OBJECTIVE: To examine the factors associated with liver steatosis in severely obese subjects and to test the potential reversibility of fatty liver after weight loss. DESIGN: Retrospective clinical study. SUBJECT: 528 obese patients before bariatric surgery and 69 obese subjects of the initial cohort evaluated before and 27 AE 15 months after gastroplasty. MEASUREMENTS: Fatty deposition (scored as mild, moderate or severe) and in¯ammatory changes were evaluated in liver biopsies; clinical (body mass index (BMI), age, gender, duration of obesity) and biological (glucose, triglycerides, liver enzymes) parameters were related to histological ®ndings. RESULTS: 74% of the 528 biopsies showed fatty change, estimated as mild in 41% of cases, moderate in 32% and severe in 27%. The prevalence of steatosis was signi®cantly higher in men than in women (91% vs 70%, P 0.001) and in patients with impaired glucose tolerance or type 2 diabetes compared with nondiabetics (89% vs 69% P 0.001). The severity of the steatosis was associated with BMI (P 0.002) but not with the duration of obesity or the age of the patient. When compared with patients without fatty change, those with liver steatosis had signi®cantly higher fasting plasma glucose (5.5 mmol/l vs 5.1 mmol/l, P 0.007) and triglycerides (1.8 mmol/l vs 1.3 mmol/l, P 0.002). Mean serum liver enzyme activities (alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyl-transpeptidase (gGT) were signi®cantly (P`0.001) increased in patients with fatty change but remained within laboratory reference values. In the 69 patients who have been evaluated after a marked weight reduction (732 AE 19 kg), 45% of the biopsies were considered as normal (vs 13% before, P`0.001) while pure fatty change was still observed in 38% of the patients (vs 83% before, P 0.001). However, the severity of the steatosis was signi®cantly (P`0.001) reduced (mild: 62% vs 21%; moderate: 23% vs 37%; severe: 15% vs 42%). In addition, a signi®cant increase of hepatitis was observed in 26% of the biopsies (vs 14% before, P`0.05). CONCLUSIONS: Liver steatosis in obese subjects is associated with men, diabetic status, BMI, higher fasting glucose and hypertriglyceridaemia. Postgastroplasty weight loss reduces liver steatosis, but seems to increase the incidence of in¯ammatory lobular hepatitis.

IB␣ is an inhibitory molecule that sequesters NF-B dimers in the cytoplasm of unstimulated cells. Upon stimulation, NF-B moves to the nucleus and induces the expression of a variety of genes including IB␣. This newly synthesized IB␣ also translocates to the nucleus, removes activated NF-B from its target genes, and brings it back to the cytoplasm to terminate the phase of NF-B activation. We show here that IB␣ enhances the transactivation potential of several homeodomain-containing proteins such as HOXB7 and Pit-1 through a NF-B-independent association with histone deacetylase (HDAC) 1 and HDAC3 but not with HDAC2, -4, -5, and -6. IB␣ bound both HDAC proteins through its ankyrin repeats, and this interaction was disrupted by p65. Immunofluorescence experiments demonstrated further that IB␣ acts by partially redirecting HDAC3 to the cytoplasm. At the same time, an IB␣ mutant, which lacked a functional nuclear localization sequence, interacted very efficiently with HDAC1 and -3 and intensively enhanced the transactivation potential of Pit-1. Our results support the hypothesis that the NF-B inhibitor IB␣ regulates the transcriptional activity of homeodomain-containing proteins positively through cytoplasmic sequestration of HDAC1 and HDAC3, a mechanism that would assign a new and unexpected role to IB␣.The paradigm of NF-B activation is based on its cytoplasmic sequestration by IB␣ through the masking of its nuclear localization sequence (NLS) 1 in unstimulated cells (1). Recent studies have challenged this hypothesis suggesting that IB␣ constantly shuttles in and out of the nucleus via nuclear import (2) and export sequences (3, 4). Because IB␣ nuclear export is more efficient than its nuclear import process, the NF-B⅐IB␣ complex remains mainly in the cytoplasm of unstimulated cells. Upon stimulation by proinflammatory cytokines, viral infection, or bacterial pathogens, IB␣ is phosphorylated by the IB kinase complex and degraded through the proteasome pathway (5). Then NF-B enters into the nucleus and activates the expression of multiple genes including IB␣. This newly synthesized IB␣ protein moves to the nucleus, removes NF-B from its target genes, and brings it back to the cytoplasm to terminate the phase of NF-B activation. IB␣ is part of a family of ankyrin-containing proteins that also includes IB␤ and IB⑀ (6) as well as p100, p105, and BCL-3 (7). In contrast to the IB proteins, BCL-3 is mainly nuclear and harbors some transactivation potential through heterodimer formation with the NF-B proteins p50 or p52 (8) and recruitment of coactivators such as JAB1 and BARD1 (9).We previously demonstrated that IB␣ enhances the transactivation potential of HOXB7, a homeodomain-containing protein (10). In this study, we elucidated further the underlying mechanism and showed that cytoplasmic IB␣ enhances the transactivation potential of other homeodomain-containing proteins such as Pit-1 and PAX8 through binding to some but not all HDAC proteins, a family of proteins sharing the ability to deacetylate their substrates a...

Ceramides are important intracellular second messengers that play a role in the regulation of cell growth, differentiation, and programmed cell death. To determine whether ceramides can mediate the apoptosis of HCT116 and OVCAR-3 cancer cells, exogenous C2-, C6-, and C16-ceramides were used to mimic the endogenous lipid increase that follows a large variety of stresses. C2-and C6-ceramides (cell-permeable ceramide analogs), but not C16-ceramide, induced nuclear factor-kB (NF-kB) DNA-binding, caspase-3 activation, poly(ADP-ribose) polymerase degradation, and mitochondrial cytochrome c release, indicating that apoptosis occurs through the caspase cascade and the mitochondrial pathway. No difference in survival was observed between control cells and cells expressing mutated IkBa and treated with the permeable ceramides. This suggests that, at least in these cell lines, stable NF-kB inhibition did not modify the ceramide-induced cytotoxicity pathway. C6-ceramide also induced a double block in G1 and G2, thus emptying the S phase. #

Colonic grafts are not associated with increased postoperative mortality or complications. Our results suggest that preoperative neoadjuvant treatment significantly increases postoperative pulmonary complications.

Abstract--The transformation of a cell and the acquisition of the invasive and metastatic phenotype result from the activation of a group of complex cellular processes rather than from the effect of a single gene product. It is likely that the coordination of the multiple genes involved in malignancy is under the control of a few genes that act as master genes or orchestrator genes. The latter probably code for transcription factors that control the genetic program for tumor invasion and metastasis. Homeobox genes are a family of transcription factors that contain a 183 bp highly conserved nucleotide sequence coding for a 61 amino acid domain that binds specifically to DNA. First discovered in Drosphila as genes controlling segmentation and segment identity, homeobox genes have since been identified in many other species including nematodes, frog, mouse and human. There is strong support for the suggestion that homeobox genes play a key role in development and differentiation. In humans, there are 38 homeobox genes organized in four clusters that are localized on chromosomes 2, 7, 12 and 17. The specific functions of each of these genes are generally unknown. Alterations in expression of several homeobox genes have been reported in a variety of malignant lesions, suggesting that they could play a role in the development of cancer. Using reverse transcriptase reaction coupled with polymerase chain reaction and degenerate oligonucleotides corresponding to the 5' and 3' ends of the highly conserved homeodomain, we amplified 130 bp cDNA fragments from the human breast cancer cell line MCF7 that were subsequently cloned into pBluescript vector. Sequencing of the clones, resulted in the identification of the homeodomains of four different human homeobox genes: HOXB6, HOXA1, HOXA10 and HOXC6. Further studies should determine the specific role of these four homeobox genes in the development and progression of human breast cancer and potentially determine if they might be good targets for gene therapy.