Ahmet Ayav

Characterization and Clinical Application of Human CD34+ Stem/Progenitor Cell Populations Mobilized into the Blood by Granulocyte Colony‐Stimulating Factor

A phase I study was performed to determine the safety and tolerability of injecting autologous CD34+ cells into five patients with liver insufficiency. The study was based on the hypothesis that the CD34+ cell population in granulocyte colony‐stimulating factor (G‐CSF)‐mobilized blood contains a subpopulation of cells with the potential for regenerating damaged tissue. We separated a candidate CD34+ stem cell population from the majority of the CD34+ cells (99%) by adherence to tissue culture plastic. The adherent and nonadherent CD34+ cells were distinct in morphology, immunophenotype, and gene expression profile. Reverse transcription‐polymerase chain reaction‐based gene expression analysis indicated that the adherent CD34+ cells had the potential to express determinants consistent with liver, pancreas, heart, muscle, and nerve cell differentiation as well as hematopoiesis. Overall, the characteristics of the adherent CD34+ cells identify them as a separate putative stem/progenitor cell population. In culture, they produced a population of cells exhibiting diverse morphologies and expressing genes corresponding to multiple tissue types. Encouraged by this evidence that the CD34+ cell population contains cells with the potential to form hepatocyte‐like cells, we gave G‐CSF to five patients with liver insufficiency to mobilize their stem cells for collection by leukapheresis. Between 1 × 106 and 2 × 108 CD34+ cells were injected into the portal vein (three patients) or hepatic artery (two patients). No complications or specific side effects related to the procedure were observed. Three of the five patients showed improvement in serum bilirubin and four of five in serum albumin. These observations warrant further clinical trials.

TNFα up-regulates apelin expression in human and mouse adipose tissue

We have recently identified apelin as a novel adipokine up‐regulated by insulin and obesity. Since obesity and insulin resistance are associated with chronically elevated levels of both insulin and TNFα, the present study was performed to investigate a putative regulation of apelin expression in adipocytes by TNFα. Herein, we report a tight correlation between apelin and TNFα expression in adipose tissue of lean and obese humans. Apelin regulation by TNFα was further studied in cultured explants of human adipose tissue. The endogenous expression of TNFα in adipocytes isolated from the explants was accompanied by a 6–9 h subsequent increase of apelin expression in adipocytes. This increase was reversed by inhibiting TNFα expression with 100 µM isobutylmethylxanthine. In different mouse models of obesity, expression of both TNFα and apelin was also significantly increased in adipocytes of obese mice. Furthermore, short‐term exposure to an i.p. injection of TNFα in C57Bl6/J mice induced an increase of apelin expression in adipose tissue as well as apelin plasma levels. Finally, a direct positive effect of TNFα has been shown in differentiated 3T3F442A adipocytes on apelin expression and secretion. The signaling pathways of TNFα for the induction of apelin were dependent of PI3‐kinase, c‐Jun NH2‐terminal kinase (JNK), and MAPK but not PKC activation. All together, these findings suggest that apelin might be a candidate to better understand potential links between obesity and associated disorders such as inflammation and insulin resistance.—Daviaud, D., Boucher, J., Gesta, S., Dray, C., Guigne, C., Quil‐liot, D., Ayav, A., Ziegler, O., Carpene, C., Saulnier‐Blache, J.‐S., Valet, P., Castan‐Laurell, I. TNFα up‐regulates apelin expression in human and mouse adipose tissue. FASEB J. 20, E796–E802 (2006)

Prospective evaluation of 100 robotic-assisted unilateral adrenalectomies.

BACKGROUND Our aim was to determine the learning curve for robotic adrenalectomy and factors that influence operative time and cost. METHODS We prospectively evaluated of 100 consecutive patients who underwent robotic, unilateral, transperitoneal adrenalectomy. RESULTS The mean operative time for robotic-assisted adrenalectomy was 95 minutes and conversion rate was 5%. Pathology was aldosteronoma (n = 39), pheochromocytoma (n = 24), nonfunctional adenoma (n = 19), Cushing adenoma or hyperplasia (n = 16), and cyst (n = 2). Morbidity and mortality rates were 10% and 0%, respectively. The mean operative time decreased by 1 minute every 10 cases. Operative time improved more for junior surgeons than for senior surgeons (P = .006) after the first 50 cases. By multiple regression analysis, surgeons experience (-18.9 +/- 5.5), first assistant level (-7.8 +/- 3.2), and tumor size (3 +/- 1.4) were independent predictors of operative time (P < .001 each). The robotic procedure was 2.3 times more costly than lateral transperitoneal laparoscopic adrenalectomy (euro4102 vs euro1799). CONCLUSIONS Surgeon experience, resident training level, and tumor size are important variables for robotic-assisted, unilateral adrenalectomy and should be taken into account when this approach is evaluated. Controlled studies need to be performed to show potential relevant clinical benefits that could balance costs.

Robotic-assisted adrenalectomy: what advantages compared to lateral transperitoneal laparoscopic adrenalectomy?

BACKGROUND This study evaluates the perioperative outcomes of robotic-assisted adrenalectomy (RA) compared with lateral transperitoneal laparoscopic adrenalectomy (LA). METHODS Prospective evaluation of 50 patients who underwent unilateral RA versus 59 patients who underwent unilateral LA. RESULTS RA was associated with lower blood loss (49 mL) but longer operative times (104 minutes) (P < .001). However, the difference in operative time was not significant after the learning curve of 20 cases. In patients with body mass index (BMI) > or = 30 kg/m(2), mean operative time was longer in the LA group (90 vs 78 minutes, P = .03) but not in the RA group. In patients with large tumors (> or = 55 mm), mean operative time was longer in the LA group (100 vs 80 minutes, P = .009) but not in the RA group. Conversion rate, morbidity, and hospital stay were similar in both groups. CONCLUSIONS After a learning curve of 20 cases, RA has similar perioperative outcomes compared to lateral transperitoneal LA. Several criteria (previous laparoscopic expertise, first assistants skill and tumor side) remain determinative on RA operative time.

Robotic-assisted pelvic organ prolapse surgery

BackgroundThis study describes technical aspect and short-term results of pelvic organ prolapse surgery using the da Vinci robotic system.MethodsDuring a 1-year period, 18 consecutive patients with pelvic organ prolapse were operated on using the da-Vinci system. Clinical data were prospectively collected and analyzed.ResultsAll but one procedure was successfully completed robotically (95%). Performed procedures were colpohysteropexy (n = 12), mesh rectopexy (n = 2), or sutured rectopexy combined with sigmoid resection (n = 4). Average setup time was 21 min and significantly decreased with experience. Mean operative time was 172 min (range, 45–280). There were no mortality and no specific morbidity due to the robotic approach. Mean hospital stay was 7 days. At 6 months, all patients were free of pelvic organ prolapse and stated that they were satisfied with anatomical and functional results.ConclusionOur experience indicates that using the da-Vinci robotic system is feasible, safe, and effective for the treatment of pelvic organ prolapse.

Does Robotic Adrenalectomy Improve Patient Quality of Life When Compared to Laparoscopic Adrenalectomy

The purpose of this study was to evaluate and compare perioperative quality of life in patients after laparoscopic versus robotic adrenalectomy. From November 2000 through August 2003, 33 consecutive patients underwent laparoscopic (n = 14) and robotic (n = 19) adrenalectomy. Data were obtained prospectively during management and by patient questionnaire (SF36, State-Trait Anxiety Inventory) preoperatively and postoperatively, at day 4 and at 6 weeks. Physical functioning, role limitations due to physical health problems, and bodily pain (Physical SF36 scores) were decreased at day 4 (p = 0.004) in all patients when compared to preoperative levels; and became similar to preoperative levels after 6 weeks. Patients who underwent robotic adrenalectomy had an increased score at 6 weeks of role limitations due to emotional problems (Mental SF36 score) (p = 0.03). No other significant difference was observed between patients after laparoscopic or robotic adrenalectomy. Although state anxiety was decreased postoperatively at day 4 and at 6 weeks (p = 0.01) in all patients, there was no significant difference between laparoscopic and robotic adrenalectomy. Postoperative pain was similar in both groups but had a tendency to be higher when patients underwent a left adrenalectomy (p = 0.07). Similarly, state anxiety had a tendency to be higher postoperatively at day 4 in patients after left adrenalectomies (p = 0.06). This study provides an evaluation of perioperative quality of life in patients after minimally invasive (laparoscopic and/or robotic) adrenalectomy. We observed no major difference between patients who underwent laparoscopic or robotic adrenalectomy. Thus, patients’ perioperative quality of life is not a justifiable parameter on which to base promotion of robotic adrenalectomies.

Effects of vitamin B12 and folate deficiencies on DNA methylation and carcinogenesis in rat liver.

Abstract Deficiencies of the major dietary sources of methyl groups, methionine and choline, lead to the formation of liver cancer in rodents. The most widely investigated hypothesis has been that dietary methyl insufficiency results in abnormal DNA methylation. Vitamin B12 and folate also play important roles in DNA methylation since these two coenzymes are required for the synthesis of methionine and S-adenosyl methionine, the common methyl donor required for the maintenance of methylation patterns in DNA. The aim of this study was to review the effects of methyl-deficient diets on DNA methylation and liver carcinogenesis in rats, and to evaluate the role of vitamin B12 status in defining carcinogenicity of a methyl-deficient diet. Several studies have shown that a methyl-deficient diet influences global DNA methylation. Evidence from in vivo studies has not clearly established a link between vitamin B12 and DNA methylation. We reported that vitamin B12 and low methionine synthase activity were the two determinants of DNA hypomethylation. Choline- or choline/methionine-deficient diets have been shown to cause hepatocellular carcinoma in 20–50% of animals after 12–24 months. In contrast, the effect of vitamin B12 withdrawal, in addition to choline, methionine and folate, induced hepatocellular carcinoma in less than 5% of

Radiofrequency ablation of unresectable liver tumors: factors associated with incomplete ablation or local recurrence.

BACKGROUND Radiofrequency ablation (RFA) of liver tumors is associated with a risk of incomplete ablation or local recurrence. METHODS One hundred sixty-eight patients with 311 unresectable liver tumors were included. Effects of different variables on incomplete ablation and local recurrence were analyzed. RESULTS There were 132 hepatocellular carcinomas and 179 liver metastases. Tumor size was 24 (±13) mm. Two hundred twenty-six tumors were treated percutaneously, and 85 through open approach (associated with liver resection in 42 cases). There was no mortality. Major morbidity rate was 7%. Incomplete ablation and local recurrence rates were 14% and 18.6%. Follow-up was 29 months. On multivariate analysis, factors associated with incomplete ablation were tumor size (>30 mm vs ≤30 mm, P = .004) and approach (percutaneous vs open, P = .0001). Factors associated with local recurrence were tumor size (>30 mm vs ≤30 mm, P = .02) and patient age (>65 years vs ≤65 years, P = .05). CONCLUSIONS RFA is effective to treat unresectable liver tumors. However, there is a risk of incomplete ablation when percutaneously treating tumors >30 mm. When tumor ablation is completely achieved, the main factor associated with local recurrence is tumor size >30 mm.

Serum aldosterone is correlated positively to parathyroid hormone (PTH) levels in patients with primary hyperparathyroidism

BACKGROUND Primary hyperparathyroidism is associated with an increased cardiovascular morbidity and mortality. However, mechanisms underlying this association are currently unclear. As there is clear evidence of the independent role of aldosterone on the cardiovascular system, the aim of this study was to evaluate aldosterone levels in patients with primary hyperparathyroidism. METHODS A prospective study of 134 consecutive patients with primary hyperparathyroidism before and 3 months after parathyroidectomy. RESULTS Pre-operative serum aldosterone and parathyroid hormone (PTH) levels were correlated positively in all patients (.238; P = .005). In the 62 patients (46%) that were not on antihypertensive medications, this correlation was stronger (.441; P = .0003). In the 72 patients (54%) treated with at least 1 antihypertensive medication, no correlation between preoperative aldosterone and PTH serum levels was observed. By multivariate analysis, pre-operative PTH level (.409; P = .005) was an independent predictor of aldosterone. Pre-operative PTH level >100 ng/L was an independent predictor of abnormally elevated plasma aldosterone level (odds ratio 3.5; P = .01). At 3 months after parathyroidectomy, no correlation was observed between postoperative PTH and aldosterone levels. CONCLUSION Aldosterone is correlated positively to preoperative PTH levels in patients with primary hyperparathyroidism. Aldosterone might be a key mediator of cardiovascular symptoms in patients with primary hyperparathyroidism.

Long-Term Results of Delorme’s Procedure and Orr–Loygue Rectopexy to Treat Complete Rectal Prolapse

PURPOSEThe aim of this study was to assess long-term outcome of Orr–Loygue rectopexy and Delorme’s procedures in total rectal prolapse management.METHODSData were collected retrospectively from 1978 to 2001. Statistical analysis was performed by chi-squared test and Student’s t -test.RESULTSOne hundred nine patients underwent either a Orr–Loygue rectopexy (49 patients) or a Delorme’s procedure (60 patients). Mean follow-up was 88 (range, 1–300) months. In the rectopexy group, the overall complication rate and the recurrence rate were 33 percent and 4 percent, respectively. In patients with preoperative constipation, this symptom was improved or completely resolved in 33 percent and worsened in 58 percent postoperatively. Seventy-three percent of patients with preoperative incontinence were continent or had continence improvement postoperatively. In Delorme’s group, overall complication and recurrence rates were 15 percent and 23 percent, respectively. Mortality was 7 percent. In patients with preoperative constipation, this symtom was improved or completely resolved in 54 percent and worsened in 12.5 percent of patients postoperatively. Forty-two percent of patients with preoperative incontinence were continent or had continence improvement postoperatively.CONCLUSIONSIn this study, Orr–Loygue rectopexy had a lower long-term recurrence rate. However, this surgical procedure is associated with a higher complication rate. We believe that Delorme’s procedure is still a valuable option in selected patients with postoperative minimal morbidity but higher recurrence rate.