS: Thirty-six biopsies from 34 patients were analyzed retrospectively. The samples had been requested for one of the following reasons: suspected rejection, relapsed hepatitis C infection, or systematic check-up 1 year after the transplant. RESULTS: C4d expression was common in biopsies classified as acute rejection (33%) and chronic rejection (100%). C4d was never detected in the event of recurrent hepatitis C infection without rejection. CONCLUSION: These results, which are comparable to recently published data, give credence to the theory that C4d could be used as a marker for rejection following hepatic transplantation.

Improved liver function and decreased hepatitis C viral load after tacrolimus was replaced by cyclosporine.

Potential antiviral properties of cyclosporine against hepatitis C virus have been highlighted in several publications. Therefore, we investigated the effect of a switch from tacrolimus to cyclosporine in a liver transplant recipient with recurrent hepatitis C who did not respond to antiviral therapy. The patient received a liver transplant for hepatitis C cirrhosis. Initial immunosuppressive treatment was based on tacrolimus. Because of viral activity, a combined therapy was initiated 20 months later including interferon and ribavirine. Then, due to a lack of virological and biochemical response, tacrolimus was replaced by cyclosporine (Neoral), while maintaining the same antiviral therapy. Decreases in the viral load and transaminases levels were observed.

Preoperative treatment of hepatocellular carcinoma with intra-arterial injection of 131I-labelled lipiodol.

BACKGROUND: Recurrence is common after surgery for hepatocellular carcinoma (HCC). METHODS: The efficacy of, and tolerance to, preoperative intra-arterial injection of (131)I-labelled lipiodol was examined in 34 patients with HCC, including 29 with cirrhosis. Twenty-five patients had a single hepatic tumour and the mean(s.d.) tumour size was 5.2(3.7) (range 2-15) cm. The patients received between one and three injections of (131)I-labelled lipiodol (60 mCi per injection) before surgery. Operations included 14 liver transplants, 13 minor hepatectomies, six major hepatectomies and one exploratory laparotomy. RESULTS: There was one complication after lipiodol injection due to acute ischaemia of the small bowel. Three of 34 patients died within 28 days, two after transplantation and one after resection. An objective tumour response (decrease in tumour size) was observed in 19 of 34 patients, and a complete histological response in eight of 34. There was an objective tumour response or major histological necrosis of lesions in 25 of 34 patients. The 5-year survival rate was 48.4(8.0) per cent, 69.0 per cent after transplantation and 36.0 per cent in patients who underwent resection. CONCLUSION: This preoperative method appeared to be well tolerated, and provided promising results in terms of macroscopic and microscopic tumour responses.

The bispectral index declines during neuromuscular block in fully awake persons.

UNLABELLED: Bispectral index (BIS) is an electroencephalographic variable promoted for measuring depth of anesthesia. Electromyographic activity influences surface electroencephalography and the calculation of BIS. In this study, we sought to determine the effect of spontaneous electromyographic activity on BIS. BIS was monitored in three volunteers by using an Aspect A-1000 monitor. The experiment was repeated in one volunteer. Electromyographic activity was recorded. Alcuronium and succinylcholine were administered. No other drugs were used. In parallel with spontaneous electromyographic activity of the facial muscles, BIS decreased in response to muscle relaxation to a minimum value of 33 and, in the repeated measurement, to a minimum value of 9 when total neuromuscular block was achieved. In two volunteers, no total block was achieved. BIS decreased to a minimal value of 64 and 57, respectively. In turn, recovery of BIS coincided with the reappearance of spontaneous electromyographic activity. During the entire experiment, the volunteers had full consciousness. BIS, assessed by software Version 3.31, correlates with spontaneous electromyographic activity of the facial muscles. BIS failed to detect awareness in completely paralyzed subjects. Thus, in paralyzed patients, BIS monitoring may not reliably indicate a decline in sedation and imminent awareness. IMPLICATIONS: The bispectral index (BIS) is an electroencephalographic variable intended for measuring depth of anesthesia. Electromyographic activity influences the calculation of BIS. We found that the administration of a muscle relaxant to unanesthetized volunteers decreases the bispectral index value. Thus, awareness in totally paralyzed patients cannot be excluded.

Use of recombinant factor VIIa to treat persistent bleeding following dental extractions in two cirrhotic patients.

BACKGROUND AND OBJECTIVES: A single dose of recombinant factor VIIa (rFVIIa) has been shown to be effective and safe in correcting the prothrombin time (PT) in cirrhotic patients, but no clinical data exists demonstrating its efficacy in arresting active bleeding. MATERIALS AND METHODS: rFVIIa was used in two cirrhotic patients for persistent bleeding following dental extractions despite repeated treatment at the wound site and, in one case, repeated administrations of fresh-frozen plasma (FFP). RESULTS: Bleeding stopped promptly in both patients after administration of rFVIIa. However, bleeding recurred in the patient who had not received concomitant treatment at the extraction sites. No recurrence of bleeding was observed in the second patient, who underwent local treatment 15 min after rFVIIa. CONCLUSIONS: Recombinant factor VIIa arrested bleeding after dental extractions in two cirrhotic patients who had been unsuccessfully treated with FFP. However, additional local treatment is needed to limit the risk of recurrence as a result of the short half-life of rFVIIa.

Presence of melatonin in the human hepatobiliary-gastrointestinal tract.

A variety of speculations about the possible origin and physiological role of the neurohormone melatonin in the gastrointestinal tract exist. However, the experimental evidence supporting any of these theories is not substantial and are missing for humans. We studied the distribution of melatonin which was measured with radioimmunoassay in the following compartments and organs of the human hepatobiliary-gastrointestinal tract: bile (obtained by endoscopic retrograde cholangiopancreaticography), peripheral venous and portal venous blood (obtained from patients undergoing liver transplantation), endoscopically derived biopsies (mainly consisting of mucosa and submucosa) of stomach, duodenum, large intestine as well as in resected liver tissue. Melatonin concentrations in gastrointestinal mucosa were between 136 +/- 27 pg/100 mg (stomach) and 243 +/- 37 pg/100 mg (descending colon, each n = 5). Biliary melatonin concentrations (85 +/- 45 pg/ml) correlated well with plasma concentrations (55 +/- 38 pg/ml, each n = 14) and a considerable amount of melatonin (about 51 ng/24 hours) appears to be excreted into the gut via the bile duct. Melatonin concentrations were slightly higher in portal than in peripheral venous blood and also the liver contained higher concentrations of melatonin than the blood. In conclusion the presence and distribution of melatonin in human gut, bile, liver and portal blood and the various reports on modulatory actions of melatonin on gut and liver functions suggest that melatonin may act as a mediator of inter-organ communication between gut and liver.

Low rejection rates with tacrolimus-based dual and triple regimens following liver transplantation.

We studied the outcome of 345 liver transplant patients who received tacrolimus-based immunosuppressive therapy either as a dual regimen (with corticosteroids, n=172) or as a triple regimen (with corticosteroids and azathioprine, n=173) for 3 months after transplantation (3-month cohort). A further analysis was conducted for the first 195 patients randomised (dual n=100, triple n=95) who were followed up for 12 months after transplantation (12-month cohort). For the 3-month cohort, patient survival was 90.7% (dual) and 91.9% (triple), graft survival after 3 months was 88.4% (dual therapy) and 89.6% (triple therapy). Acute rejections were experienced by 67/172, 39.0% of patients on dual therapy and by 60/173, 34.7% of patients on triple therapy; corticosteroid-resistant rejections were reported in 9 patients (5.2%) in either treatment group. The overall safety profile was similar for the two treatment groups. Significant differences, however, were found for thrombocytopenia (dual 13/172, 7.6%, triple 37/173, 21.4%, p<0.001) and leukopenia (dual 4/172, 2.3%, triple 24/173, 13.9%, p<0.001). For the 12-month cohort, patient survival was 85.6% (dual) and 88.4% (triple) after 1 year. Graft survival was 81.7% (dual) and 85.2% (triple) 12 months after transplantation. Acute rejections were reported for 38/100, 38.0% of patients on dual therapy and 36/95, 37.9% of patients on triple therapy, corticosteroid-resistant rejections were 7/100, 7.0% (dual) and 7/95, 7.4% (triple) of patients. In the 12-month cohort, no significant differences in the safety profiles of the treatment groups were found. We conclude that both tacrolimus-based dual and triple drug regimens provide effective and safe immunosuppression following orthotopic liver transplantation.

Risk assessment for Cryptosporidium: a hierarchical Bayesian analysis of human dose response data.

Three dose-response studies were conducted with healthy volunteers using different Cryptosporidium parvum isolates (IOWA, TAMU, and UCP). The study data were previously analyzed for median infectious dose (ID50) using a simple cumulative percent endpoint method (Reed and Muench, 1938). ID50s were derived using two definitions of infection: one as subjects having oocysts detected in stool by direct fluorescence assay, and the other by a clinical finding of diarrhea with or without detected oocysts (Chappell et al., 1998; Okhuysen et al., 1999). In the present study, the data were analyzed using the broader definition of infection (i.e., presence of oocysts in stool and/or diarrheal illness characteristic of cryptosporidiosis). Maximum likelihood dose-response parameter estimates for UCP, IOWA, and TAMU were 2980, 190, and 17.5, respectively. Based on these estimates, the ID50s of the three respective isolates were 2066, 132, and 12.1. The three oocyst isolates were considered representative of a larger population of human-infecting strains and analyzed as combined data using a hierarchical Bayesian model. Hyperparameters defined the distribution of dose-response parameters for the population of strains. Output from Markov Chain Monte Carlo analysis described posterior distributions for the hyperparameters and for the parameters of the IOWA, TAMU, and UCP strains. Point estimates of dose-response parameters produced by this analysis were similar to the maximum likelihood estimates. Finally, the utility of these results for probabilistic risk assessment was evaluated. The risk of infection from single oocyst doses was derived for a mixture of the three isolates (where IOWA, TAMU, or UCP are equally likely), and for an oocyst selected at random from the larger population of strains. These estimated risks of infection were 0.018 and 0.028, respectively.

Interferon and ursodeoxycholic acid combined therapy in chronic viral C hepatitis: controlled randomized trial in 203 patients.

AIMS: This prospective randomized trial was carried out in order to determine whether the long-term administration of ursodeoxycholic acid after discontinuation of interferon had any beneficial effect on the clinical course of hepatitis C virus infection. METHODS: Enrolled in the study were 203 patients with chronic active hepatitis C. They were all given: interferon alpha-2a (3 MU subcutaneously thrice a week) and ursodeoxycholic acid (10 mg/kg/day) for 9 months. At month 9, biochemical responders only were randomized into ursodeoxycholic acid treatment or placebo for 12 additional months (double blind study). RESULTS: At the end of interferon therapy, 71 patients (37%) were virological responders and 107 (56%) patients were biochemical responders and were randomized: 54 into the ursodeoxycholic acid group and 53 into the placebo group. Sustained response was evaluated 12 months after withdrawal of interferon. Sustained biochemical and virological responses were, respectively, 30% and 22% in the ursodeoxycholic acid group and 46% and 32% in the placebo group, which did not significantly differ. Histological evolution of fibrosis and necrotic inflammatory activity were similar in the two groups. CONCLUSION: Continuation of ursodeoxycholic acid therapy after withdrawal of interferon in patients with end-of-treatment response did not result in any significant improvement either in the maintenance of response to interferon or in liver histology.

[Polyradiculoneuropathy in an adult with primitive hyperoxaluria]. / Polyradiculoneuropathie au cours d'une hyperoxalurie primitive de l'adulte.

From the age of 31 a patient began to suffer from recurrent calcium oxalate urolithiasis. Liver biopsy showed a decrease in catalytic activity of the hepatic peroxisomal enzyme alanine: glyoxilate aminotransferase (AGT), which was mistargeted from peroxisomes to mitochondria. The genetic analysis revealed a mutation of the AGT gene. At age 47 he developed end-stage renal failure and underwent hemodialysis. After 12 months of hemodialysis he presented a rapidly declining clinical condition, a decrease of the residual renal function, a livedo reticularis with painful of extremities, and shortly thereafter a general weakness, which predominated on lower limbs. Apart from renal failure, routine biological examination and CSF were normal. Nerve conduction studies and electromyography supported the diagnosis of polyradiculoneuropathy. Pathological studies revealed mixed demyelinating-axonal lesions and deposits of calcium oxalate crystals within the media and the intima of epineural arterioles. A combined liver-kidney transplant was rapidly performed. The patient's condition improved in a few months and motor signs completely disappeared.

[Patient-oriented anesthesia] . / Patientenorientierte Anästhesie.

Goals of this study were to quantify patients' preferences for anaesthesia care and to identify what they know about various tasks of an anaesthetist. On the day before surgery, 122 patients scheduled for elective procedures were interviewed using a structured questionnaire. A reliable pain relieve and unawareness as well as stable vital functions have priority in patients' preferences. Patients are also concerned with good postoperative pain relieve and the avoidance of nausea and vomiting. Not important are short preoperative soberness, rapid awakening and initial wide awakeness. Not informed about typical tasks of an anaesthetist are 28-51% of the patients. In order to obtain maximum patient satisfaction, a thorough education plus further continuous training are the essential items for a patient orientated health care management in anaesthesia, along with good medical and technical equipment. The wide spectrum of tasks of an anaesthetist must be better represented in order to strengthen the position of anaesthesia in the competition for rare resources. A postoperative visit, which is judged of 77% of the patients as important, offers a beginning.

Liver graft infection by HBV S-gene mutants in transplant patients receiving long-term HBIg prophylaxis.

BACKGROUND/AIMS: HBV reinfection of transplant livers occurs frequently even in the presence of high doses of anti-HBs immunoglobulins. We analyzed, retrospectively, whether and which type of S-gene variants were selected by long-term polyclonal anti-HBs (HBIg) treatment leading to reinfection of patients transplanted because of chronic HBs-positive end-stage liver disease. METHODOLOGY: The preS2/S gene of the viral genomes obtained from sera before transplantation and during HBV reinfection was amplified by PCR and directly sequenced. RESULTS: According to transaminase and HBV DNA hybridization analysis, 3/18 (17%) liver transplant patients had HBV and hepatitis recurrence during anti-HBs therapy. A HBV S-gene mutant containing a G to A nucleotide mutation at position 587, converting Glycine to Arginine (G145A), was identified in all three patients as the dominant population at reinfection but not pre-transplantation. Contrary to the S-gene, no consistent nucleotide changes were found in the pre-S2 region of HBV genomes when comparing the reinfection and pre-transplantation samples. CONCLUSIONS: These data demonstrate that long-term polyclonal anti-HBs immunoprophylaxis selected the most commonly described G145R S-gene escape HBV variant which became the dominant virus population and was responsible for graft infection. Therefore, immunoglobulins with high affinity for the G145R HBs variant should be included in HBIg to prevent recurrent HBV infection in transplant patients.

Evaluation of efficacy of liver transplantation in alcoholic cirrhosis using matched and simulated controls: 5-year survival. Multi-centre group.

BACKGROUND/AIMS: Alcoholic cirrhosis is the most common cause of liver transplantation in US males. The limited number of donor livers calls for "prioritisation", favouring those patients who will benefit most. The aim was to assess the efficacy of liver transplantation in patients with alcoholic cirrhosis. METHODS: We compared the survival of 169 transplanted patients with two conservatively treated control groups, one of 169 patients matched for prognostic factors (age, cirrhosis severity, bleeding history) and one of 169 simulated patients. RESULTS: The probability of survival to 5 years in the transplanted group was 66% (95% confidence interval 58-74%) vs. 52% (44-60; p = 0.03) in the matched group and 54% (51-57; p = 0.01) in the simulated controls. Transplantation was associated with survival (relative risk = 1.51; p = 0.02), independently of risk score (risk = 2.07; p<0.001), indication, period of inclusion, centre experience, and alcohol abstinence. Patients with severe disease (Pugh C11-15) benefited most in terms of 5-year survival: 58% (44-72) vs. 31% (17-45; p = 0.008) in the matched and 35% (30-40; p<0.001) in the simulated control groups. For patients at lower risk there was no significant difference. CONCLUSIONS: Liver transplantation increases the 5-year survival of patients with severe alcoholic cirrhosis. In patients at lower risk, efficacy of transplantation should be confirmed by longer follow-up or by randomised trial.