Efficacy and safety of canagliflozin when used in conjunction with incretin-mimetic therapy in patients with type 2 diabetes.

AIMS: To assess the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes enrolled in the CANagliflozin cardioVascular Assessment Study (CANVAS) who were on an incretin mimetic [dipeptidyl peptidase-4 (DPP-4) inhibitor or glucagon-like peptide-1 (GLP-1) receptor agonist]. METHODS: CANVAS is a double-blind, placebo-controlled study that randomized participants to canagliflozin 100 or 300 mg or placebo added to routine therapy. The present post hoc analysis assessed the efficacy and safety of canagliflozin 100 and 300 mg compared with placebo in subsets of patients from CANVAS who were taking background DPP-4 inhibitors or GLP-1 receptor agonists with or without other antihyperglycaemic agents at week 18. RESULTS: Of the 4330 patients in CANVAS, 316 were taking DPP-4 inhibitors and 95 were taking GLP-1 receptor agonists. At 18 weeks, canagliflozin 100 and 300 mg provided larger placebo-subtracted reductions in glycated haemoglobin (HbA1c) in patients taking DPP-4 inhibitors [-0.56% (95% confidence interval [CI]: -0.77, -0.35), and -0.75% (95% CI: -0.95, -0.54), respectively] and GLP-1 receptor agonists [-1.00% (95% CI: -1.35, -0.65), and -1.06% (95% CI: -1.43, -0.69), respectively]. Body weight and blood pressure (BP) reductions were seen with canagliflozin versus placebo in both subsets. Higher incidences of genital mycotic infections and osmotic diuresis-related adverse events (AEs) were seen with canagliflozin compared with placebo. The incidence of hypoglycaemia was numerically higher with canagliflozin versus placebo; nearly all events occurred in patients on background insulin or insulin secretagogues. CONCLUSIONS: In patients on background incretin mimetics, canagliflozin improved HbA1c, body weight and BP, with an increased incidence of AEs related to SGLT2 inhibition.

Apparent subadditivity of the efficacy of initial combination treatments for type 2 diabetes is largely explained by the impact of baseline HbA1c on efficacy.

AIM: To explain the subadditive efficacy typically observed with initial combination treatments for type 2 diabetes. METHODS: Individual subject data from 1186 patients with type 2 diabetes [mean glycated haemoglobin (HbA1c) = 8.8%] treated with metformin, canagliflozin or canagliflozin + metformin were used. The baseline HbA1c versus ΔHbA1c relationships for monotherapy arms were determined using analysis of covariance and then used to predict efficacy in the combination arms by modelling how applying one treatment lowers the 'effective baseline HbA1c' for a second treatment. The model was further tested using data from several published combination studies. RESULTS: The mean ΔHbA1c levels were -1.25, -1.33, -1.37, -1.77 and -1.81% with metformin, canagliflozin 100 mg, canagliflozin 300 mg, canagliflozin 100 mg/metformin and canagliflozin 300 mg/metformin, respectively. Using the monotherapy results, the predicted efficacy for the canagliflozin/metformin arms was within 10% of the observed values using the new model, whereas assuming simple additivity overpredicted efficacy in the combination arms by nearly 50%. For 10 other published initial combination studies, predictions from the new model [mean (standard error) predicted ΔHbA1c = 1.67% (0.14)] were much more consistent with observed values [ΔHbA1c = 1.72% (0.12)] than predictions based on assuming additivity [predicted ΔHbA1c = 2.19% (0.21)]. CONCLUSIONS: The less-than-additive efficacy commonly seen with initial combination treatments for type 2 diabetes can be largely explained by the impact of baseline HbA1c on the efficacy of individual treatments. Novel formulas have been developed for predicting the efficacy of combination treatments based on the efficacy of individual treatments and the baseline HbA1c of the target patients.

A novel 8-color flow cytometry panel to study activation, maturation and senescence of CD4 and CD8 T lymphocytes in HIV-infected individuals at different stages of disease.

Multicolor flow cytometry allows to study the markers differentially expressed during maturation, activation, function and senescence on immune cells. Despite the availability of reagents and technology, scarce agreement has been gained regarding phenotypic markers of HIV disease progression other than CD4 T-cell count. In this work, we present a novel high-throughput global analysis of CD4 and CD8 T-lymphocyte profiles by standardized 8-color combinations of antibodies aimed at analyzing HIV disease course progression. For this purpose, two tubes with lyophilized reagent cocktails (CD4- and CD8-specific tubes) were designed to compare the immunological characteristics of HIV-infected persons (37 "high CD4" HAART-treated and 32 "low CD4" naïve or failed-treatment patients) with healthy donors (HD). In particular, T-cell activation (CD25, CD38, CD69), differentiation (CD45RA, CCR7), apoptosis (CD95) and immune suppression profiles (CD25(high)CD127-) in HIV+ patients were compared with HD. Statistical analysis was performed by identifying the parameters associated with disease progression, namely markers that were found to be significantly different between groups with high CD4 counts (including HD) and low CD4 counts (restricted to HIV patients) but not between the HD and the "high CD4" group. This set of markers, including those identifying different maturation and senescence subtypes of CD4 and CD8 T cells, was found to be associated with therapy failure, and it is in fact evaluated in an ongoing study aimed to verify its prognostic value. This robust assay was found feasible on a semi-routine scale for HIV-infected persons, and allows for broader clinical studies aimed at defining markers associated with treatment outcome, possibly having a high impact on the clinical management of HIV disease.

Effect of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, on bacteriuria and urinary tract infection in subjects with type 2 diabetes enrolled in a 12-week, phase 2 study.

OBJECTIVE: To examine the effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor that lowers blood glucose by increasing urinary glucose excretion (UGE), on asymptomatic bacteriuria and urinary tract infections (UTIs). RESEARCH DESIGN AND METHODS: In a randomized, double-blind, placebo-controlled, multicenter, dose-ranging phase 2 study, subjects with type 2 diabetes with inadequate glycemic control while receiving metformin were enrolled and randomized to one of seven arms - placebo; canagliflozin doses 50 mg, 100 mg, 200 mg, 300 mg daily, or 300 mg twice daily; and sitagliptin 100 mg daily - for 12 weeks. CLINICAL TRIAL REGISTRATION: This study is registered under Clinicaltrials.gov identification number NCT00642278. RESULTS: Canagliflozin increased renal glucose excretion by 35.4-61.6 mg/mg creatinine in the five dose groups. In the placebo group renal glucose excretion was increased by 1.9 mg/mg creatinine, and in the sitagliptin group it decreased by 1.9 mg/mg creatinine. Asymptomatic bacteriuria (ASB) were present in 6.4% of canagliflozin and 6.5% of placebo/sitagliptin (control) subjects at randomization and, at 12 weeks, in 7.7% and 6.3% of subjects, respectively (odds ratio [OR] 1.23; 95% confidence interval [CI], 0.45-3.89). For subjects with initially negative urine cultures at baseline, 3 out of 82 (3.7%) who received controls and 10 out of 207 (4.8%) who received canagliflozin developed bacteriuria (p = 0.76) at week 12. There were 21 adverse event (AE) reports of UTI; 16 (5.0%) in canagliflozin subjects and 5 (3.8%) in control subjects (OR 1.31; 95% CI, 0.45-4.68). CONCLUSIONS: In this trial, when compared with control subjects, canagliflozin increased UGE but was not associated with increased bacteriuria or AE reports of UTI. However, further studies enrolling larger numbers of subjects with longer term exposure to canagliflozin will be necessary to more fully understand the impact of this agent on the risk of developing UTI.

Surgical management of morbidity due to lymphatic filariasis: the usefulness of a standardized international clinical classification of hydroceles.

The objective of this work is to evaluate the usefulness of a standardized clinical classification of hydroceles in lymphatic filariasis endemic countries to guide their surgical management. 64 patients with hydroceles were operated in 2009-2010, in Level II hospitals (WHO classification), during two visits to Fiji, by the same mobile surgical team. The number of hydroceles treated was 83. We developed and evaluated a much needed clinical classification of hydroceles based on four criteria: Type (uni/bilateral); Side (left/right); Stage of enlargement of the scrotum rated from I to VI; Grade of burial of the penis rated from 0 to 4. It lead to the conclusion that 1) A Stage I or II hydrocele, associated with Grade 0 or 1 penis burial could be considered a "Simple Hydrocele". The surgical treatment is simple with no anticipated early complication. WHO Level II of health care structure seems adapted. 2) A Stage III or IV hydrocele associated with Grade 2, 3 or 4 penis burial could be considered a "Complicated Hydrocele". The operation is longer, more complicated and the possibility of occurrence of complications seems greater. A level III health care facility would be more adapted under the normal functioning of the health system. We conclude that a standardized clinical classification of hydroceles based on the Stage of enlargement of the scrotum and the Grade of burial of the penis appears to be a useful tool to guide the decision about the level of care and the surgical technique required. We use the same classification for penoscrotal lymphoedema. A decision tree is presented for the management of hydroceles in lymphatic filariasis endemic countries which could usefully complement the "Algorithm for management of scrotal swelling" proposed by WHO in 2002. An international classification system of hydroceles would also allow standardization and facilitate study design and comparisons of their results.

Universal features of the melt elasticity of interacting polymer nanocomposites.

We study the structure and linear viscoelasticity of interacting polymer nanocomposites based on mixtures of poly(ethylene oxide) and fumed silica particles. The filler is dispersed within the polymer using two different techniques which lead to different dispersion states. The analysis of the dynamic response of our systems highlights the formation of a stress-bearing network above a critical volume fraction, Φ(c). Extending a two-phase model used to describe weakly interacting systems, we show that above Φ(c) the melt-state elasticity of the composites arises from the independent contributions of a polymer-particle network and a viscous matrix. We also find that, although Φ(c) depends on the initial state of dispersion, the network elasticity scales with volume fraction following a universal power-law, with an exponent ν ≈ 1.8. Such a scaling law has been recently predicted for the stress-bearing mechanism governed by polymer-mediated interactions.

Surgical management of morbidity due to lymphatic filariasis: The usefulness of a standardized international clinical classification of hydroceles

Abstract. The objective of this work is to evaluate the usefulness of a standardized clinical classification of hydroceles in lymphatic filariasis endemic countries to guide their surgical management. 64 patients with hydroceles were operated in 2009-2010, in Level II hospitals (WHO classification), during two visits to Fiji, by the same mobile surgical team. The number of hydroceles treated was 83. We developed and evaluated a much needed clinical classification of hydroceles based on four criteria: Type (uni/bilateral); Side (left/right); Stage of enlargement of the scrotum rated from I to VI; Grade of burial of the penis rated from 0 to 4. It lead to the conclusion that 1) A Stage I or II hydrocele, associated with Grade 0 or 1 penis burial could be considered a “Simple Hydrocele”. The surgical treatment is simple with no anticipated early complication. WHO Level II of health care structure seems adapted. 2) A Stage III or IV hydrocele associated with Grade 2, 3 or 4 penis burial could be considered a “Complicated Hydrocele”. The operation is longer, more complicated and the possibility of occurrence of complications seems greater. A level III health care facility would be more adapted under the normal functioning of the health system. We conclude that a standardized clinical classification of hydroceles based on the Stage of enlargement of the scrotum and the Grade of burial of the penis appears to be a useful tool to guide the decision about the level of care and the surgical technique required. We use the same classification for penoscrotal lymphoedema. A decision tree is presented for the management of hydroceles in lymphatic filariasis endemic countries which could usefully complement the “Algorithm for management of scrotal swelling” proposed by WHO in 2002. An international classification system of hydroceles would also allow standardization and facilitate study design and comparisons of their results.

Brain abscess due to Klebsiella pneumoniae in a liver-transplanted child.

Brain abscesses are a rare, severe complication of orthotopic liver transplantation (OLT). They are almost exclusively due to fungi, Nocardia, or Toxoplasma, and usually occur within months of surgery. Here we report the case of an adolescent who developed a brain abscess due to Klebsiella pneumoniae 11.5 years after OLT. Fever was absent and laboratory parameters were not indicative of infectious disease, and therefore the diagnosis of a central nervous system neoplasm was considered. Subsequent magnetic resonance imaging and spectroscopy led to a diagnosis of a brain abscess, and to prompt appropriate antibiotic treatment. This case shows that K. pneumoniae may cause a brain abscess long after liver transplantation. The appearance of neurological symptoms should alert clinicians to consider a brain abscess even in the absence of overt clinical/laboratory signs of inflammation, which may be blunted by chronic immunosuppression.

An unusual case of ascites.

A 76-year-old woman with abdominal pain and diarrhoea developed ascites that did not respond to treatment. There were no signs of liver damage. Abdominal ultrasonography with colour Doppler revealed an arterial-like flow in the enlarged splenic vein. Using selective mesenteric arteriography, we were able to diagnose a shunt between the inferior mesenteric artery and the inferior mesenteric vein. This is an unusual case of ascites due to prehepatic portal hypertension secondary to an extrahepatic arterioportal fistula.

Tamoxifen in the treatment of hepatocellular carcinoma: 5-year results of the CLIP-1 multicentre randomised controlled trial.

BACKGROUND: In 1998, when data of a meta-analysis on tamoxifen in the treatment of hepatocellular carcinoma (HCC) had suggested a little advantage for this treatment, we published the results of a multicenter randomised controlled trial, that showed no survival benefit for tamoxifen vs. control. Here we report an updated analysis of the study results 4.5 years after the closure of enrollment. METHODS: The study had a planned sample size of 480 patients. Patients with any stage HCC were eligible, irrespective of locoregional treatment. Tamoxifen was given orally, 40 mg/die, from randomisation until death. RESULTS: 496 patients were randomised by 30 Institutions from January 1995 to January 1997. Information was available for 477 patients. As of July 2001, 374 deaths (78%) were recorded, and median survival times were 16 and 15 months (p=0.54), in the control and tamoxifen arm. Data were further analysed separately for advanced patients and for those eligible to potentially curative locoregional treatments: relative hazard of death for patients receiving tamoxifen was equal to 0.98 (95% CI 0.76-1.25) for the former group and 1.38 (95% CI 0.95-2.01) for the latter. The prognostic score recently devised by our group (CLIP score) was, as expected, strictly correlated (p<0.0001) to the locoregional treatment received and strongly correlated with prognosis. CONCLUSIONS: the update of the present study confirms that tamoxifen is not effective in prolonging survivals, both in advanced patients and in those potentially curable and that the CLIP score is able to predict prognosis.

Correlation between self-reported adherence to highly active antiretroviral therapy (HAART) and virologic outcome.

The Patient Medication Adherence Questionnaire Version 1.0 (PMAQ-V1.0) is a patient-reported adherence instrument to assess medication-taking behaviors and identify barriers to adherence with antiretroviral therapy. To assess the correlation between adherence and virologic outcome, the PMAQ-V1.0 was administered to 194 antiretroviral-experienced adults with HIV infection enrolled in a 16-week evaluation of protease inhibitor-containing regimens featuring a lamivudine/zidovudine combination tablet. At baseline, plasma HIV-1 RNA levels were less than 10,000 copies/mL and CD4(+)-cell counts were equal to or greater than 300 x 10(6)/L; patients had been receiving a conventional regimen of lamivudine + zidovudine (separately) plus a protease inhibitor for at least 10 weeks immediately prior to the study. Forty-eight percent of patients who reported missing at least one dose of a nucleoside reverse-transcriptase inhibitor (NRTI) during the study had detectable plasma HIV-1 RNA, compared with 26% of patients who reported no missed doses (P = .002). Patients who missed at least one dose of an NRTI or protease inhibitor were 2.5 times more likely to have quantifiable HIV-1 RNA than those who reported no missed doses. Patients who reported fewer barriers and more motivators to adherence had better virologic outcomes (P = .001). Several dimensions of the PMAQ-V1.0 did not function as well as hypothesized. In this study, self-reported adherence derived from the PMAQ-V1.0 predicted virologic outcomes, but further refinement of the dimensions appears warranted.

[Suspected acute appendicitis. Role of enhanced helical computed tomography. Prospective study of 100 patients]. / Suspicion d'appendicite aiguë. Intérêt de l'examen tomodensitométrique hélicoïdal. Etude prospective chez 100 patients.

AIM OF STUDY: To assess the diagnosis accuracy of helical computed tomography (CT) in patients with suspected appendicitis. PATIENTS AND METHODS: This prospective study included 100 consecutive patients hospitalized for suspected appendicitis. There were 57 men and 43 women with a median age of 30 years (range: 17-91). An enhanced helical CT was performed at admission, without digestive opacification. Four criteria were interpreted as positive signs for appendicitis: appendix enlarged > or = 7 mm, right lower quadrant inflammation, stercorolith, and peri-appendicular collection. The patient was managed by the surgeon without knowing the result of CT. The final diagnosis was made pathologically. RESULTS: Eighty-one patients were operated on laparoscopically for suspected appendicitis. Intraoperative diagnosis was corrected in three cases and 78 appendectomies were performed (73 histological appendicitis, six normal appendix). Final diagnosis was a medical disease in 19 patients. The findings of 67 CT were interpreted as positive (63 true positive and four false positive) and the findings of 33 CT were interpreted as negative (24 true negative, nine false negative). Sensitivity was 87%, specificity was 86%, positive predictive value was 94%, and negative predictive value was 73%. If the nine false negative cases with minimal lesions at pathological examination were considered as true negative, the rates would be 100%, 89%, 94%, 100%, respectively. CONCLUSION: Enhanced helical CT is a good imaging diagnostic tool for suspected appendicitis. It may reduce the number of patients admitted for observation and decrease the rate of negative appendectomy.

Combination of paclitaxel and etoposide in the treatment of advanced non-small cell lung cancer: a phase I-II study.

Thirty-six patients (pts) with unpretreated advanced non-small cell lung cancer (NSCLC) stages IIIB and IV were enrolled in this two-stage phase I-II study aimed to establish the maximum tolerated dose (MTD) of paclitaxel and to evaluate the efficacy and safety of paclitaxel combined with etoposide every 3 weeks for a maximum of 6 courses, increasing the dose of paclitaxel according to a modified Fibonacci scheme. Nineteen pts were enrolled in the first stage and 17 pts in the second stage. The characteristics of the pts were as follows: median age 56 years (40-70), median Karnofsky's Performance Status 80% (70-80), 11 pts were stage IIIB and 25 pts stage IV. The doses of etoposide administered were 50 mg/m2 for 15 pts and 100 mg/m2 for 21 pts. MTD has not been reached and the study proceeded with the dose of paclitaxel 250 mg/m2. We obtained 9 (25%) partial remissions (PR) and 11 (31%) stable disease (SD) in 33 objectively evaluable pts. Median time to progression (TTP) was 4 months (0.3-21), median survival was 9.3 months (0.3-27). The main toxicity was neutropenia and neurotoxicity, while the gastrointestinal toxicity was mild. Two pts deceased after the first course. The causes of death were necrotizing enteritis in the first pt and congestive heart failure in the second pt. A total of 156 courses were administered at 7 dose levels, with a median of 4 courses per patient (1-6). The results seem to support the use of this combination in advanced non-small cell lung cancer.

Cryptic epitopes on alpha-fetoprotein induce spontaneous immune responses in hepatocellular carcinoma, liver cirrhosis, and chronic hepatitis patients.

To determine alpha-fetoprotein (AFP) immunogenicity in vivo, the presence of antibodies in sera of 60 hepatocellular carcinoma, 15 liver cirrhosis, and 15 chronic hepatitis patients was evaluated by Western blotting and immunoprecipitation analyses using purified human AFP. High titers of anti-AFP immunoglobulins were detected in 14 hepatocellular carcinomas (P = 0.0006), 3 liver cirrhosis (P = 0.0173), and 1 chronic hepatitis patient, but they were not detected in 40 healthy individuals. Therefore, spontaneous immune responses to AFP are significantly associated to liver diseases (P = 0.0015). Patient immunoglobulins recognized proteic linear epitopes that were cryptic in the native protein, as demonstrated by their restricted reactivity with denatured deglycosylated AFP. Thus, in pathological liver conditions, tolerance to this self-molecule is circumvented. The identification of AFP immunogenic epitopes may contribute to defining novel immunotherapeutic strategies targeting this antigen.

[Anthropometric measurements of the male inguinal canal]. / Misure antropometriche del canale inguinale maschile.

BACKGROUND: A problem in the use of a prosthesis in the treatment of inguinal hernia is the form and dimension the mesh should have. There are no precise indications in the international literature and manufactured pre-cut prostheses available are not always suitable for all patients. In this study some measurements within the male inguinal canal have been compared with the patients' physical characteristics, such as weight, height and body mass index, and with inguinal hernia too. The purpose was to look for a relation between these data, in order to establish the form and size of the ideal mesh prosthesis for every patient before operation. A "list" of different prosthesis sizes could help both the surgeon and the manufacturers. METHODS: The study was carried out on 150 male patients who underwent surgery for inguinal hernia. RESULTS: The analysis of the results does not demonstrate a relationship between the data examined. CONCLUSIONS: The conclusion is drawn that there could be two solutions to the problem of mesh size: one being the expensive prepacking of meshes of various sizes, and the cheaper one being to find out a method which, not considering the internal ring variability, will not influence the production of a universal mesh.

[Loco-regional persistence and recurrences of operated differentiated thyroid cancers. 22 cases on 589 treated patients from 1964 to 1990, follow-up from 5 to 31 years]. / Persistance et récidives loco-régionales des cancers thyroïdiens différenciés opérés. 22 cas sur 589 patients traités de 1964 à 1990, suivis de 5 à 31 ans.

AIM OF THE STUDY: Evaluation of frequency and outcome of loco-regional persistance and recurrences of differentiated thyroid carcinomas after surgery. MATERIAL AND METHODS: from 1964 to December 1990, we operated and followed up more than 5 years (from 5 to 31 years): 589 thyroid cancers (309 papillary, 262 follicullar et 18 Hürthle cells); 145 patients were lost to follow-up (24%), 33% of them were microcarcinomas. Surgery consisted ultimately in 411 total thyroidectomies, 51 sub-total thyroidectomies, 113 lobectomies with isthmusectomies, 9 isthmusectomies or tumorectomies and 4 tracheotomies. Neck dissection was not routinely performed but rather selectively (n = 137). All Patients were put under suppressive hormone therapy. After total thyroidectomy, ablative 131 iodine was almost routinely done. All patients have been controlled by clinical examination, radio-iodine scanning and, since 1983, by sequential thyroglobulin assays. We have analysed the course of patients according to L. J. Degroot's staging (Stage I: Patient with intrathyroidal disease. Stage II: Patient with cervical node involvement. Stage III: Patient with extra-thyroidal neck invasive disease. Stage IV: Distant metastasis). RESULTS: Stage I, n = 383, Stage II, n = 96. Total = 479. Local recurrences in the bed of total thyroidectomy were exceptional: n = 2/323 (0.6%). Recurrences in the thyroid remnant after non total thyroidectomy were rare: n = 3/156 (2%). Cervical nodal recurrences were also rare: n = 7/479 (1.5%). Stage III (n = 73): 34/306 papillary, 9/78, well differentiated follicular, 25/175 poorly differentiated follicular. 2/9 follicular of other type and 3/18 hurtle cell. In 67 patients, the loco-regional sterilization was achieved, 5 of which were reoperated for nodal cervical metastasis. 6 patients died from continuing loco-regional disease and 10 presented distant metastases. 4 of which died from. Among opered patients are still alive (52/73 = 71,2%) no loco-regional recurrence persisted. CONCLUSION: The true problem is not recurrence but the persistance after surgery in stage III patients, despite the application of 1131. The determining factor of the persistance and recurrence is the initial stage of the carninomatous disease at the time of treatment.

[The dynamic self-regulating prosthesis. A new method for the treatment of hernias in the inguinal area: preliminary notes on 153 cases]. / Protesi Autoregolantesi Dinamica (PAD). Una nuova metodica per il trattamento delle ernie della regione inguinale: note preliminari su 153 casi.

BACKGROUND: Good results have been obtained by using prosthesis in the treatment of inguinal hernia. However, there is still some uncertainty on "free tension" and "suture less" techniques, about traction, tension or torsion, wrinkle and dislocation and the consequences on the postoperative period. To resolve these problems a new procedure by using a new prosthesis, called PAD, by polypropylene (Prolene), is proposed; excellent results about recurrences, excluding every traction, torsion, wrinkle and dislocation and improved postoperative comfort, have been observed. The PAD is suitable in all inguinal hernias in males and is composed of two layers superposed and fixed to some structures of inguinal canal on one side only, opposite to the other, to allow movements of aponeurotic and muscular structures, of the inguinal region. METHODS: The study has been carried out on 153 patients, males, non selected, having primary inguinal hernia, all subjected to PAD procedure and followed-up from 30 to 48 months. RESULTS AND CONCLUSIONS: The results show a remarkable reduction in use of analgesics by patients in the postoperative period due to a better comfort achieved. This procedure avoids the risk of a prosthesis placed under the transversalis fascia and is easily repeatable.

Prognostic value of the galactose test in predicting survival of patients with cirrhosis evaluated for liver transplantation. A prospective multicenter Italian study. AISF Group for the Study of Liver Transplantation. Associazione Italiana per lo Studio del Fegato.

AIMS/METHODS: The present study aimed to examine whether the galactose elimination capacity can be used to predict the survival of patients with advanced liver disease. We studied 194 patients with cirrhosis, belonging to Child class B and C, for 2 years each. RESULTS: The overall probability of survival was 79% at 6 months, 72% at 1 year and 62% at 2 years. Variables significantly associated with the duration of survival, as assessed by univariate analysis, were the Child-Pugh score, presence of ascites, size of esophageal varices, prothrombin time, albumin, bilirubin, urea, creatinine, glucose and galactose elimination capacity. By a multivariable analysis, only Pugh score (p = 0.005), creatinine (p < 0.001), varices (p = 0.001) and galactose elimination capacity (p < 0.001) were independent predictors of mortality. The galactose elimination capacity was even more sensitive when the end-point was limited to deaths due to liver failure and hepatorenal syndrome. A new score obtained by summing the Pugh score with a score derived from galactose elimination capacity was quite simple and accurate for predicting survival. CONCLUSIONS: The quantitative measurement of liver function as the galactose elimination capacity could be of use to identify patients with cirrhosis and probable short survival who might benefit most from urgent transplantation.

Nicotinamide methylation and hepatic energy reserve: a study by liver perfusion in vitro.

BACKGROUND/AIMS: The synthesis of pyridine nucleotides from nicotinamide requires adenosine triphosphate. In man when exogenous nicotinamide is poorly utilized in this synthesis, the excess follows a dissipative metabolic pathway and is excreted in urine as N-methylnicotinamide. In human cirrhosis N-methylnicotinamide serum levels are higher than normal, in basal condition and after nicotinamide oral load. The aim of this study was to verify N-methylnicotinamide production in relation to hepatic content of adenosine triphosphate during in vitro perfusion of rat liver, in normal conditions and after adenosine triphosphate depletion by metabolic stress. METHODS: "Stress" was obtained by pre-washing with saline for 15 min before the perfusion with nutritive medium. RESULTS: The adenosine triphosphate decrease in the stressed liver was 38% after pre-washing with saline and 80% at the end of nutritive perfusion. In control liver the corresponding decreases were 1% after pre-washing with nutritive medium and 65% at the end of perfusion with the same medium. The total nicotinamide adenine dinucleotide decreases were 44% and 56% in the stressed liver, and 19% and 52% in the control liver. The output levels of N-methylnicotinamide at 90 min of rat liver nutritive perfusion were 31.50 +/- 4.72 nmol/g for normal liver and 66.40 +/- 13.17 for stressed liver (p<0.001). Liver adenosine triphosphate was inversely related to N-methylnicotinamide production (r=0.93; p<0.001). CONCLUSIONS: These data suggest that nicotinamide methylation may be enhanced when there is hepatic adenosine triphosphate decrease and energy failure induced by hypoxia or metabolic stress, similar to that obtained in vitro by saline washing before perfusion with nutritive medium. This study shows that the evaluation of N-methylnicotinamide production in man (before and after nicotinamide load) might be useful to explore the energy state of diseased liver.