Assessment of operator performance during oocyte retrievals: residents' learning curve and continuous monitoring of senior physicians.

BACKGROUND: The learning curve cumulative summation test (LC CUSUM test) allows to define an individualized learning curve and determine the moment when clinical proficiency is attained. After acquisition of the skills, the cumulative summation test (CUSUM test) allows to monitor the maintenance of the required level over time. The LC CUSUM test has been frequently used in the field of Obstetrics and Gynecology (Ob/Gyn) for several procedures, but only once for OR. METHODS: We performed a retrospective study at Angers university hospital between May 2017 and September 2018. Seven Ob/Gyn residents and 5 senior physicians were included, and all OR performed during that time (n = 690) were analyzed. The performance index assessed was the oocyte retrieval rate (ORR), defined as the ratio of oocytes retrieved to follicles aspirated. We used the LC CUSUM test to analyze the learning curves of residents, and the CUSUM test to monitor the performance of senior physicians. An ORR ≥50% in 60% of retrievals was defined as the threshold for clinical proficiency. RESULTS: Six hundred seventy-four oocyte retrieval (OR) were included: 315 were performed by residents, 220 by senior physicians, and 139 by both residents and physicians (mixed retrievals). Four residents (57%) reached the threshold after aspirating 82, 67, 53 and 46 ovaries, respectively. The mean number of ovaries aspirated in order to reach clinical proficiency was 62, and the mean number of weeks needed was 21. The duration of the learning period varied between 26 and 80 days. Two senior physicians (40%) remained proficient across the duration of the study, while two physicians (40%) had one statistically "suboptimal" OR, and one physician (20%) had two suboptimal retrievals. CONCLUSION: There is a large variability in the duration of the learning period and the number of procedures needed for a resident to master OR. Senior physicians maintain an adequate performance.

[Alzheimer's disease and pharmacists in contact with the public]. / La maladie d'Alzheimer et les pharmaciens en contact avec le public.

All healthcare professionals are concerned by Alzheimer's disease, which in France will affect, in just a few years, over one million persons, mainly women. Pharmacists have shown particular interest, irrespective of their sector of activity. Here, we wanted to better define the role of colleagues who are constantly in contact with the public, i.e. in France in drug dispensaries and biology laboratories. Within the framework of the French pharmacy committee for health and social education, Cespharm, the Ethics and Communications working group of the 2008-2012 Alzheimer Disease Committee headed by Professor Joël Menard proposed a project worksheet which can be used by French pharmacists in their action to help Alzheimer patients and their caregivers. This project, prepared by Fabienne Blanchet, the Cespharm director and Christine Curty, mission head, was approved by the Menard commission and is inscribed in the National Alzheimer Plan 2008-2012 presented by this commission in November 2007. Here, our objective is to motivate pharmacists to participate in a structured initial and continuing training program proposed by specialists from the School of Pharmacy and other organizations duly approved by the High Committee for Continuing Education in Pharmacy. In keeping with the general operative procedures of Cespharm, information tools should be developed for colleagues and the public. Available interventions, in terms of prevention, diagnosis and treatment should be updated permanently and transmitted to professionals. Information which can be delivered to patients, and most importantly to their caregivers, concerning local assistance programs should be collected and transmitted to the local professionals. The role of the pharmacist can be summarized with four verbs: listen, reassure, orient, support. It is important to identify all available means enabling a confidential relationship with the persons needing help. Of particular interest are the relationship guides which have been developed to help allied professionals adapt their approach to the patient without evoking the diagnosis, which belongs to the medical physician. Finally, we emphasize the importance of the creation of multidisciplinary local networks where healthcare professionals, medicosocial workers, local public authorities, and patient groups and associations can unite their efforts to develop personalized assistance for patients and caregivers. We also mention the evaluation of the actions undertaken, their funding, and the remuneration of colleagues who devote time to these actions. Pharmacists have a special role to play in the assistance for persons suffering from Alzhiemer's disease and other neurodegenerative diseases. More than four million persons visit drug dispensaries or biology laboratories every day in France. These persons often confide in our colleagues, sharing their worries and problems related not only to their medical condition, but also to their psychological and social environment. We should provide our colleagues with the necessary means to fulfill their mission of assistance to patients and families suffering from a poorly understood disease. We encourage pharmacists to participate in the major public health action initiated by the President of the Republic and well defined in the Alzheimer Plan 2008-2012.

[In vitro fertilization versus conversion to intrauterine insemination in patients with poor response to controlled ovarian hyperstimulation]. / Réponse insuffisante à la stimulation en vue de FIV : maintenir la ponction ou choisir l' insémination ?

In women undergoing controlled ovarian hyperstimulation (COH) for in vitro fertilization (IVF), a poor ovarian response, defined as three of fewer mature follicles, can lead to cancellation of the cycle. However, in women with at least one patent tube and normal semen parameters, conversion to intrauterine insemination (IUI) is considered an option, offering reasonable pregnancy rates at a lower cost and without the complications associated with oocyte retrieval. Studies have shown that in cycles with only one mature follicle, IVF should be canceled. However, in cycles with 2 or 3 mature follicles, patients have the choice between IVF and conversion to IUI. Some studies have shown that IVF is superior to IUI in such cases, whereas other reports failed to find any difference. Most of these studies are retrospective and limited by the presence of several biases and low numbers of cycles, and to this date, there is no consensus on the best approach. We have thus designed a multicenter, randomized non-inferiority study, comparing live birth rates following conversion to IUI or IVF in patients with 2 or 3 mature follicles in COH cycles. Nine hundred and forty patients will be randomized on trigger day to either IVF or conversion to IUI. Our study will also include a medico-economic analysis.

Surgical treatment of septate uterus in cases of primary infertility and before assisted reproductive technologies.

Septate uterus is the most common congenital uterine malformation in women with infertility. Several criteria are available for the definition of septate uteri, such as the one proposed by the European Society of Human Reproduction and Embryology (ESHRE)/European Society for Gynecological Endoscopy (ESGE) (ESHRE/ESGE), or by the American Society for Reproductive Medicine (ASRM), with notable differences between the two. Recently, a simplified classification was proposed by the Congenital Uterine Malformations Experts (CUME), where a septum is defined as an internal indentation depth≥10mm. To date, there is no consensus on the management of women with a septate uterus and infertility. We have performed an extensive literature appraisal and reviewed all the available international guidelines in order to propose a management strategy for infertile patients with a uterine septum. Hysteroscopic septum incision seems to improve natural conception rates in the year following surgery. Moreover, it improves in vitro fertilization (IVF) outcomes when performed before the embryo transfer, by improving embryo implantation rates. On the other hand, for patients with an arcuate uterus (indentation<1.5cm according to the ASRM guidelines) and infertility, it seems that assisted reproductive technologies are the most appropriate first line treatment. However, in cases of recurrent implantation failure or recurrent pregnancy loss following IVF, hysteroscopic section could be proposed. Overall, we recommend hysteroscopic septum incision for patients with primary infertility, and for patients undergoing assisted reproductive technologies.

[Blood screening of glucose and lipid disorders as coronary atherosclerosis risks factors in French adolescents 16 to 19-20 years old]. / Dépistage des anomalies sanguines glucidolipidiques à risque coronarien, de 16 à 19-20 ans. A propos d'une enquête menée chez 599 jeunes volontaires.

A screening of fasting blood glucose and lipids disorders, presumely linked to premature atherosclerosis namely affecting Coronary arteries, has been performed among 599 adolescents of both sexes with the goal of establishing the actual prevalence of these disorders in French population recruited through different areas of the country. All of them were between ages of 16 and 19-20 years old, and invited to give, in total gratuity, their blood samples to private and accreditable laboratories close to their living habitation. After 262 exclusions due to either previous screening not signaled before or present use of contraceptive pill in girls, only 202 boys and 135 girls remained eligible for such a prevalence study. Using plasma enzymatic dosages of CT, HDL C, (calculated) LDLC, TG, and blood glucose, cut off points for each of these parameters, were analysed as well as calculated international index of CT/HDLC and CT minus HDLC. But the first one index was shown the best tool for the final estimation of the frequency of lipid disorders, which requires primary prevention. Indeed, despite of a rather high frequency of overlaps of CT and LDLC respectively found at 16.3 and 22.5% for boys, and 27.3 and 27.5% for girls, the still higher increase of frequency of HDL C at 31% for boys and 28.1% for girls has shown a very significant compensation of these previous increases. In such a way as the authentic prevalence of atherogenic lipid disorders is found reduced in boys to 8.4% and in girls to 7.4% for CT/HDLC>/=4.5 ratio, and to 5.4% in boys and 5.2% in girls for CT less HDLC. A Familial Dominant Hypercholesterolemia was discovered only two times in two girls 16 years old. Other abnormal lipid profiles were rather those of Mixed H., type IV, chiefly mild Hypercholesterolemia, and some rare cases of HypoHDLemia. The only greater linked cardiovascular risk factor was direct parental C.V. heredity, round 30% among lipid disorders. Obesity remained rare, as well as Metabolic Syndrome in the present recruitment. Contraceptive pill increases significantly all lipid parameters and atherogenic index: chiefly CT minus HDLC which reaches almost the double of frequency (15%) versus that of girls without pill. But 53% of boys with proatherogenic lipid disorders are smokers, while only 10% of these dyslipidemic girls smoke.

Pharmacokinetics of oral all-trans retinoic acid in patients with acute promyelocytic leukemia.

It has been shown that patients with acute promyelocytic leukemia (AML3 subtype) treated with all-trans retinoic acid (all-trans RA), 45 mg/m2/day, achieve complete remission through differentiation of the leukemic clone to mature myeloid cells, which die spontaneously. The pharmacokinetics of all-trans RA given by mouth were studied in 15 AML3 patients. Blood samples were drawn for 24 h following a single oral dose of 45 mg/m2 and assayed for all-trans RA and 13-cis retinoic acid (13-cis RA) plasma concentrations by specific high-performance liquid chromatography. In one patient all-trans RA and 13-cis RA levels were below the detection limits at all times. In the other patients, the time to peak concentration of all-trans RA was between 60 and 210 min (median 90 min) after ingestion, with maximum concentrations between 0.03 and 2.5 micrograms/ml (median 0.4 micrograms/ml). These concentrations were within the in vitro differentiating concentration range of all-trans RA for these patients' cells. In nine patients, enterohepatic cycling was suggested by the presence on the concentration versus time curve of a secondary peak that occurred at meal times. The apparent plasma elimination half-life was between 16.8 and 77.4 min (median 30 min). Detectable plasma levels of 13-cis RA in 12 patients indicated in vivo isomerization of all-trans RA. Despite the high inter-individual variability of all-trans RA pharmacokinetics in these patients, high blast cell counts and failure to respond to differentiation treatment tended to be associated with low all-trans RA Cmax values and high clearance estimates.

Adrenocortical 11 beta-hydroxylation defect in adult women with postmenarchial onset of symptoms.

Four cases in adults of a deficiency in the 11 beta-hydroxylation of corticosteroids were investigated by both basal and dynamic biological studies. Symptoms varied from patient to patient; hirsutism, menstrual disturbance, acne, deepening of the voice, and arterial hypertension appeared post puberty. Basal testing demonstrated elevated levels of plasma androgens. These include delta 4-androstenedione (patients, 3.80-6.43 ng/ml; normal, 1.33 +/- 0.33 ng/ml), urinary 17-ketosteroids (patients, 11.8-16.7 mg/24 h; normal, 5-10 mg/24 h), and urinary dehydroepiandrosterone. The basal tests were often insufficient to show the accumulation of the precursors (especially 17-hydroxyprogesterone) which are often given as evidence for an increase in ACTH stimulation. In studying the levels of the mineralocorticoids, there was shown to be an increased basal level of tetrahydrodeoxycorticosterone (patients, 142-317 microgram/24 h; normal, 60-80 microgram/24 h) which was raised by ACTH stimulation. These results, therefore, confirm the characteristic partial enzyme defect and give evidence for the heterogeneity of this syndrome. Based on the above observations, we believe it is appropriate to rename this condition adult adrenocortical 11 beta-hydroxylation defect rather than late-onset congenital adrenal hyperplasia.

Prenatal diagnosis of 21-hydroxylase deficiency congenital adrenal hyperplasia by simultaneous radioimmunoassay of 21-deoxycortisol and 17-hydroxyprogesterone in amniotic fluid.

Amniotic fluid levels of 21-deoxycortisol (21-DOF) and 17-hydroxyprogesterone (17-OHP) were measured in 49 pregnancies, including 31 pregnancies at risk for CAH. The results were compared with those obtained by HLA typing and linkage analysis to a HLA DNA probe. The mean amniotic fluid levels in the control pregnancies were 0.28 nmol/L for 21-DOF and 4.1 nmol/L for 17-OHP. The levels were similar in early and midpregnancy for 21-DOF (0.29 vs. 0.27 nmol/L) and 17-OHP (3.4 vs. 4.2 nmol/L). The amniotic fluid 21-DOF level was 1.75 nmol/L in affected pregnancies, significantly higher than in the control pregnancies (mean, 0.28 nmol/L). The mean amniotic fluid 17-OHP level in the affected pregnancies (30.5 nmol/L) also was significantly higher than that in the control pregnancies (4.10 nmol/L). Simultaneous measurement of 21-DOF and 17-OHP levels in amniotic fluid from 10-18 weeks of gestation can be used for early diagnosis of congenital adrenal hyperplasia.

Circadian variations in plasma levels of hypophyseal, adrenocortical and testicular hormones in men infected with human immunodeficiency virus.

Alterations in the circadian time structure of the secretion of several hormones were investigated in 13 male patients infected with human immunodeficiency virus (HIV). Seven were asymptomatic (classified CDC II, according to the criteria of the Atlanta Centers for Disease Control), and 6 had acquired immunodeficiency syndrome (CDC IV). Ten healthy males volunteered as controls. Plasma levels of dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S), cortisol, testosterone, ACTH, and beta-endorphin were determined by RIA in blood samples obtained every 4 h from 0830-0830 h the next morning. Data were analyzed both by two-way analysis of variance and the cosinor method. Circadian rhythms were statistically validated for each of the six hormones in each of the three groups of subjects. Compared with the control subjects, mesors (24-h adjusted means) were significantly higher for cortisol and lower for DHEA, DHEA-S, and ACTH (P less than 0.001 for all four hormones) in all HIV-infected patients. Plasma testosterone mesors were similar in controls and CDC II patients, but decreased significantly in the CDC IV patient group (P less than 0.05). Analysis of the circadian rhythms of plasma hormone levels clearly indicated an altered adrenal hormonal state in HIV-infected male patients, even during the asymptomatic period of the infection. For instance, plasma cortisol at 0430 h was more than twice as high in HIV-infected patients as it was in time-qualified controls. Although patients already had elevated plasma cortisol and lowered adrenal androgen levels at this stage, hypogonadism was not observed, as gauged by plasma testosterone concentrations. We speculate that the primary hormonal defect in HIV-infected patients is increased cortisol secretion resulting from circadian-varying stimulation of the adrenal cortex by a factor other than pituitary ACTH. This factor might be a stimulating substance secreted primarily by infected immune cells. Excess cortisol would lower adrenal androgen secretion by shifting adrenal steroid biosynthesis toward glucocorticoids and decreasing pituitary ACTH secretion via a negative feedback mechanism.

Importance of the presence of the N-terminal tripeptide of substance P for the stimulation of phosphatidylinositol metabolism in rat parotid gland: a possible activation of phospholipases C and D.

In this study, we have compared the effects of Substance P (SP) and an SP deprived of the N-terminal tripeptide, SP(4-11), on phosphoinositide metabolism by measuring phosphoinositide breakdown, inositol phosphate production and inositol incorporation into phosphoinositides. This work shows that SP and SP(4-11) have similar effects on phosphatidylinositol-4.5 bisphosphate (PIP2) metabolism. In fact, SP(4-11), like SP, induces a rapid PIP2 breakdown. On the contrary, SP and SP(4-11) have different effects on phosphatidylinositol (PI) metabolism since SP induces a decrease of radioactivity in PI, whereas SP(4-11) does not. Both peptides stimulate [3H]-inositol mono-, bis- and trisphosphate (respectively IP1, IP2, IP3) production in a time and dose-dependent manner. The kinetic of IP3 production is directly correlated with the one of PIP2 breakdown. The time course of IP1 production after SP(4-11) shows a time delay, while the one after SP does not. Since SP evokes an IP1 production without any delay and a large decrease of radioactivity in PI (which cannot account for the small amount measured in IP1 accumulation) we suggest that SP could activate a PI specific phospholipase C (leading to a PI breakdown) and a phospholipase D. These activations would require the complete structure of SP while the classical PIP2 specific phospholipase C activation (which induces PIP2 breakdown) would only require the carboxamide part of the peptide. So the complete structure of SP would be necessary to have a complete response (stimulation of PIP2 and PI metabolism).

The impact of clinical biochemistry on university education in France.

In France, clinical biochemistry, similar to other disciplines of laboratory medicine, is taught in both the regular medical and pharmacy curricula, but medical teaching is oriented more towards the interpretation of laboratory findings than test performance. At present, there is no compulsory program of lifelong continuing education, but it is planned to introduce such an obligation in the near future. The practice of laboratory medicine is regulated strictly by the national Health Administration. Clinical laboratories are multidisciplinary, covering simultaneously clinical biochemistry, microbiology, parasitology, hematology and immunology. The only officially recognized laboratory profession is that of 'Director of a Laboratory for Medical Analysis'. The practice of this profession is only open to physicians and pharmacists, provided they graduated in 'Medical Biology' after 4 years of specialized training through a particular type of residency called the 'internat'. The 'interns' are selected by competitive examination. After completing their curriculum, specialized physicians or pharmacists can without further examination or certification either enter a career in a hospital, a university, or both, or direct or co-direct a private laboratory. In this scheme, clinical biochemistry exists as a separate academic discipline, but barely as a distinct profession.

The cholesterol content of HDL2 and HDL3 subfractions of high density lipoproteins in different normocholesterolemic populations.

Two normocholesterolemic populations, selected for either high triglyceridemia or low HDL cholesterol content, both known to have increased artery disease risks, were studied for their cholesterol content in HDL2 and HDL3 subfractions. These subfractions were isolated by a precipitation method. The results showed that, in both populations, total HDL cholesterol values were similar and HDL2 and HDL3 cholesterol content were decreased when compared with a control population. In percentage of total HDL cholesterol, the HDL2 cholesterol subfraction appeared significantly diminished only in female subjects for both populations studied.

A simple radioimmunoassay of acebutolol in plasma.

Antisera against acebutolol were produced in rabbits immunized by means of this drug conjugated with bovine serum albumin. These antisera were used to develop a method of radioimmunoassay for acebutolol. The plasma radioimmunoassay, described here, requires no extraction and is very easy to perform besides being quick, specific and sensitive. As little as 2.97 X 10(-9) mol/l of acebutolol can be detected. This radioimmunoassay is suitable for assaying the large number of samples usually measured in pharmacological studies.

'Pseudohypertriglyceridemia' caused by hyperglycerolemia due to congenital enzyme deficiency.

A 76-year-old man was found to have a false hypertriglyceridemia due to a 40-fold increased glycerolemia. This metabolic change was due to a deficiency in glycerol kinase (ATP:glycerol phosphotransferase, EC 2.7.1.30) activity in the cells of this patient as shown by incubation of his white blood cells with [14 C]glycerol. Several chromatographic analyses and quantitative assays were performed on plasma and urine of this patient and of his relatives. The small number of this family's members did not allow to specify the mode of transmission of this genetic trait.

Melatonin synthesis by rabbit platelets.

Platelets of reserpinized rabbits, incubated in buffer containing tritiated 5-hydroxytryptamine (3H-5HT), have the ability to convert 3H-5HT into labeled compound(s) extractable with alkaline-chloroform. The bulk of the chloroform-extractable radioactivity showed a Rf value similar to authentic melatonin on silicagel thin-layer chromatography. The labelled product eluted with ethanol from the silicagel area where melatonin was suspected to reside was identified as melatonin by mass spectrometry and radioimmunoassay. Our in vitro experiments demonstrate that rabbit platelets are capable of converting 5-HT into melatonin apparently because they possess the enzymatic equipment necessary for this biosynthesis i.e. serotonin N-acetyltransferase and hydroxyindole-O-methyltransferase.

The diffuse neuroendocrine (APUD) system.

The bulk of experimental evidence indicates that the APUD series of cells is a distinct system based upon common pathophysiological features. The diffuse nature of this system with elements in the central and peripheral nervous system suggests a more complex interaction of the body's homeostasis than has been established. It is probable that as radioimmunological and radioenzymatic assays become more widely available and standardized, other apudomas will be described. Finally, an understanding of the APUD concept, with its peculiar pluripotential for the production of biogenic amines and peptides, the multicentric nature of the disease and the possibility of multiple cell involvement, is of key importance in managing patients. Studies of the apudomas will also advance the understanding of the normal physiologic interrelationships of the APUD cells.

Catecholamines metabolism in infantile autism: a controlled study of 22 autistic children.

In a group of 22 autistic children aged 5 to 16 years and a group of normal controls matched for age and sex, catecholamines metabolism was investigated in plasma, platelets, and urine. This investigation was part of a research project in which several biological parameters (including serotonin) were explored simultaneously in the same children. In the autistic group, epinephrine and norepinephrine were significantly elevated in plasma, while epinephrin, norepinephrine, and dopamine were significantly lower in isolated platelets. No significant difference was found between the two groups for the urinary excretion of epinephrine, norepinephrine, dopamine, DOPAC, and MHPG. Other differences between the two groups in the statistical correlations of several biochemical parameters also suggest abnormalities of bioamine metabolism in the platelets of autistic children.

Catecholamines in autistic disorder: effects of amisulpride and bromocriptine in a controlled crossover study.

ABSTRACT The biochemical effects on catecholaminergic systems of the dopamine antagonist amisulpride and the dopamine agonist bromocriptine were evaluated in a double-blind, randomized, crossover study in children with autistic disorder. Plasma levels of dopamine, norepinephrine, and epinephrine; urinary concentrations of homovanillic acid (HVA), vanillyImandelic acid (VMA) and 3-methoxy-4-hydroxyphenylethylene glycol (MHPG); and plasma prolactin were measured. At doses of amisulpride and bromocriptine that had the expected opposing effects on plasma prolactin, the drugs' effects on the catecholaminergic systems were similar. Both agents unexpectedly lowered urinary HVA (total, free, and sulfated) although only amisulpride decreased the HVA levels significantly. This paradoxical decrease in HVA levels suggests that both dopamine agonists and antagonists could act on autoreceptors or presynaptic dopaminergic receptors in the central nervous system. There was no significant action of either drug on plasma epinephrine, urinary VMA, or urinary MHPG, suggesting that neither drug altered norepinephrine or epinephrine systems; however, a weak increase of plasma norepinephrine occurred after amisulpride treatment, consistent with effects observed with other neuroleptics. Neither agent altered plasma dopamine, suggesting that peripheral dopamine metabolism was unchanged. The clinical effects of amisulpride and bromocriptine have been reported to be unexpectedly complementary. The complementary clinical effects of a dopamine agonist and dopamine antagonist might speculatively be related to their similar action on dopamine autoreceptors, leading to a correction of the dopaminergic hyperactivity that has been postulated in autistic children.

Influence of hepatic insufficiency in pharmacokinetics of drugs: example for an anthranilic diuretic.

Hepatic insufficiency is responsible for numerous modifications of drug metabolism and pharmacokinetics, because the liver is the most important organ for the transformation and, with the kidney, elimination of drugs. Pharmacokinetics of furosemide, an anthranilic diuretic, was compared in normal subjects and cirrhotics with hepatic insufficiency, after oral administration. In patients, we observed few modifications of the bioavailability. The total elimination of the drug was normal when the urinary excretion compensated a slight reduction in biliary secretion, but when this reduction was important the total clearance of furosemide decreased. In urine, the elimination time was lengthened, but the percentage of excretion was about the same as for normal subjects. The pharmacological effects were also modified for cirrhotics with decrease of sodium and water excretion, for the same blood concentration of drug as in controls. Also, we observed a shift between the salidiuretic effect and the blood concentration in patients, when there was an exact concordance of these times in control subjects. Two hypotheses have been proposed to explain this phenomenon: (1) modifications in hepatic metabolism or, (2) in drug protein binding.