Laparoscopic adjustable gastric banding versus Roux-en-Y gastric bypass: 10-year results of a prospective,randomized trial

BackgroundThere are few studies of long-term outcomes for either laparoscopic adjustable gastric banding (LAGB) or laparoscopic Roux-en-Y gastric bypass (LRYGB). The objective of this study was to compare outcomes of patients randomly assigned to undergo LAGB or LRYGB at 10 years.MethodsLAGB, using the pars flaccida technique, and standard LRYGB were performed. From January 2000 to November 2000, 51 patients (mean age 34.0 ± 8.9 years; range 20–49) were randomly allocated to undergo either LAGB (n = 27, 5 men and 22 women; mean age 33.3 years; mean weight 120 kg; mean body mass index [BMI] 43.4 kg/m²) or LRYGB (n = 24, 4 men and 20 women; mean age 34.7; mean weight 120 kg; mean BMI 43.8 kg/m²). Data on complications, reoperations, weight, BMI, percentage of excess weight loss, and co-morbidities were collected yearly. The data were analyzed using Student’s t test and Fisher’s exact test, with P<.05 considered significant.ResultsFive patients in the LAGB group and 3 patients in the LRYGB group were lost to follow-up. No patient died. Conversion to laparotomy was performed in 1 (4.2%) of 24 LRYGB patients. Reoperations were required in 9 (40.9%) of 22 LAGB patients and in 6 (28.6%) of the 21 LRYGB patients. At 10-year follow-up, the LRYGB patients had a greater percentage of mean excess weight loss than did the LAGB patients (69±29% versus 46±27%; P = .03).ConclusionLRYGB was superior to LAGB in term of excess weight loss results (76.2% versus 46.2%) at 10 years. However, LRYGB exposes patients to higher early complication rates than LAGB (8.3% versus 0%) and potentially lethal long-term surgical complications (internal hernia and bowel obstruction rate: 4.7%).     

Experience with the EndoPap device for the cytologic detection of uterine cancer and its precursors: a comparison of the EndoPap with fractional curettage or hysterectomy

Cytologic assessment of the endometrium with the EndoPap sampler was compared with curettage or hysterectomy in 249 women with symptoms. The sensitivities for the detection of primary corpus cancer and hyperplasia were 0.90 (59/66) and 0.58 (18/31), respectively. All six cases of atypical endometrial hyperplasia were detected by the EndoPap device. Malignant EndoPap cytologic findings were present in 4 of 10 patients with a primary adnexal malignancy and normal endometrial histologic findings. Ninety-two percent of primary uterine cervical cancers were detected by EndoPap cytologic sampling. The specificity for the cytologic diagnosis of benign conditions was 0.93. EndoPap cytologic sampling has a reasonably high sensitivity for the detection of uterine cancers and preinvasive endometrial lesions with a high risk of progression to carcinoma. Further evaluation as to its usefulness in a screening program for uterine and adnexal cancers in postmenopausal women should be considered.     

Myelin basic protein induces heme oxygenase-1 in human astroglial cells.

Heme oxygenase-1 (HO-1), also known as heat-shock protein 32 (HSP-32), is induced in many cells by a large variety of stimuli. Its induction in nervous system cells following toxic and oxidative stress was suggested to play a protective role. Its presence was recently detected by immunohistochemical studies at the level of inflammatory lesions of rat experimental autoimmune encephalomyelitis. In the present study, we demonstrate that myelin basic protein (MBP) induces HO-1 in human astroglial cells, as shown by Western blots and RT-PCR. Proteolytic fragments derived from the whole MBP show a different behavior in the HO-1 induction: MBP152-167 was able to produce a light but still significant increase in HO-1 mRNA and protein levels, whereas MBP68-84 was not. The increase in HO-1 production seems to be mediated by a Ca(2+)-dependent mechanism, since MBP addition to astrocytoma cultures induced a strong and immediate increment of [Ca(2+)](i) increase; MBP152-167 elicited a delayed and less pronounced [Ca(2+)](i) increase; no [Ca(2+)](i) changes were induced following cell treatment with MBP68-84. NO pathway involvement in the induction of HO-1 by MBP was ruled out since the expression of the inducible isoform of nitric oxide synthase was not upregulated in treated cells, neither nitrite levels were modified, as demonstrated by Greiss reaction. The possible significance of HO-1 induction following MBP stimulation is discussed.     

New 1,2,3-triazolo[1,5-a]quinoxalines: synthesis and binding to benzodiazepine and adenosine receptors. II

On pursuing research about 1,2,3-triazolo[1,5-a]quinoxalines, in this paper we report synthesis and binding assays toward the benzodiazepine and A(1) and A(2A) adenosine receptors, of a new series of derivatives, bearing some structural changes (introduction of fluorine and trifluoromethyl in the seventh position, amino substituents in the fourth position, benzyl group in the fifth position and aroyl substituents in the third position). The biological tests have shown that only the 7-fluorosubstituted compounds 3a and 4a and the N-benzyl derivative 7 have a good affinity toward the benzodiazepine receptors, while only the 7-trifluoromethyl substituted compound 3b presents a moderate affinity with low selectivity toward the A(1) adenosine receptors. The other structural modifications strongly decreased biological activity.     

The GABA(B) receptor agonists baclofen and CGP 44532 prevent acquisition of alcohol drinking behaviour in alcohol-preferring rats

AIMS: The present study investigated the effect of the gamma-aminobutyric acid (GABA)(B) receptor agonists, baclofen and CGP 44532, on the acquisition of alcohol drinking behaviour in selectively bred Sardinian alcohol-preferring (sP) rats. METHODS: Baclofen [0, 1 and 3 mg/kg, intraperitoneally (i.p.)] and CGP 44532 (0, 0.1, 0.3 and 1 mg/kg, i.p.) were administered immediately before alcohol presentation to alcohol-naive sP rats. Alcohol was offered under the two-bottle free-choice regimen with unlimited access for 24 h/day. Drug treatment was repeated once daily for 10 consecutive days. RESULTS: Baclofen and CGP 44532, dose-dependently and with comparable efficacy, suppressed alcohol intake; compensatory increases in water intake left total fluid intakes virtually unchanged. CONCLUSIONS: These results demonstrate that baclofen and CGP 44532 prevent the acquisition of alcohol drinking behaviour in sP rats, and suggest the involvement of the GABA(B) receptor in the mechanisms underlying the disclosure and experience of the reinforcing properties of alcohol in this rat line.     

Adjuvant chemotherapy in gastric cancer: a meta-analysis of randomized trials and a comparison with previous meta-analyses

AIMS AND BACKGROUND: Up to now adjuvant chemotherapy after curative resection for gastric cancer (GC) has been considered an experimental approach. The results of existing phase III randomized trials comparing chemotherapy with control after surgery are controversial. Three meta-analyses have been published in recent years. It is likely that each of them presents a theoretical bias, mainly as regards the inclusion criteria of the trials. In this article we re-examine this potential bias, highlighting the differences between the present and past meta-analyses on adjuvant chemotherapy for GC. METHODS: Only randomized controlled clinical trials comparing systemic adjuvant chemotherapy with control after radical resection of GC were eligible. Total mortality was assessed as outcome measure of the treatment effect and a pooled odds ratio was calculated using the Peto-Mantel-Haenszel method. RESULTS: After the selection process 17 papers (18 comparisons) proved eligible for inclusion in the meta-analysis with a total of 3118 patients, of whom 1546 randomized to the treatment arms and 1572 to the control arms; 762 and 871 deaths occurred in the treatment and control arms, respectively. Statistical analysis suggests an absence of significant heterogeneity between the trials and a significant advantage in survival for adjuvant chemotherapy (pooled odds ratio, 0.72, 95% Cl, 0.62-0.84). CONCLUSIONS: Our meta-analysis would seem to indicate that adjuvant chemotherapy results in a significant survival advantage in patients with GC. However, this observation undoubtedly requires confirmation in large randomized controlled trials including cisplatin before adjuvant chemotherapy after curative resection for GC can be proposed for use in clinical practice.     

Cellular bases of the antitumor activity of the novel taxane IDN 5109 (BAY59-8862) on hormone-refractory prostate cancer.

Taxane-based therapies appear to have a significant efficacy in clinical trials on hormone-refractory prostate carcinoma. In the present study, we investigated the cellular response of androgen-independent prostate carcinoma cell lines to the novel taxane IDN 5109 (BAY 59-8862) and evaluated its antitumor activity. In previous preclinical studies, this new paclitaxel (PTX) analogue was characterized by high tolerability and antitumor efficacy, ability to overcome multidrug resistance, and activity by oral administration. Upon treatment, DU145 and PC3 prostate carcinoma cell lines underwent a transient mitotic arrest. This was followed by G1 arrest and rapid occurrence of apoptosis in DU145 cells, whereas in PC3 cells, which are defective for the postmitotic checkpoint, a slow cell death was preceded by DNA endoreduplication. At the biochemical level, such events were associated with tubulin polymerization, activation of the mitosis-promoting factor, and phosphorylation of Bcl-X(L)/Bcl-2/Raf-1. In addition, IDN 5109 shared with PTX the ability to down-regulate the expression of the two potent angiogenic factors vascular endothelial growth factor and basic fibroblast growth factor. These findings indicated that IDN 5109 affected the same pathways involved in the cellular response to PTX and suggested that an antiangiogenic effect mediated by inhibition of paracrine stimulation of endothelial cells might contribute to the antitumor effect of both drugs. In in vivo experiments, the new taxane displayed a superior and more persistent effect compared with PTX against DU145 tumor xenografts. Such an effect was associated with pronounced reduction of the tumor microvessel density, superior to that achieved by PTX. These results support a potential therapeutic advantage of IDN 5109 over PTX against hormone-refractory prostate carcinoma.     

Tissue protein turnover during liver carcinogenesis

Overall rates of tissue protein degradation in vivo during chemicalhepatocarcinogenesis were estimated by a double-isotope methodas well as from the accumulation of peptide intermediates inprotein degradation induced by bestatin. Several parametersestimating rates of cell proliferation and cell loss have beenmeasured in parallel. The two procedures adopted consistentlyindicated that protein turnover was significantly slowed downthrough the whole observation period (12 months after the initiatingadministration of DENA) in both ‘preneoplastic’nodules and hepatomas as compared with control livers or perinodulartissue. Such a difference may confer a selective growth advantageto ‘preneoplastic’ and tumoral cells. Since proteindegradation rates did not appreciably differ between nodulesand hepatomas, either such advantage originated from some earlystep in the carcinogenetic process or it merely reflected theproliferative events in the two cell populations. Yet neitherliver nodules nor hepatomas were characterized by very highrates of cell proliferation, however much increased with respectto control liver.     

Acute Isovolemic Anemia Does Not Impair Peripheral or Central Nerve Conduction

Background: Previous studies have found subtle slowing of responses in tests of addition and digit-symbol substitution during acute severe isovolemic anemia to a hemoglobin concentration of 5 g/dl in healthy unmedicated humans. In this study, the authors tested the hypothesis that such changes relate to the slowing of afferent neural traffic.

Methods: The median nerve was stimulated at the wrist in seven healthy unmedicated volunteers before and after induction of acute isovolemic anemia to a nadir hemoglobin concentration of 5.1 +/- 0.3 g/dl (mean +/- SD). Times for neural impulses to travel from the stimulus site to the brachial plexus, cervical spinal cord, and cerebral cortex were measured using somatosensory evoked potentials. Tests were repeated during acute anemia with the subject breathing oxygen. As a control for time and intrasubject variation, the testing was repeated on a separate day when anemia was not produced at times equivalent to those on the experimental day.

Results: Induced acute severe isovolemic anemia decreased nerve conduction latencies from the wrist to the contralateral cerebral cortex (i.e., to the N20 peak) by 2.3 +/- 1.6% compared with values at a mean hemoglobin concentration of 12.7 g/dl (P < 0.01). These decreased latencies were due solely to an increased peripheral conduction velocity, from the wrist to the brachial plexus (P < 0.05), and were not altered when subjects breathed oxygen (P > 0.05). Conduction velocity from the brachial plexus or cervical spinal cord to the cerebral cortex did not change with acute anemia (P > 0.05). Latencies did not differ on the control day among the times of testing (all P > 0.05), nor did they differ at baseline between the control and experimental days (all P > 0.05).     

The plant-type ferredoxin-NADP+ reductase/ferredoxin redox system as a possible drug target against apicomplexan human parasites

Apicomplexa are unicellular, obligate intracellular parasites of great medical importance. They include human pathogens like Plasmodium spp., the causative agent of malaria, and Toxoplasma gondii, an opportunistic parasite of immunosuppressed individuals and a common cause of congenital disease (toxoplasmosis). They alone affect several hundred million people worldwide so that new drugs, especially for plasmodial infections, are urgently needed. This review will focus on a recently emerged, potential drug target, a plant-type redox system consisting of ferredoxin-NADP(+) reductase (FNR) and its redox partner, ferredoxin (Fd). Both reside in an unique organelle of these parasites, named apicoplast, which is of algal origin. The apicoplast has been shown to be required for pathogen survival. In addition to other pathways already identified in this compartment, the FNR/Fd redox system represents a promising drug target because homologous proteins are not present in host organisms. Furthermore, a wealth of structural information exists on the closely related plant proteins, which can be exploited for structure-function studies of the apicomplexan protein pair. T. gondii and P. falciparum FNRs have been cloned, and the T. gondii enzyme was shown to be a flavoprotein active as a NADPH-dependent oxidoreductase. Both phylogenetic and biochemical analyses indicate that T. gondii FNR is similar in function to the isoform present in non-photosynthetic plastids whereby electron flow is from NADPH to oxidized Fd. The resulting reduced Fd is then presumably used as a reductant for various target enzymes whose nature is just starting to emerge. Among the likely candidates is the iron-sulfur cluster biosynthesis pathway, which is also located in the apicoplast and dependent on reducing power. Furthermore, lipoic acid synthase and enzymes of the isoprenoid biosynthetic pathway may be other conceivable targets. Since all these metabolic steps are vital for the parasite, blocking electron flow from FNR to Fd by inhibition of either FNR activity or its molecular interaction with Fd should also interfere with these pathways, ultimately killing the parasite. Although the three-dimensional structure of FNR from T. gondii is not yet known, experimental and computational evidence shows that apicomplexan and plant enzymes are very similar in structure. Furthermore, single amino acid changes can have profound effects on the enzyme activity and affinity for Fd. This knowledge may be exploited for the design of inhibitors of protein-protein interaction. On the other hand, specifically tailored NAD(P) analogues or mimetics based on previously described substances might be useful lead compounds for apicomplexan FNR inhibitors.