Elevated ratio of acylated to unacylated ghrelin in children and young adults with Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is characterized by a switch from failure to thrive to excessive weight gain and hyperphagia in early childhood. Hyperghrelinemia may be involved in the underlying mechanisms of the switch. The purpose of this study is to evaluate acylated ghrelin (AG) and unacylated ghrelin (UAG) levels in PWS and investigate their associations with hyperphagia. This is a cross-sectional clinical study conducted in three PWS expert centers in the Netherlands and France. Levels of AG and UAG and the AG/UAG ratio were determined in 138 patients with PWS (0.2-29.4 years) and compared with 50 age-matched obese subjects (4.3-16.9 years) and 39 healthy controls (0.8-28.6 years). AEBSF was used to inhibit deacylation of AG. As a group, PWS patients had higher AG but similar UAG levels as healthy controls (AG 129.1 vs 82.4 pg/ml, p = 0.016; UAG 135.3 vs 157.3 pg/ml, resp.), resulting in a significantly higher AG/UAG ratio (1.00 vs 0.61, p = 0.001, resp.). Obese subjects had significantly lower AG and UAG levels than PWS and controls (40.3 and 35.3 pg/ml, resp.), but also a high AG/UAG ratio (1.16). The reason for the higher AG/UAG ratio in PWS and obese was, however, completely different, as PWS had a high AG and obese a very low UAG. PWS patients without weight gain or hyperphagia had a similar AG/UAG ratio as age-matched controls, in contrast to those with weight gain and/or hyperphagia who had an elevated AG/UAG ratio. The switch to excessive weight gain in PWS seems to coincide with an increase in the AG/UAG ratio, even prior to the start of hyperphagia.

Medical, psychological and social features in a large cohort of adults with Prader-Willi syndrome: experience from a dedicated centre in France.

BACKGROUND: Prader-Willi syndrome (PWS) is a developmental genetic disorder characterised by a variable expression of medical, cognitive and behavioural symptoms. In adulthood, the prevalence and severity of these symptoms determine the quality of life of the affected persons. Because of their rare disease condition, data on health and social problems in adults with PWS are scarce. In this research, we present medical, psychological and social features of a large cohort of adults admitted to a specialised PWS centre in France and analyse the differences according to genotype, gender and age. METHODS: Data from 154 patients (68 men/86 women), with a median age of 27 years (range 16-54), were collected during their stay in our centre. Clinical histories were completed using information from parents or main caregivers, and the same medical team performed the diagnosis of different clinical conditions. Statistical analyses were performed to determine the influence of factors such as genotype, age or gender. RESULTS: Paternal deletion genotype was the most frequent (65%) at all ages. Most patients had mild or moderate intellectual disability (87%). Only 30% had studied beyond primary school and 70% were in some special educational or working programme. Most of them lived in the family home (57%). The most prevalent somatic comorbidities were scoliosis (78%), respiratory problems (75%), dermatological lesions (50%), hyperlipidaemia (35%), hypothyroidism (26%), Type 2 diabetes mellitus (25%) and lymph oedema (22%). Some form of psychotropic treatment was prescribed in 58% of subjects, and sex hormones in 43%. Patients with deletion had a higher body mass index (44 vs. 38.9 kg/m(2)) and displayed higher frequency of sleep apnoeas. Non-deletion patients received insulin treatment (19% vs. 4%) and antipsychotic treatment (54.8% vs. 32.7%) more frequently. No difference was observed in the prevalence of Type 2 diabetes between the two genotype groups. Patients >27 years of age had a higher rate of comorbidities (Type 2 diabetes, hypertension, respiratory problems and lymph oedema). Gender differences were minor. CONCLUSIONS: Adult patients with PWS showed high prevalence of comorbid health problems that need to be monitored for early treatment. Some of them are influenced by genotype and age. Another salient problem concerns the lack of adapted structures for better social integration. Further data about the real life and health conditions of adults with PWS are necessary to further our knowledge of the natural history of the disease and to design appropriate care strategies.

Impairment of adipose tissue in Prader-Willi syndrome rescued by growth hormone treatment.

BACKGROUND: Prader-Willi syndrome (PWS) results from abnormalities in the genomic imprinting process leading to hypothalamic dysfunction with an alteration of growth hormone (GH) secretion. PWS is associated with early morbid obesity and short stature which can be efficiently improved with GH treatment. OBJECTIVES: Our aims were to highlight adipose tissue structural and functional impairments in children with PWS and to study the modifications of those parameters on GH treatment. SUBJECTS AND METHODS: Plasma samples and adipose tissue biopsies were obtained from 23 research centers in France coordinated by the reference center for PWS in Toulouse, France. Lean controls (n=33), non-syndromic obese (n=53), untreated (n=26) and GH-treated PWS (n=43) children were enrolled in the study. Adipose tissue biopsies were obtained during scheduled surgeries from 15 lean control, 7 untreated and 8 GH-treated PWS children. RESULTS: Children with PWS displayed higher insulin sensitivity as shown by reduced glycemia, insulinemia and HOMA-IR compared with non-syndromic obese children. In contrast, plasma inflammatory cytokines such as TNF-α, MCP-1 and IL-8 were increased in PWS. Analysis of biopsies compared with control children revealed decreased progenitor cell content in the stromal vascular fraction of adipose tissue and an impairment of lipolytic response to ß-adrenergic agonist in PWS adipocytes. Interestingly, both of these alterations in PWS seem to be ameliorated on GH treatment. CONCLUSION: Herein, we report adipose tissue dysfunctions in children with PWS which may be partially restored by GH treatment.

Association analysis of ten candidate genes in a large multinational cohort of small for gestational age children and children with idiopathic short stature (NESTEGG study).

BACKGROUND: Fetal growth failure has been associated with an increased risk of hypertension, cardiovascular disease and diabetes in adulthood. Exploring the mechanisms underlying this association should improve our understanding of these common adult diseases. PATIENTS AND METHODS: We investigated 225 SNPs in 10 genes involved in growth and glucose metabolism (GH1, GHR, IGF1, IGF1R, STAT5A, STAT5B, MAPK1, MAPK3, PPARγ and INS) in 1,437 children from the multinational NESTEGG consortium: 345 patients born small for gestational age who remained short (SGA-S), 288 who showed catch-up growth (SGA-Cu), 410 idiopathic short stature (ISS) and 394 controls. We related genotype to pre- and/or postnatal growth parameters, response to growth hormone (if applicable) and blood pressure. RESULTS: We found several clinical associations for GH1, GHR, IGF1, IGF1R, PPARγ and MAPK1. One SNP remained significant after Bonferroni's correction: IGF1R SNP rs4966035's minor allele A was significantly more prevalent among SGA and associated with smaller birth length (p = 0.000378) and birth weight (weaker association), independent of gestational age. CONCLUSION: IGF1R SNP rs4966035 is significantly associated with birth length, independent of gestational age. This and other associations suggest that polymorphisms in these genes might partly explain the phenotype of short children born SGA and children with ISS.

Are you good enough for your patients? The European certification model in laparoscopic surgery.

Quality control, training and education in gynaecological surgery are challenged and urgent measures are emerging. The implementation of a structured and validated program for training and quality control seems the most urgent measurement to be taken. The European Academy of Gynaecological Surgery has made a first attempt to do so. Through a practical and theoretical tests system, the skills of an individual surgeon is measured and the conditions to enter the different level of expertise are clearly defined. This certification system based on the best possible level of scientific evidence provides a first practical tool, universally implementable for a decent quality control and structured training program in Gynaecological laparoscopic surgery.

Endothelial function and mechanical arterial properties in children born small for gestational age: comparison with obese children.

BACKGROUND: Early cardiovascular events preceding atherosclerosis have been reported in children born small for gestational age (SGA). AIMS: To describe in detail the mechanical and functional arterial properties of SGA children and to compare the data to those of obese children in order to gain a better understanding of the severity of the dysfunction. A control group was required to overcome the lack of normal values. METHODS: Three groups of 7- to 15-year-old children were included. Sixty children born SGA without obesity, 49 children with obesity and not SGA, and 55 controls underwent complete carotid and brachial arterial measurements using ultrasound and flow-mediated dilation. Biological measurements were performed in the obese and SGA groups. RESULTS: Mean blood pressure and intima-media thickness were lower in SGA children than in the obese group (p < 0.001 and p = 0.004, respectively), but not different from the control group. Flow-mediated dilation was lower in SGA than in obese children and in controls (p < 0.001). CONCLUSION: These data show that children born SGA have endothelial dysfunction with normal intima-media thickness.

Efficacy of modafinil on excessive daytime sleepiness in Prader-Willi syndrome.

Excessive daytime sleepiness is a frequent and a highly disruptive symptom to the daily routine of children with Prader-Willi Syndrome (PWS) and their families. The objective of the study was to evaluate the efficacy of modafinil, a central stimulant, on excessive daytime sleepiness in children and adolescents with PWS. The efficacy of modafinil was evaluated in this open label pilot study comparing the Epworth sleepiness scale before and after treatment. Ten patients with molecularly confirmed PWS and a complaint of excessive daytime sleepiness underwent a night-time sleep recording and multiple sleep latency tests. One patient was excluded because of severe obstructive sleep apnea syndrome. Nine patients (4 males) with median age of 16 years (8-21) received modafinil at a starting dose of 100 mg/day. We found that all patients had excessive daytime sleepiness with an Epworth sleepiness scale at 14 (11-20) and mean sleep latency on multiple sleep latency tests at 5 (3-6) minutes. Moreover, six patients had at least two sleep-onset rapid eye movement periods showing a narcolepsy-like phenotype. Modafinil significantly improved sleepiness in all patients on the Epworth sleepiness scale from 14 (11-20) to 4 (3-12), (P = 0.007). Body mass index of the patients did not change significantly under treatment. No side effects were reported, and the drug was well-tolerated. We posit that this open label case series shows good efficacy of modafinil in nine children and adolescents with PWS.

Endocrine disorders in children with Prader-Willi syndrome--data from 142 children of the French database.

AIM: The first results from the French National Prader-Willi pediatric database in a cohort of 142 children aged 0.2-18.8 years are reported. This database gathers information about the endocrine dysfunctions traditionally described in Prader-Willi patients. METHODS: Questionnaires were filled in by the patients' practitioners. The coordination team of the reference center performed the statistical analysis. RESULTS: Median BMI Z-score was +1.3 for a median age of 7.1 years, and 40% of the population were overweight or obese (International Obesity Task Force 2000 criteria). Growth hormone deficiency was present in 80% of patients and 86.7% were treated, with a height gain of +1 SD and a BMI reduction of -0.8 Z-score achieved in the first year of treatment. Hypogonadism was present in 49% of patients, and hypothyroidism in 24.4%. Glucose intolerance was found in 4% of patients, but no diabetes mellitus was detected in the 74 patients explored. CONCLUSION: Our report gives an overview of endocrine dysfunctions recorded in a large registry database of French children and adolescents with Prader-Willi syndrome. The database, which now encompasses six southern regions of France, will be further extended to the whole country and to adult patients.

Cognitive profile in a large French cohort of adults with Prader-Willi syndrome: differences between genotypes.

BACKGROUND: Prader-Willi syndrome (PWS) is a rare genetic disorder characterised by developmental abnormalities leading to somatic and psychological symptoms. These include dysmorphic features, impaired growth and sexual maturation, hyperphagia, intellectual delay, learning disabilities and maladaptive behaviours. PWS is caused by a lack of expression of maternally imprinted genes situated in the 15q11-13 chromosome region. The origin is a 'de novo' deletion in the paternal chromosome in 70% of the cases and a maternal uniparental disomy in 25%. The two main genotypes show differences, notably regarding cognitive and behavioural features, but the mechanisms are not clear. This study assessed cognitive impairment in a cohort of adults with genetically confirmed PWS, analysed their profiles of cognitive strengths and weaknesses, and compared the profiles in terms of genotype. METHODS: Ninety-nine male and female adults participated, all inpatients on a specialised unit for the multidisciplinary care of PWS. The Wechsler Adult Intelligence Scale (WAIS-III) was administered to all patients in identical conditions by the same psychologist. Eighty-five patients were able to cope with the test situation. Their scores were analysed with non-parametric statistical tools. The correlations with sex, age and body mass index were explored. Two genotype groups were compared: deletion (n = 57) and non-deletion (n = 27). RESULTS: The distribution of intelligence quotients in the total cohort was non-normal, with the following values (medians): Full Scale Intelligence Quotient (FSIQ): 52.0 (Q1:46.0; Q3:60.0), Verbal Intellectual Quotient (VIQ): 53.0 (Q1:48; Q3:62) and Performance Intellectual Quotient (PIQ): 52.5 (Q1:48; Q3:61). No correlation was found with sex, age or body mass index. Comparison between groups showed no significant difference in FSIQ or VIQ. PIQ scores were significantly better in the deletion group. The total cohort and the deletion group showed the VIQ = PIQ profile, whereas VIQ > PIQ was observed in the non-deletion group. The subtest scores in the two groups showed significant differences, with the deletion group scoring better in three subtests: object assembly, picture arrangement and digit symbol coding. Some relative strengths and weaknesses concerned the total cohort, but others concerned only one genotype. DISCUSSION: We documented a global impairment in the intellectual abilities of a large sample of French PWS patients. The scores were slightly lower than those reported in most other studies. Our data confirmed the previously published differences in the cognitive profiles of the two main PWS genotypes and offer new evidence to support this hypothesis. These results could guide future neuropsychological studies to determine the cognitive processing in PWS. This knowledge is essential to improve our understanding of gene-brain-behaviour relationships and to open new perspectives on therapeutic and educational programmes.

Adhesion formation after laparoscopic surgery: what do we know about the role of the peritoneal environment?

In spite of the approaches that have been proposed to reduce postoperative peritoneal adhesions, they remain a major clinical problem because of the associated intestinal obstruction, chronic pelvic pain, female infertility and difficulties at the time of reoperation. The pathogenesis of the process have been focused almost exclusively on the local events induced by the surgical trauma, and the strategies for adhesion prevention thus focused on barriers to separate surgically denuded areas. The important role of the peritoneal cavity environment only recently became apparent and is not yet incorporated in adhesion reducing strategies. Recent data demonstrate that, in the presence of a direct surgical trauma, the entire peritoneal environment is quantitatively the most important factor in adhesion formation and hence adhesion prevention after both open and laparoscopic surgery. Indeed mesothelial hypoxia (CO2 pneumoperitoneum) or hyperoxia (open surgery), desiccation and surgical manipulation have been identified as factors cumulatively enhancing adhesions--. The clinical implication is especially relevant for laparoscopic surgery because the pneumoperitoneum, being a closed environment, can be easily conditioned. Although human studies are lacking, animal data indicate that peritoneal adhesions can be reduced by over 80% with a good surgical technique, with adequate pneumoperitoneum conditioning as adding 3-4% of oxygen to the CO2 pneumoperitoneum, prevention of desiccation and slight cooling. Adhesion prevention barriers remain additionally effective, although quantitatively less important. The relevance of all these strategies for adhesion prevention still have to be confirmed in humans, but since it seems that the peritoneal environment is quantitatively much more important than the surgical trauma, adhesion prevention research and strategies should be directed more to conditioning the peritoneal cavity than to the use of agents.

Review of 64 cases of death in children with Prader-Willi syndrome (PWS).

Several deaths have been reported in children with Prader-Willi syndrome (PWS) following treatment with growth hormone (GH). We collected all of the reports of deaths in PWS children, both in treatment and non-treatment groups, analyzed the causes of the death and compared the two groups. We conducted an exhaustive search for reports using bibliographic databases, toxicology pharmacovigilance databases, and personal communications. Sixty-four PWS children (42M/22F) aged from a few days to 19 years were identified, 28 received GH treatment. Our results show that respiratory disorders were the most common cause of death (respiratory insufficiency or infections) which were reported in 61% of the children (68% in GH-treated and 55.5% in -untreated patients). We found no significant differences in gender, prevalence of obesity or prevalence of sleep apnea, between the patients treated with GH and the untreated patients. Nevertheless, most of the deaths in GH-treated children (75%) occurred during the first 9 months after the initiation of GH treatment. Our analysis shows the high frequency of respiratory infections in both GH-treated and -untreated PWS children. The first 9 months of GH treatment seems to be a high-risk period emphasizing the need for comprehensive care before and during GH treatment.

Early diagnosis and multidisciplinary care reduce the hospitalization time and duration of tube feeding and prevent early obesity in PWS infants.

BACKGROUND/AIMS: To describe and evaluate the impact of very early diagnosis and multidisciplinary care on the evolution and care of infants presenting with Prader-Willi syndrome (PWS). METHODS: 19 infants diagnosed with PWS before the second month of life were followed by a multidisciplinary team. Median age at the time of analysis was 3.1 years [range 0.4-6.5]. The data were compared with data collected in 1997 from 113 questionnaires filled out by members of the French PWS Association. The patients from this latter data set were 12.0 years [range 4 months to 41 years] at the time of analysis, with a median age of 36 months at diagnosis. RESULTS: The duration of their hospitalization time was significantly reduced from 30.0 [range 0-670] to 21 [range 0-90] days (p = 0.043). The duration of gastric tube feeding was significantly reduced from 30.5 [range 0-427] to 15 [range 0-60] days (p = 0.017). Growth hormone treatment was started at a mean age of 1.9 +/- 0.5 years in 10 infants and L-thyroxine in 6 infants. Only 1 infant became obese at 2.5 years. CONCLUSION: Early diagnosis combined with multidisciplinary care decreases the hospitalization time, duration of gastric tube feeding and prevents early obesity in PWS infants.

GH responsiveness in a large multinational cohort of SGA children with short stature (NESTEGG) is related to the exon 3 GHR polymorphism.

OBJECTIVE: The polymorphic deletion of exon 3 of the GH receptor (d3-GHR) has recently been linked to the magnitude of growth response to recombinant human GH (rhGH) therapy in short children with or without GH deficiency. We investigated this association in a large multinational cohort from the Network of European Studies of Genes in Growth (NESTEGG), comprising short children born small for gestational age (SGA). DESIGN: The study included short prepubertal SGA children treated with rhGH for 1 or 2 years. POPULATION: Two hundred and forty white Caucasian SGA children (138 male, 102 female) aged 6.6 +/- 2.3 years with a height at -3.0 +/- 0.7 SDS at start of rhGH treatment; 193 ethnically matched controls. METHODS: The GHR polymorphism (fl/fl, fl/d3 or d3/d3) was genotyped by polymerase chain reaction (PCR) multiplex assay. Growth velocity (G/V) in cm/year and changes in GV during the first and second year of rhGH treatment were evaluated. RESULTS: The change in GV was significantly greater in SGA children carrying one or two copies of the d3-GHR allele (P = 0.038 for the first year and P = 0.041 for the second year of GH treatment), but the change in height was not significantly different. Birthweight was significantly lower in SGA children with the d3/d3 genotype than in SGA children with the fl/fl genotype (P = 0.034) and in those with the fl/d3 genotype (P = 0.016). CONCLUSION: Our data, based on a large cohort, showed that the exon 3 GHR polymorphism is associated with responsiveness to rhGH treatment in SGA children with short stature.

Effect of reactive oxygen species scavengers, antiinflammatory drugs, and calcium-channel blockers on carbon dioxide pneumoperitoneum-enhanced adhesions in a laparoscopic mouse model.

BACKGROUND: Postoperative adhesions are a clinical problem. They can cause female infertility, intestinal obstruction, chronic pelvic pain, and difficulties at the time of reoperation. A variety of approaches described to prevent adhesions have shown variable and inconsistent results. Therefore, this study aimed to evaluate most known substances in a laparoscopic mouse model to obtain quantitative and comprehensive information on adhesion prevention. Specifically, this first study aimed to investigate the effects of reactive oxygen species (ROS) scavengers, antiinflammatory agents, and a calcium-channel blocker on pneumoperitoneum-enhanced adhesions. METHODS: Adhesions were induced during laparoscopy in BALB/c female mice by creation of a bipolar lesion. Carbon dioxide (CO2) pneumoperitoneum was maintained for 60 min using humidified CO2. Six experiments were conducted to evaluate the effects of ROS scavengers (superoxide dismutase [SOD], catalase, melatonin, and ascorbic acid), antiinflammatory agents (dexamethasone, tenoxicam, ibuprofen, parecoxib, nimesulide, anti-tumor necrosis factor [TNF]-alpha), and a calcium-channel blocker (diltiazem). Adhesions were scored after 7 days during laparotomy. RESULTS: Adhesions were reduced by SOD (p < 0.01, proc general linear methods (GLM) of experiments 1 and 2), diltiazem (p = 0.05, Wilcoxon), and dexamethasone (p < 0.03), but not by nonsteroidal antiinflammatory drugs (NSAIDs) nor by anti-TNF-alpha. When all the experiments were grouped for analysis, adhesions also decreased with one and three doses of SOD (p < 0.01 and p < 0.01, respectively) and with one and three doses of ascorbic acid (p < 0.02 and p = 0.05, respectively). CONCLUSIONS: These experiments confirm that SOD, diltiazem, and dexamethasone can decrease adhesion formation. The absence of effect from the other antiinflammatory drugs and anti-TNF-alpha is surprising.

Effect of temperature upon adhesion formation in a laparoscopic mouse model.

BACKGROUND: Pneumoperitoneum can be a cofactor in adhesion formation. Pneumoperitoneum with non-humidified gas causes desiccation in the peritoneal cavity which decreases temperature. The effect of desiccation upon adhesion formation is widely accepted. The specific effect of the associated cooling upon adhesion formation remains unexplored, and was addressed specifically in our laparoscopic mouse model. METHODS: Adhesions were induced during laparoscopy and scored after 7 days during laparotomy. Pneumoperitoneum was performed using CO2 or CO2 with oxygen with or without humidification. Animals were placed at different environmental temperatures to modulate body and intraperitoneal temperature. RESULTS: Anaesthesia, environment with a lower temperature and pneumoperitoneum all independently decrease body temperature. A decrease in body temperature decreases adhesion formation (P=0.004). Therefore, at 37 degrees C, pneumoperitoneum-enhanced adhesion formation is more important than at room temperature (P=0.04). As was observed at room temperature, adhesion formation at 37 degrees C increases with the duration (P=0.01) of pneumoperitoneum and decreases with the addition of 3% of oxygen (P=0.03). CONCLUSIONS: Hypothermia reduces pneumoperitoneum-enhanced adhesion formation, which supports hypoxia as a driving mechanism, since hypothermia decreases the toxic effects of hypoxia and of the ischaemia-reperfusion process. These data could open up new possibilities for adhesion prevention in laparoscopic surgery.

Reactive oxygen species and adhesion formation: clinical implications in adhesion prevention.

Postoperative adhesion formation is a major clinical problem. It has been demonstrated that the pneumoperitoneum used during laparoscopy is a cofactor in adhesion formation. Reactive oxygen species (ROS) are produced in a hyperoxic environment and during the ischaemia/reperfusion process. ROS activity is deleterious for cells, which protect themselves by an antioxidant system known as ROS scavengers. ROS activity can increase by up-regulation of ROS themselves or by down-regulation of ROS scavengers. Recent data also point to a role for ROS in adhesion formation since the administration of ROS scavengers decreases adhesion formation in several animal models. ROS activity increases during both laparotomy and laparoscopy. During laparoscopy, the pneumoperitoneum determines ischaemia at the time of insuflation and reperfusion at the time of deflation. During laparotomy, the environment has a 150 mmHg partial pressure of oxygen (pO(2)), which is much higher than the intracellular pO(2) (5-40 mmHg). This can explain the increase in ROS activity. The aim of this debate is to open a discussion about the importance of ROS activity, besides the known players and mechanisms involved, in adhesion formation and in adhesion prevention.

Peritoneal mesothelial hypoxia during pneumoperitoneum is a cofactor in adhesion formation in a laparoscopic mouse model.

OBJECTIVE: To develop a laparoscopic mouse model to evaluate the hypothesis that mesothelial hypoxia during pneumoperitoneum is a cofactor in adhesion formation. DESIGN: Prospective randomized trials. SETTING: Academic research center. ANIMAL(S): One hundred thirty female Naval Medical Research Institute (NMRI) mice. INTERVENTION(S): Adhesions were induced by opposing monopolar lesions in uterine horns and pelvic side walls during laparoscopy and evaluated after 7 or 28 days under microscopic vision during laparotomy. The following pneumoperitoneum variables were assessed: duration (10 or 60 minutes), insufflation pressure (5 or 15 cm of water), insufflation gas (CO(2) or helium), and addition of oxygen (0-12%). MAIN OUTCOME MEASURE(S): Adhesions were scored quantitatively and qualitatively for extent, type, and tenacity. RESULT(S): Scoring of adhesions 7 or 28 days after laparoscopic surgery was comparable. Adhesions increased with duration of pneumoperitoneum and with insufflation pressure and decreased with the addition of oxygen. Half-maximal reduction of adhesions was obtained at 1.5% oxygen, whereas a maximal reduction required only 2%-3%. The effect of CO(2) and helium was similar. CONCLUSION(S): These data demonstrate the feasibility of the intubated laparoscopic mouse model and confirm previous observations in rabbits, indicating that mesothelial hypoxia plays a key role in adhesion formation.

Hypoxaemia induced by CO(2) or helium pneumoperitoneum is a co-factor in adhesion formation in rabbits.

A prospective randomized trial in a rabbit model was performed to test the hypothesis that the increase in adhesion formation following prolonged pneumoperitoneum is mediated by peritoneal hypoxaemia. Laparoscopic standardized opposing lesions were performed in uterine horns and pelvic sidewalls by bipolar coagulation and CO(2) laser in six groups of eight animals. Pure CO(2) or helium pneumoperitoneum was used for 10 (groups I and IV) or 45 min (groups II and V) to confirm the effect of duration of pneumoperitoneum and 96% of CO(2) or helium with 4% of oxygen (group III and VI) for 45 min to assess the effect of the addition of oxygen. After 7 days, adhesion formation was scored by laparoscopy. By two-way analysis of variance, total, extent, type and tenacity of adhesion scores increased (P = 0.0003, P = 0.0004, P = 0.0004 and P = 0.004) with increasing duration of pneumoperitoneum and decreased (P = 0.02, P = 0.03, P = 0.01 and P = 0.05) with the addition of oxygen. No differences were found between CO(2) and helium. In conclusion these data confirm the effect of pneumoperitoneum upon adhesions and demonstrate its reduction by oxygen, strongly suggesting that the main cause of adhesion formation is the relatively superficial hypoxaemia produced by the pneumoperitoneum.

Effect of the diameter of the endoscope and of surgeon training on the duration and quality of laparoscopic surgery in a rabbit model.

STUDY OBJECTIVE: To evaluate the effect of diameter of the endoscope on the duration and quality of laparoscopic surgery. DESIGN: Prospective, randomized trial (Canadian Task Force classification I). SETTING: Centre for Surgical Technologies. SUBJECTS: Sixty adult, female, New Zealand, white rabbits. INTERVENTION: Two series of laparoscopic nephrectomies, one each performed by an experienced and an inexperienced surgeon comparing 10-, 5-, 4-, and 2-mm endoscopes. MEASUREMENTS AND MAIN RESULTS: Besides duration of surgery and occurrence of bleeding, the quality of dissection was scored by adding scores of dissection of renal vessels, ureters, and kidneys. During consecutive nephrectomies, the duration of surgery (p = 0. 001) and occurrence of bleeding (p = 0.02) decreased, whereas the quality of dissection increased (p = 0.002), demonstrating the learning curve, mainly for the less experienced surgeon. Duration of surgery (p = 0.04) decreased and quality of dissection increased (p = 0.05) when the larger endoscope was used. This was the case only for the less experienced surgeon, whereas for the experienced surgeon it had only a slight effect on learning curve. CONCLUSION: These results confirm a learning curve of nephrectomy consisting of some 20 animals. In addition, the endoscope diameter and thus quality of image affect both duration and quality of surgery, especially for less experienced surgeons.

Heterozygous mutation in the WSXWS equivalaent motif of the growth hormone receptor in a child with poor response to growth hormone therapy.

Besides complete GH insensitivity syndrome (GHIS) described by Laron, clinical and molecular evidences have accumulated concerning partial GHIS. We studied GH receptor (GHR) gene in children who show poor response to GH treatment and detected a patient with a heterozygous mutation in exon 7 leading to the Y222H substitution. This missense mutation, located in the YGEFS motif of the GHR equivalent to the WSXWS motif highly conserved throughout all members of the cytokine receptor family, has not been described so far. Although we cannot conclude on the deleterious effect of this mutation, there are several lines of evidence suggesting that it could account for the partial GH insensitivity: (i) hormonal data including IGF-I generation test; (ii) molecular data - no other mutation was identified in the coding sequence, the father who has the same mutation is short, the brother did not inherit the mutated allele and was of normal height.