Results of Shouldice hernia repair after 18 years of follow-up in all the patients.

PURPOSE: Evaluate the long-term efficacy of the Shouldice technique performed by non-specialized surgeons and also to reflex on the quality parameters necessary to safely assess hernia recurrence rates. METHODS: During 3 years, a prospective study was conducted in 243 adult men who underwent surgery for primary inguinal hernias by 13 junior surgeons with an interest in hernia surgery. Using local anesthesia, a classic 4 step Shouldice repair, with polypropylene or polyester, was performed. All patients were followed for 18 years. The follow-up met the nine quality criteria proposed by the authors. RESULTS: At 18 years, 80.2% of patients were followed and only 6.5% were lost. There were 7 recurrences in the first 10 years, 5 of them secondary to a direct hernia, and the same after 18 years. The recurrence rate was 2.88%. Tolerance of the local anesthesia was excellent in 91.4%of patients and, after 3 years, the pain was considered moderate or severe in 4 patients (1.8%). CONCLUSIONS: It is necessary to incorporate more demanding criteria in the assessment of recurrence, to give more valid results. The Shouldice technique remains a useful technique today not only in patients under 30 years of age, and in the absence of risk factors, but also in cases of intolerance, patient rejection or absence of mesh. In addition, it provides the clinical and economic advantages of being possible to perform it under local anesthesia.

Human BRS-3 receptor: functions/role in cell signaling pathways and glucose metabolism in obese or diabetic myocytes.

Several studies showed that the orphan Bombesin Receptor Subtype-3 (BRS-3) - member of the bombesin receptor family - has an important role in glucose homeostasis (v.g.: BRS-3-KO mice developed mild obesity, and decreased levels of BRS-3 mRNA/protein have been described in muscle from obese (OB) and type 2 diabetic (T2D) patients). In this work, to gain insight into BRS-3 receptor cell signaling pathways, and its implication on glucose metabolism, primary cultured myocytes from normal subjects, OB or T2D patients were tested using high affinity ligand - [d-Tyr(6),ß-Ala(11),Phe(13),Nle(14)]bombesin6-14. In muscle cells from all metabolic conditions, the compound significantly increased not only MAPKs, p90RSK1, PKB and p70s6K phosphorylation levels, but also PI3K activity; moreover, it produced a dose-response stimulation of glycogen synthase a activity and glycogen synthesis. Myocytes from OB and T2D patients were more sensitive to the ligand than normal, and T2D cells even more than obese myocytes. These results widen the knowledge of human BRS-3 cell signaling pathways induced by a BRS-3 agonist, described its insulin-mimetic effects on glucose metabolism, showed the role of BRS-3 receptor in glucose homeostasis, and also propose the employing of BRS-3/ligand system, as participant in the obese and diabetic therapies.

Obesity-dependent metabolic signatures associated with nonalcoholic fatty liver disease progression.

Our understanding of the mechanisms by which nonalcoholic fatty liver disease (NAFLD) progresses from simple steatosis to steatohepatitis (NASH) is still very limited. Despite the growing number of studies linking the disease with altered serum metabolite levels, an obstacle to the development of metabolome-based NAFLD predictors has been the lack of large cohort data from biopsy-proven patients matched for key metabolic features such as obesity. We studied 467 biopsied individuals with normal liver histology (n=90) or diagnosed with NAFLD (steatosis, n=246; NASH, n=131), randomly divided into estimation (80% of all patients) and validation (20% of all patients) groups. Qualitative determinations of 540 serum metabolite variables were performed using ultraperformance liquid chromatography coupled to mass spectrometry (UPLC-MS). The metabolic profile was dependent on patient body-mass index (BMI), suggesting that the NAFLD pathogenesis mechanism may be quite different depending on an individual's level of obesity. A BMI-stratified multivariate model based on the NAFLD serum metabolic profile was used to separate patients with and without NASH. The area under the receiver operating characteristic curve was 0.87 in the estimation and 0.85 in the validation group. The cutoff (0.54) corresponding to maximum average diagnostic accuracy (0.82) predicted NASH with a sensitivity of 0.71 and a specificity of 0.92 (negative/positive predictive values=0.82/0.84). The present data, indicating that a BMI-dependent serum metabolic profile may be able to reliably distinguish NASH from steatosis patients, have significant implications for the development of NASH biomarkers and potential novel targets for therapeutic intervention.

Phosphocalcic metabolism after biliopancreatic diversion.

BACKGROUND: Malabsorptive techniques to treat morbid obesity have been followed by alterations in phosphocalcic metabolism. Knowledge of the preoperative situation is important to assess the influence of these techniques on phosphocalcic metabolism and to consider treatments for these alterations. METHODS: 61 consecutive morbidly obese patients (50 women, 11 men, age 19 to 63 years) having had biliopancreatic diversion (BPD) were studied in a prospective manner. Preoperative and postoperative levels of calcium, phosphorus, 25-hydroxyvitamin D, tartrate resistant acid phosphate, plasma parathormone (PTH), tubular absorption of phosphate, and urinary calcium and pyridinolines were analyzed, as well as the potential risk factors for their alterations. Follow-up of all patients was a minimum of 4 years. RESULTS: Before BPD, 42.3% of patients presented an increase in PTH and 54% a decrease in the 25-OH vitamin D, but the values of calcium and plasma phosphorus maintained at normal level. 81.8% of the patients with an increase in the PTH maintained high levels after BPD, while 60% of those with a normal preoperative PTH also presented hyperparathyroidism 4 years after the intervention. A correlation between the levels of plasma PTH and body mass index was not found. CONCLUSION: Morbid obesity is accompanied by a high percentage of hyperparathyroidism. BPD produces malabsorption of vitamin D during the first years, favoring the persistence or appearance of hyperparathyroidism. It is important to recognize and treat the secondary hyperparathyroidism. The postoperative period could necessitate more energetic interventions to get more efficient control of the phosphocalcic metabolism.

Relationship between the upper airway and obstructive sleep apnea-hypopnea syndrome in morbidly obese women.

BACKGROUND: The authors studied changes in the upper airway in morbidly obese women and the relationship to sleep apnea-hypopnea syndrome (OSAS). METHODS: Patients underwent a cardiorespiratory polygraphic study, respiratory function test (spirometry, plethysmography, maximum inspiratory pressures and arterial blood gas analysis), and computed tomographic studies of the upper airway. RESULTS: 40 morbidly obese women being evaluated for bariatric surgery (mean age 39.6 +/- 9.6 years old, BMI 48.7 +/- 5.6 kg/m2) were studied. 37 women had OSAS, and 14 had severe OSAS. Results on respiratory function tests were normal. BMI and weight had a positive correlation with apnea-hypopnea index (AHI), apnea index (AI), desaturation index (DI), lowest oxygen saturation and CT90. Uvula diameter had a negative correlation with FEV1, FVC, VC IN and a positive correlation with TLC. Retropharynx soft tissue at the retropalatal level had a negative correlation with FEV1, FVC and VC IN. The oropharynx area at maximal inspiration (total lung capacity) obtained a negative correlation with the AHI (r = - 0.423, P = 0.044), AI (r = - 0.484, P = 0.042) and DI (r = - 0.484, P = 0.019). CONCLUSIONS: Prevalence of OSAS in morbidly obese women is very high. Our results show the significant correlation between BMI and AHI in morbidly obese women. Uvula diameter and retropharynx soft tissue are the upper airway parameters with higher relationship with pulmonary function. A reduction in the cross-sectional area of the airway at the level of the oropharynx could be related to the severity of OSAS in morbidly obese women.

Clinical value of CEA and CA125 regarding relapse and metastasis in resectable non-small cell lung cancer.

BACKGROUND: The aim of the present study was to evaluate the value of serum Carcinoembryonic Antigen (CEA) and CA125 antigen assay for monitoring the activity of non-small cell lung cancer (NSCLC) after curative surgical resection. PATIENTS AND METHODS: Serum CEA and CA 125 were determined preoperatively and at every postoperative visit, in 113 patients with NSCLC (TNM stages I, II, IIIA). Both markers were assayed by magnetic particle enzyme immunoassay. RESULTS: Tumor recurrence was more frequent in patients with preoperative CA 125 levels above the cut-off (15 U/ml) (28 out of 47) (59.5%) than in those with low values (18 out of 66) (27.2%) (p < 0.001). The 36-month disease-free survival was lower for patients with elevated CA 125 (37%) than among those with low levels (72%) (p = 0.006). High CA 125 was an independent predictor of the risk of postoperative recurrence (Hazard Ratio: 3.02)(95% CI: 1.41-6.49). No relationship was detected between preoperative serum CEA and risk of recurrence. High preoperative CA125 indicated elevated risk for disseminated recurrence (Hazard Ratio: 7) (95% CI: 2.39-20.51), but not for locoregional failure. No significance was detected for CEA, either in locoregional or disseminated recurrence. Forty-six subjects (40.7%) developed tumor recurrence. At the diagnosis of relapse, serum CEA was elevated in 16 patients (34.7%) and CA125 in 26 (56.5%). Sensitivity was higher in the case of disseminated recurrence (63% for CA125 and 43.3% for CEA) and decreased in locoregional relapse (43.7% for CA125 and 18.7% for CEA). The specificity was 97% for CEA and 59% for CA125. CONCLUSION: Serum CA125 is a useful prognostic marker in NSCLC. The predictive information is especially useful to estimate the risk of disseminated recurrence. Serial determinations of CEA and CA125 during the postoperative follow-up do not show enough sensitivity/specificity to recommend their use for diagnosis of tumor relapse.

Hyperhomocysteinemia in liver cirrhosis: mechanisms and role in vascular and hepatic fibrosis.

Numerous clinical and epidemiological studies have identified elevated homocysteine levels in plasma as a risk factor for atherosclerotic vascular disease and thromboembolism. Hyperhomocysteinemia may develop as a consequence of defects in homocysteine-metabolizing genes; nutritional conditions leading to vitamin B(6), B(12), or folate deficiencies; or chronic alcohol consumption. Homocysteine is an intermediate in methionine metabolism, which takes place mainly in the liver. Impaired liver function leads to altered methionine and homocysteine metabolism; however, the molecular basis for such alterations is not completely understood. In addition, the mechanisms behind homocysteine-induced cellular toxicity are not fully defined. In the present work, we have examined the expression of the main enzymes involved in methionine and homocysteine metabolism, along with the plasma levels of methionine and homocysteine, in the liver of 26 cirrhotic patients and 10 control subjects. To gain more insight into the cellular effects of elevated homocysteine levels, we have searched for changes in gene expression induced by this amino acid in cultured human vascular smooth muscle cells. We have observed a marked reduction in the expression of the main genes involved in homocysteine metabolism in liver cirrhosis. In addition, we have identified the tissue inhibitor of metalloproteinases-1 and alpha1(I)procollagen to be upregulated in vascular smooth muscle cells and liver stellate cells exposed to pathological concentrations of homocysteine. Taken together, our observations suggest (1) impaired liver function could be a novel determinant in the development of hyperhomocysteinemia and (2) a role for elevated homocysteine levels in the development of liver fibrosis.

Modifications to Rives technique for midline incisional hernia repair.

Between 1990 and 1997, 284 patients were treated in our hospital for abdominal hernias. In the original group, 239 patients (84.15%) had midline hernia, and 45 (15.8%) had lateral hernia. A total of 152 midline hernia patients (63.5%) were treated using our variant of Rives technique. In all these cases, preperitoneal and retromuscular polypropylene mesh was used as a reinforcement and was subsequently attached by means of absorbable sutures to the external border of the rectus muscles. There were no deaths. A total of 42 of all patients operated on (27.6%) suffered from long-term postoperative pain. In seven cases (4.6%) it was necessary to remove the prosthesis because of chronic infection, and there were two recurrences in patients in whom the prosthesis had to be removed. In our experience, the Rives technique is a suitable and safe treatment for the repair of midline incisional hernias. The use of absorbable sutures and fixation of the mesh to the external oblique aponeurosis can reduce the original problems of abdominal pain and unaesthetic skin scars.

Reduced mRNA abundance of the main enzymes involved in methionine metabolism in human liver cirrhosis and hepatocellular carcinoma.

BACKGROUND/AIMS: It has been known for at least 50 years that alterations in methionine metabolism occur in human liver cirrhosis. However, the molecular basis of this alteration is not completely understood. In order to gain more insight into the mechanisms behind this condition, mRNA levels of methionine adenosyltransferase (MAT1A), glycine methyltransferase (GNMT), methionine synthase (MS), betaine homocysteine methyltransferase (BHMT) and cystathionine beta-synthase (CBS) were examined in 26 cirrhotic livers, five hepatocellular carcinoma (HCC) tissues and ten control livers. METHODS: The expression of the above-mentioned genes was determined by quantitative RT-PCR analysis. Methylation of MAT1A promoter was assessed by methylation-sensitive restriction enzyme digestion of genomic DNA. RESULTS: When compared to normal livers MAT1A, GNMT, BHMT, CBS and MS mRNA contents were significantly reduced in liver cirrhosis. Interestingly, MAT1A promoter was hypermethylated in the cirrhotic liver. HCC tissues also showed decreased mRNA levels of these enzymes. CONCLUSIONS: These findings establish that the abundance of the mRNA of the main genes involved in methionine metabolism is markedly reduced in human cirrhosis and HCC. Hypermethylation of MAT1A promoter could participate in its reduced expression in cirrhosis. These observations help to explain the hypermethioninemia, hyperhomocysteinemia and reduced hepatic glutathione content observed in cirrhosis.

S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial.

BACKGROUND/AIM: The efficacy of S-adenosylmethionine (AdoMet) in the treatment of liver cell injury has been demonstrated in several experimental models. The aim of this study was to investigate the effects of AdoMet treatment in human alcoholic liver cirrhosis. METHODS: A randomized, double-blind trial was performed in 123 patients treated with AdoMet (1200 mg/day, orally) or placebo for 2 years. All patients had alcoholic cirrhosis, and histologic confirmation of the diagnosis was available in 84% of the cases. Seventy-five patients were in Child class A, 40 in class B, and 8 in class C. Sixty-two patients received AdoMet and 61 received placebo. RESULTS: At inclusion into the trial no significant differences were observed between the two groups with respect to sex, age, previous episodes of major complications of cirrhosis, Child classification and liver function tests. The overall mortality/liver transplantation at the end of the trial decreased from 30% in the placebo group to 16% in the AdoMet group, although the difference was not statistically significant (p = 0.077). When patients in Child C class were excluded from the analysis, the overall mortality/liver transplantation was significantly greater in the placebo group than in the AdoMet group (29% vs. 12%, p = 0.025), and differences between the two groups in the 2-year survival curves (defined as the time to death or liver transplantation) were also statistically significant (p = 0.046). CONCLUSIONS: The present results indicate that long-term treatment with AdoMet may improve survival or delay liver transplantation in patients with alcoholic liver cirrhosis, especially in those with less advanced liver disease.

Characteristics of thoracic duct lymph in multiple organ dysfunction syndrome.

OBJECTIVE: To investigate the presence of endotoxin, bacteria, and potential humoral and cellular mediators in thoracic duct lymph and peripheral blood in patients with severe refractory multiple organ dysfunction. DESIGN: Convenience sample. SETTING: General intensive care unit of a university hospital. PATIENTS: Two men and 2 women were studied after a mean of 7.25 days (range, 6-9 days) of multiple organ dysfunction syndrome. The primary injury was thoracic in 1 patient and abdominal in 3 patients. INTERVENTION: The thoracic duct was cannulated with a 7F catheter and samples of lymph and peripheral blood were obtained. MAIN OUTCOME MEASURES: Simultaneous lymph and serum levels of lipopolysaccharide, tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6, and activation markers on T lymphocytes. RESULTS: Lipopolysaccharide and cytokine levels were low in lymph and serum, except for a mean lymph-to-serum ratio of 53.4 for interleukin-1 beta. There was phenotypical evidence of intense polyclonal T-lymphocyte activation in both lymph and peripheral blood with increased lymph-to-peripheral blood ratios. Increased percentages in lymph of CD45RA + CD45RO + lymphocytes were observed. In 1 patient, Proteus mirabilis grew simultaneously in lymph, pancreatic necrosis fluid, and a central venous catheter tip. All simultaneous blood cultures were negative. CONCLUSIONS: Our results provide evidence of the participation of the gut-associated lymphatic tissue in the pathogenesis of the multiple organ dysfunction syndrome, suggesting that T-cell activation and cytokine production occur at the gut level. Future studies are needed to confirm and extend our findings.

Characterization of a full-length cDNA encoding human liver S-adenosylmethionine synthetase: tissue-specific gene expression and mRNA levels in hepatopathies.

The sequence of a full-length cDNA coding for human liver S-adenosylmethionine synthetase has been determined. It spans 3217 nucleotides and encodes a protein of 395 amino acid residues, with a calculated molecular mass of 43,647 Da. The structural features deduced from the amino acid sequence show a close similarity to those of the rat liver enzyme. The liver-specific S-adenosylmethionine synthetase gene appears to be present as a single copy in the genome, as revealed by Southern analysis. The occurrence of a single mRNA species for this enzyme has been determined by primer extension and Northern analysis. Among several human tissues examined, this gene is expressed only in the liver. Similar S-adenosylmethionine synthetase mRNA levels have been detected in biopsies from normal human liver and from patients with alcoholic cirrhosis and hepatocellular carcinoma. Based on these results, a possible mechanism of regulation of human liver S-adenosylmethionine synthetase is discussed.

[Is the introduction and realization of the Japanese system of staging and surgical treatment for stomach cancer possible in Spain?]. / Es posible la implantación y realización, en nuestro país, del sistema de estadiaje y tratamiento quirúrgico japonés para el cáncer de estómago?

Discrepancies in the five-year survival rates after treatment of gastric cancer between the West and the East have been attributed to differences in the biological behavior of the tumor or in the incidence of early cancer. Alternatively, the better staging system and the national standardization of the diagnosis and treatment used in the East may explain their findings. Poor definition of stages and curability, scarce interest in standardization of techniques, and lack of basic information in many pathological reports are frequent in Western countries. Between May 1988 and April 1991 a prospective study on a consecutive series of 89 patients diagnosed of gastric carcinoma in the Hospital "Príncipe de Asturias" using the directions given by the Japanese Research Society for Gastric Cancer has been made. Our results support the use of the Japanese system in a General Hospital of our country and confirm its accuracy in defining the type of surgery performed, the later being its main advantage over the TNM staging system.

Inactivation and dissociation of S-adenosylmethionine synthetase by modification of sulfhydryl groups and its possible occurrence in cirrhosis.

Catalytically active human and rat liver S-adenosylmethionine synthetase exists mainly in tetramer and dimer form. In liver biopsy samples from cirrhotic patients a marked reduction in total S-adenosylmethionine synthetase activity and a specific loss of the tetrameric form of the enzyme exist. We have investigated the possible role of sulfhydryl groups in maintaining the structure and activity of S-adenosylmethionine synthetase. Both forms of S-adenosylmethionine synthetase are rapidly inactivated by N-ethylmaleimide, and the loss of enzyme activity correlates with the incorporation of approximately 2 moles N-ethylmaleimide per mole of subunit. In addition, reaction with N-ethylmaleimide resulted in displacement of the tetramer-dimer equilibrium of the enzyme toward the dimer, but no monomer was detected under these conditions. A catalytically active monomeric S-adenosylmethionine synthetase was detected in the cytosolic extract from a liver biopsy sample from a cirrhotic patient, supporting our model for the structure of S-adenosylmethionine synthetase. Because treatment of S-adenosylmethionine synthetase with N-ethylmaleimide resembles the situation of this enzyme in cirrhotic patients, it is proposed that impaired protection of the enzyme from oxidizing agents caused by a decreased synthesis of glutathione can explain the diminished synthesis of S-adenosylmethionine in liver cirrhosis.