Relationship between insulin resistance, inflammation and liver cell apoptosis in patients with severe obesity.

BACKGROUND: In obesity, insulin resistance appears frequently after activation of proinflammatory molecules. Caspase-generated cytokeratin-18 (CK-18) fragments are produced during the apoptosis of hepatic cells. The main objective in the present study is to investigate the relationship between insulin resistance and caspase-generated CK-18 fragments in patients with severe obesity. METHODS: Sixty-two patients selected for bariatric surgery were clinically studied (sex, age, weight, waist diameter, body mass index, arterial pressure and type 2 diabetes mellitus) and analytic parameters were measured in blood (glucose concentration, cholesterol, triglycerides, insulin, glycosylated hemoglobin, aspartate aminotransferase, alanine aminotransferase, high-sensitivity C-reactive protein, adiponectin, interleukin 6, interleukin 18 and CK-18 fragments). Patient group division was based on 70th percentile of insulin resistance as measured by homeostasis model assessment (HOMA) and also according to liver histology. RESULTS: Patients with greater insulin resistance (percentile > 70th) showed higher values of CK-18 fragments, interleukin 6 and transaminases. A positive correlation between the HOMA score, value of CK-18 fragments and triglyceride level was found. A correlation between CK-18 fragments with interleukin 6, triglycerides and transaminases was also observed. HOMA score and value of CK-18 fragments correlated with the degree of liver fibrosis. CONCLUSIONS: Greater degree of insulin resistance induces apoptosis of hepatic cells as measured by the serum levels of CK-18 fragments.

Risk factors for advanced lesions undetected at prior colonoscopy: not always poor preparation.

BACKGROUND AND STUDY AIM: Colonoscopy is regarded as the gold standard for diagnosis of colonic lesions. However, adenoma miss rates in tandem colonoscopy studies vary from 2 % to 26 %. We aimed to investigate the rates of advanced neoplasia in patients with a prior normal colonoscopy in an outpatient endoscopy unit. METHODS: Review of reports for colonoscopies performed in our Endoscopy Unit from 2000 to 2005. Undetected lesions were defined as advanced adenoma or colorectal cancer (CRC) not reported in a colonoscopy performed in the previous 2 or 3 years, respectively. Patients with hereditary nonpolyposis CRC (HNPCC) and familial adenomatous polyposis (FAP) were excluded. RESULTS: Between 2002 and 2005, 795 patients were diagnosed with at least one advanced adenoma and 386 with CRC. Among these, 107/795 patients (13.5 %) had advanced adenoma that had been undetected in a previous colonoscopy (39 % [53/135 lesions] in the right colon); 92/107 (86 %) had an undetected advanced adenoma ≥ 10 mm. Previously undetected CRCs were found in 27/386 patients (6.7 %), located in the left colon in 21/27 (78 %); in 7 the area had not been reached in the previous colonoscopy. Risk factors for undetected advanced adenoma were advanced age, male gender, the presence of another advanced adenoma at first colonoscopy, and history of advanced neoplasia. CONCLUSIONS: Failure to detect advanced neoplasia is common in a community-based endoscopy facility. Previously undetected advanced lesions are more frequently found in the left colon and rectum. Risk factors for non-detection of advanced adenoma are similar to those for advanced neoplasia recurrence. Lowering non-detection rates is crucial for correct follow-up recommendations. Patients should be aware of rates of detection of advanced neoplasia after previous normal colonoscopic findings.

The uncalibrated prothrombinase-induced clotting time test. Equally convenient but more precise than the aPTT for monitoring of unfractionated heparin.

The activated partial thromboplastin time test (aPTT) represents one of the most commonly used diagnostic tools in order to monitor patients undergoing heparin therapy. Expression of aPTT coagulation time in seconds represents common practice in order to evaluate the integrity of the coagulation cascade. The prolongation of the aPTT thus can indicate whether or not the heparin level is likely to be within therapeutic range. Unfortunately aPTT results are highly variable depending on patient properties, manufacturer, different reagents and instruments among others but most importantly aPTT's dose response curve to heparin often lacks linearity. Furthermore, aPTT assays are insensitive to drugs such as, for example, low molecular weight heparin (LMWH) and direct factor Xa (FXa) inhibitors among others. On the other hand, the protrombinase-induced clotting time assay (PiCT®) has been show to be a reliable functional assay sensitive to all heparinoids as well as direct thrombin inhibitors (DTIs). So far, the commercially available PiCT assay (Pefakit®PiCT®, DSM Nutritional Products Ltd. Branch Pentapharm, Basel, Switzerland) is designed to express results in terms of units with the help of specific calibrators, while aPTT results are most commonly expressed as coagulation time in seconds. In this report, we describe the results of a pilot study indicating that the Pefakit PiCT UC assay is superior to the aPTT for the efficient monitoring of patients undergoing UFH therapy; it is also suitable to determine and quantitate the effect of LMWH therapy. This indicates a distinct benefit when using this new approach over the use of aPPT for heparin monitoring.

Biodegradation of aromatic compounds by Escherichia coli.

Although Escherichia coli has long been recognized as the best-understood living organism, little was known about its abilities to use aromatic compounds as sole carbon and energy sources. This review gives an extensive overview of the current knowledge of the catabolism of aromatic compounds by E. coli. After giving a general overview of the aromatic compounds that E. coli strains encounter and mineralize in the different habitats that they colonize, we provide an up-to-date status report on the genes and proteins involved in the catabolism of such compounds, namely, several aromatic acids (phenylacetic acid, 3- and 4-hydroxyphenylacetic acid, phenylpropionic acid, 3-hydroxyphenylpropionic acid, and 3-hydroxycinnamic acid) and amines (phenylethylamine, tyramine, and dopamine). Other enzymatic activities acting on aromatic compounds in E. coli are also reviewed and evaluated. The review also reflects the present impact of genomic research and how the analysis of the whole E. coli genome reveals novel aromatic catabolic functions. Moreover, evolutionary considerations derived from sequence comparisons between the aromatic catabolic clusters of E. coli and homologous clusters from an increasing number of bacteria are also discussed. The recent progress in the understanding of the fundamentals that govern the degradation of aromatic compounds in E. coli makes this bacterium a very useful model system to decipher biochemical, genetic, evolutionary, and ecological aspects of the catabolism of such compounds. In the last part of the review, we discuss strategies and concepts to metabolically engineer E. coli to suit specific needs for biodegradation and biotransformation of aromatics and we provide several examples based on selected studies. Finally, conclusions derived from this review may serve as a lead for future research and applications.

Spanish growth studies 2008. New anthropometric standards.

Cross-sectional and longitudinal growth studies have recently been conducted in Spain. These studies have allowed neonatal anthropometry in premature and term neonates and postnatal growth in children and adolescents to be evaluated. Moreover, a longitudinal study that allows pubertal growth to be evaluated for distinct groups according to maturation has also been published. Between 1999 and 2002, birth weight and vertex-heel length were evaluated in 9,362 newborns (4,884 boys and 4,478 girls), with a gestational age of 26-42 weeks. An increase in these values compared with previous Spanish studies (1987-1992) and sexual dimorphism were observed. Between 2000 and 2004, height, weight and body mass index (BMI) were evaluated in 32,064 individuals (16,607 males, 15,457 females) aged 0-24 years. An increasing secular trend was observed compared with data obtained 20 years previously. Increases in BMI exceeded those in height for BMI values above the 50th percentile. A longitudinal growth study of 458 healthy individuals (223 boys, 235 girls) born between 1978 and 1982 yielded pubertal growth and maturity standards for each of the five pubertal maturity groups. In addition, data on skinfolds, bone mass and intellectual development from birth to adulthood were also provided. Adult height in both studies was similar to that reported by European and American studies, but was lower than that reported for German, Swedish and Dutch populations. In males, BMI was higher than in other European populations and was close to that of the US population. In females, BMI was similar to that in European populations and was lower than that in the US population.

Effects of long-term cyclo-oxygenase 2 selective and acid inhibition on Barrett's oesophagus.

BACKGROUND: There is an overexpression of cyclo-oxygenase 2 (COX-2) in Barrett's oesophagus (BO). AIM: To determine the long-term effect of a COX-2 inhibitor on cellular mechanisms involved in BO. METHODS: A randomized controlled trial was conducted in BO patients allocated to continue the usual proton pump inhibitor (PPI) alone treatment, or PPI combined with rofecoxib (25 mg/day) for 6 months. Cell proliferation index and COX-2 expression in BO glands was determined in biopsy specimens at baseline and after treatment. Cell apoptosis, cyclin D1, p53 and vascular endothelial growth factor (VEGF) expression was also explored in a subset of patients. Student-t test and the U-Mann-Whitney test were used for quantitative and ordinal variables. RESULTS: Of 62 patients, 58 completed the study. A higher proportion of patients on rofecoxib + PPI exhibited a decrease in COX-2 expression compared to those treated with PPI alone, but cell proliferation index was not affected. Unlike PPI alone, rofecoxib + PPI was associated with an increase in the apoptotic cell index, a decrease in p53 cell staining and VEGF expression in mucosal vessels. No effect on low-grade dysplasia or cyclin D1 was observed. CONCLUSIONS: The addition of rofecoxib to PPI therapy does not affect cell proliferation index in BO cells after 6 months of therapy, but does reduce COX-2 and VEGF expression and increases cell apoptosis.

Procedures and recommended times in the care process of the patient with pancreatic cancer: PAN-TIME consensus between scientific societies.

PURPOSE: Pancreatic cancer (PC) is a disease with bad prognosis. It is usually diagnosed at advanced stages and its treatment is complex. The aim of this consensus document was to provide recommendations by experts that would ameliorate PC diagnosis, reduce the time to treatment, and optimize PC management by interdisciplinary teams. METHODS: As a consensus method, we followed the modified Delphi methodology. A scientific committee of experts provided 40 statements that were submitted in two rounds to a panel of 87 specialists of 12 scientific societies. RESULTS: Agreement was reached for 39 of the 40 proposed statements (97.5%). CONCLUSIONS: Although a screening of the asymptomatic population is not a feasible option, special attention to potential symptoms during primary care could ameliorate early diagnostic. It is especially important to decrease the period until diagnostic tests are performed. This consensus could improve survival in PC patients by decreasing the time to diagnose and time to treatment and by the implementation of multidisciplinary teams.

The PiCT® test is a reliable alternative to the activated partial thromboplastin time in unfractionated heparin therapy management: results from a multicenter study.

Essentials Activated partial thromboplastin time (APTT) or anti-Xa tests are used to monitor heparin. Prothrombinase-induced Clotting Time (PiCT) was compared to APTT in a clinical study. PiCT shows higher correlation to anti-Xa than APTT does and is more comparable between centers. PiCT demonstrates significantly higher accuracy and reliability than APTT in heparin monitoring. SUMMARY: Background Unfractionated heparin (UFH) is still a commonly used anticoagulant for prevention and treatment of thromboembolism in a variety of situations. Increasingly, chromogenic anti-Xa assays are used for UFH monitoring given the high variability of the activated partial thromboplastin time (APTT) in this setting. On the other hand, and despite the known variability, the APTT test remains the most frequently used monitoring tool in UFH therapy because of its broad availability, lower costs and wide acceptance. Various guidelines continue to recommend the use of the APTT as an anti-Xa surrogate, but this approach remains controversial. Objective To assess the prothrombinase-induced clotting time (PiCT® ) test, reported in seconds, as an alternative to the APTT in the management of UFH-mediated anticoagulation. Methods Plasma samples from patients receiving UFH were obtained in three different centers in the USA and Europe. Samples were analyzed for PiCT, APTT and anti-Xa activities with conditions set to allow comparability. Target-ranges in seconds for PiCT and APTT were established for a UFH concentration of 0.3-0.7 IU mL-1 , derived from anti-Xa results as suggested by the ACCP guidelines. Results PiCT demonstrated better correlation with anti-Xa IU mL-1 than APTT, higher ability to identify samples within target range and, importantly, comparable target-ranges between different centers. Conclusion Accuracy and reliability of PiCT are significantly better than those of APTT in monitoring UFH for anticoagulant therapy.

Does cerebral activity change in middle-aged adults in a visual discrimination task?

The purpose of this study was to assess changes in cerebral activity in middle-aged adults (MA: 50 years) compared to young adults (YA: 20 years). Subjects had to compare the duration or the intensity of a visual stimulus with a previously memorized standard. Evoked potentials were recorded, and a dipole model (obtained from PET data on young adults) was applied for fitting late-latency components. MA performance was poorer than YA performance. Task-specific ERP late components were found (P3 in intensity, CNV in duration), but P3 had a lower amplitude and CNV was less frontal in MAs compared to YAs. The activity of the dipoles that generate late components - cuneus in the intensity task, right frontal in the duration task, and anterior cingulate in both tasks-was less ample or less peaked in MAs than in YAs. This study characterizes neurobiological effects of aging that may already be visible during midlife.

Molecular characterization of PadA, a phenylacetaldehyde dehydrogenase from Escherichia coli.

The padA gene encoding the phenylacetaldehyde dehydrogenase involved in the catabolism of 2-phenylethylamine in Escherichia coli has been cloned, sequenced, and located at 31.0 min on the chromosome. The deduced PadA polypeptide contains 499 amino acid residues with a predicted molecular mass of 53.7 kDa, and its primary structure reveals significant similarity with that of members of the aldehyde dehydrogenase superfamily. By engineering optimal transcription and translation elements, a high expression of the padA gene has been achieved. The active PadA enzyme is a homodimer that prefers NAD+ over NADP+ as coenzyme. The enzyme efficiently oxidizes only phenylacetaldehyde-like aromatic aldehydes, and has a weak esterase activity with p-nitrophenol. The padA gene constitutes a new catabolic tool for designing DNA cassettes to expand the abilities of microorganisms to degrade toxic aromatic compounds.

COX-2 and colorectal cancer.

Metabolites of arachidonic acid participate in normal growth responses and in aberrant cellular growth and proliferation, including carcinogenesis. The key step in the conversion of free arachidonic acid to prostaglandins is catalyzed by the cyclooxygenase enzyme (COX). There are two COX enzymes, COX-1 and COX-2. COX-1 is expressed constitutively and is part of normal cell metabolic functions. COX-2, on the other hand, is induced and expressed in neoplastic growths. The connection between COX expression and carcinogenesis was first implicated in studies that demonstrated the efficacy of aspirin and non-steroidal anti-inflammatory drugs to reduce the relative risk of colon cancer and also promote tumor regression in both humans and animal models of colon cancer. Investigation of the molecular basis of these observations showed that high levels of COX-2 protein were present in both human and animal colorectal tumors. A variety of evidence gathered from epidemiological, whole animal, and cellular studies indicate that unregulated COX-2 expression is a rate-limiting step in tumorigenesis and also that the loss of regulation occurs early in carcinogenesis. The interest in the COX-2 enzyme is that specific inhibition of COX-2 could theoretically avoid the gastrointestinal and other complications observed with the use of nonspecific COX inhibitors (most NSAIDs) or COX-1 inhibitors. The mechanisms by which COX-2 inhibitors lead to decreased colon carcinogenesis are not fully understood but they involve an increase not only in COX-2 dependent but also in COX-2 independent mechanisms.

Identification of two subgroups of mantle cell leukemia with distinct clinical and biological features.

INTRODUCTION: Mantle cell leukemia (MCLeu) has been considered as a leukemic form of mantle cell lymphoma (MCL). However, the presence of certain features rarely observed in MCL, such as transformation to prolymphocytic leukemia (PLL) or indolent clinical course, suggests that MCLeu may represent a distinct disorder. METHODS: Seven cases of MCLeu with t(11;14)(q13;q32) and BCL1-IGH gene rearrangement were ascertained among 140 newly diagnosed chronic B-cell lymphoproliferative disorders with leukemic expression. Comparative genomic hybridization, FISH for specific gene loci, and immunological studies were preformed in them. RESULTS: In comparison with CLL, MCLeu cases had low immunological scores < or =2 with respect to B-CLL (P<0.0001). Expression of CD38 was absent in 43% of MCLeu and in 44% of B-CLL. Comparative genomic hybridization analysis identified genomic imbalances in 86% of MCLeu with a similar pattern than in MCL: gains of 3q, 8q involving MYC gene and 15q, and losses of 6q, 9p, 13q and 17p affecting P53 gene. Differently from MCL and CLL, genomic loss of 8p was frequently detected in MCLeu (83%). Although clinical presentation of MCLeu was indistinguishable from CLL, all patients but one had disease progression within three years. According to the immunologic and genomic profiles, two distinct subgroups of MCLeu were defined: one related to PLL, showing CD38-, deletion of P53, and MYC amplification and another which corresponds to a leukemic form of classical MCL, presenting with CD38+ and normal P53 and MYC status. CONCLUSION: MCLeu and MCL are closely related disorders, as they show similar genomic and molecular patterns. However, the deletion of the short arm of chromosome 8 may represent a specific marker for MCLeu. Two distinct subgroups of MCLeu may also be distinguished according to the immunologic and genomic cell profiles.

A comparison between the effect of intentional modulations and the action of L-dopa on gait in Parkinson's disease.

The aims of the present study were to analyze how L-Dopa allows parkinsonian patients to increase their gait velocity and to compare these L-Dopa-induced modifications with those achieved by consciously attempting to walk as fast as possible (intentional modulations). The 'intentional modulations' of velocity were also compared with those of healthy elderly subjects. The results showed that parkinsonian patients walked more slowly, with shorter strides and shorter durations of swing phase, and longer durations of stance and double support phases, although no differences were observed for cycle duration. The mechanisms involved in increasing gait velocity were found to differ according to whether this was achieved through the action of L-Dopa, or by intentional increases in velocity. Intentional increases in velocity were greater than those caused by the effect of L-Dopa. The patients, however, used efficient strategies to increase their velocity when under the influence of L-Dopa. As L-Dopa leads to a ceiling effect on stride length, the patients can increase their velocity by modifying the cycle to such an extent that it compensates for the limitation in stride length. This strategy effectively increases velocity, despite the L-Dopa ceiling effect. The effects of L-Dopa on locomotion and, more generally, on motor control aspects are discussed.

Unintentional modulations of human gait by optical flow.

Visual whole-field motion is known to trigger motor responses which minimize retinal slip (VOR, OKN and control of balance). In locomotion, however, the retinal slip is utilized to control the velocity and direction of displacement. The present experiment was aimed at determining how the velocity of optical flow affects the regulation of locomotion. Unintentional modulations in velocity, stride length and cadence were analyzed using a task in which artificial optical flow gave the subjects the impression they were walking at a different speed than they actually were. Slight but systematic modifications in locomotion were observed: experimental variation of the optical flow resulted in a decrease in stride length. None of the subjects were aware of this decrease, despite the fact that their muscular and articular afferences provided them with supraliminal information. Although visual flow velocity is usually a direct consequence of walking velocity, experimental modifications of visual flow were found here to cause unintentional modulations in locomotor parameters (stride length and cadence) more than in their product (velocity).

Quantitative analysis of gait in Parkinson patients: increased variability of stride length.

Analysis of the spatio-temporal and kinematic parameters of locomotion recorded in 21 parkinsonian patients compared to 58 normal elderly subjects showed significant differences in all the recorded parameters. However the relationship between these parameters was preserved, as was the basic locomotor pattern. The variability of stride length, more marked in parkinsonian patients, increased as a function of the clinical stages of Hoehn and Yahr. This index could be useful in assessing the course of the disease in patients.

Dopa-sensitive and dopa-resistant gait parameters in Parkinson's disease.

Quantitative analysis of gait was performed in 20 parkinsonians before and 1 h after the acute administration of L-Dopa in order to discriminate between the Dopa-sensitive and the Dopa-resistant kinematic gait parameters. The stride length and the kinematic parameters (swing velocity, peak velocity) related to the energy were Dopa-sensitive. The improvement of the bent forward posture by L-Dopa may explain the stride length increase. Temporal parameters (stride and swing duration, stride duration variability), related to rhythm, were Dopa-resistant. Experimental data argue for the importance of force control in maintaining the posture. The stride length variability, possibly related to the variability of force production shown to exist in parkinsonians was not significantly improved by L-Dopa. In Parkinson's disease different hypotheses might explain the inexorable aggravation of gait disorders along the course of the disease: (1) an advancing disorder of coordination between postural control and locomotion, (2) if some gait parameters like stride length and kinematic parameters are Dopa-sensitive, the others are Dopa-resistant and thus may involve other mechanisms than dopamine deficiency.

What is the relationship between spermatozoa per milliliter at adulthood and the tubular fertility index at surgical age for patients with cryptorchidism?

PURPOSE: The aim of this study was to find out the relationship in the patient with cryptorchidism between the number of spermatogonia at surgical age and spermiogram data at adulthood. METHODS: Between 1971 and 1996 the authors surgically treated 1,550 children for 2,249 undescended testis. In 21 unilateral and 41 bilateral cryptorchidism patients, both testis were biopsied at surgical procedure during childhood. We currently have spermiogram data for a patient at adulthood. RESULTS: By using the best Tubular Fertility Index (TFI) figures of both testis, the Sperman correlation index between the two parameters is r = 0.22, statistically nonsignificant. The TFI test sensitivity is 0.68 and the specificity is 0.60. The likehood ratio for a positive test result is 0.84 and the likehood ratio for a negative test result is 0.37. CONCLUSION: Although the authors have only one spermiogram, and there are few cases, they suspect the TFI is not a good index to predict the potential fertility in cryptorchidism patients.

A note on modulations and structuring of locomotion in children and adults.

The aim of this study was to investigate the modulations of locomotion induced by a rhythmic cognitive task (counting one's steps). Subjects (6- and 8-year-olds and adults) were requested to walk freely, and then to walk while counting their steps. Here a decrease in cadence values was observed in children only, with quasi-total repercussions on velocity at the age of 6 only. The spatiotemporal structuring of locomotion described here is already present at 6 years of age and is not altered in the step-counting situation: strong links were observed between cadence and velocity, and between stride length and velocity, and weak links between cadence and stride length.

[Should coronary patients chronically taking a low-dose of aspirin receive gastroprotective agents?]. / Deben administrarse protectores gástricos a los pacientes coronarios que toman dosis bajas de aspirina de forma crónica?

The use of low-dose aspirin (75-300 mg/day) is associated with an increased risk of gastrointestinal bleeding, which is lower than that observed with common NSAIDs. Risk factors for the development of GI bleeding in patients taking low-dose aspirin are not well defined, although patients with a previous history of peptic ulcer, concomitant NSAID use and serious diseases should receive gastroprotection. Among the available drugs, proton pump inhibitors associated, when present, to Helicobacter pylori erradication, have shown the highest efficacy. The best cost-effectiveness treatment is still undefined.

Numerical models of auto-regulation and blood flow in the cerebral circulation.

A two-dimensional time-dependent computational fluid dynamics model of the Circle of Willis has been developed. To simulate, not only the peripheral resistance of the cerebrovascular tree but also its auto-regulation function, a new "active" boundary condition has been defined and developed using control theory to provide a model of the feedback mechanism. The model was then used to simulate different common abnormalities of the Circle of Willis while a pressure drop, simulating a rapid compression of the right internal carotid artery, was imposed. Test results using a simple tube compared excellently with experiment. The total time-dependent flux for each efferent artery was tabulated and showed the important relationship between geometrical variations in the Circle of Willis and the auto-regulation of blood flow by vascular vaso-dilation and contraction. From this study, it was found that the worst case seemed to be that of a missing or dysfunctional right A1 segment of the anterior cerebral artery. The use of valid physiological models of the peripheral resistance allows for more realistic models of the blood flow in the Circle whilst allowing an easy extension to 3D patient specific simulations.