A new case of sodium-dependent multivitamin transporter defect occurring as a life-threatening condition responsive to early vitamin supplementation and literature review.

BACKGROUND: Biallelic pathogenic variants in SLC5A6 resulting in sodium-dependent multivitamin transporter (SMVT) defect have recently been described as a vitamin-responsive inborn error of metabolism mimicking biotinidase deficiency. To our knowledge, only 16 patients have been reported so far with various clinical phenotypes such as neuropathy and other neurologic impairments, gastro-intestinal dysfunction and failure to thrive, osteopenia, immunodeficiency, metabolic acidosis, hypoglycemia, and recently severe cardiac symptoms. METHODS: We describe a case report of a 5-month-old girl presenting two recurrent episodes of metabolic decompensation and massive cardiac failure in the course of an infectious disease. We compare clinical, biological, and genetic findings of this patient to previous literature collected from Pubmed database (keywords: Sodium-dependent multivitamin transporter (SMVT), SMVT defect/disorder/deficiency, SLC5A6 gene/mutation). RESULTS: We highlight the life-threatening presentation of this disease, the stagnation of psychomotor development, the severe and persistent hypogammaglobulinemia, and additionally, the successful clinical response on early vitamin supplementation (biotin 15 mg a day and pantothenic acid 100 mg a day). Metabolic assessment showed a persistent increase of urinary 3-hydroxyisovaleric acid (3-HIA) as previously reported in this disease in literature. CONCLUSION: SMVT deficiency is a vitamin-responsive inborn error of metabolism that can lead to a wide range of symptoms. Increased and isolated excretion of urinary 3-hydroxyisovaleric acid may suggest, in the absence of markedly reduced biotinidase activity, a SMVT deficiency. Prompt supplementation with high doses of biotin and pantothenic acid should be initiated while awaiting results of SLC5A6 sequencing as this condition may be life-threatening.

A robust viologen and Mn-based porous coordination polymer with two types of Lewis acid sites providing high affinity for H2O, CO2 and NH3.

A novel porous coordination polymer [Mn(pc3)(H2O)2]·xH2O (3 < x < 4) is synthesized in water at pH = 7 using the anionic viologen-carboxylate ligand 4,4'-bipyridinium,1,1'-bis-(2,4-dicarboxyphenyl) (pc32-). Dehydration of the material results in the formation of open pores containing two types of accessible Lewis acid sites: exposed Mn2+ cations and N+ atoms of viologen units. Due to this property the PCP shows high affinity and capacity in the adsorption of H2O, CO2 and NH3. Despite the presence of strong adsorption sites this material is stable in liquid water and in gaseous NH3.

Expression of the semicarbazide-sensitive amine oxidase in articular cartilage: its role in terminal differentiation of chondrocytes in rat and human.

OBJECTIVE: Semicarbazide-sensitive amine oxidase (SSAO) catalyzes the oxidation of primary amines into ammonia and reactive species (hydrogen peroxide, aldehydes). It is highly expressed in mammalian tissues, especially in vascular smooth muscle cells and adipocytes, where it plays a role in cell differentiation and glucose transport. The study aims at characterizing the expression and the activity of SSAO in rat and human articular cartilage of the knee, and to investigate its potential role in chondrocyte terminal differentiation. DESIGN: SSAO expression was examined by immunohistochemistry and western blot. Enzyme activity was measured using radiolabeled benzylamine as a substrate. Primary cell cultures of rat chondrocytes were treated for 21 days by a specific SSAO inhibitor, LJP 1586. Terminal chondrocyte differentiation markers were quantified by RT-qPCR. The basal and IL1ß-stimulated glucose transport was monitored by the entrance of (3)[H]2-deoxyglucose in chondrocytes. RESULTS: SSAO was expressed in chondrocytes of rat and human articular cartilage. SSAO expression was significantly enhanced during the hypertrophic differentiation of chondrocytes characterized by an increase in MMP13 and in alkaline phosphatase (ALP) expressions. SSAO inhibition delayed the late stage of chondrocyte differentiation without cell survival alteration and diminished the basal and IL1ß-stimulated glucose transport. Interestingly, SSAO activity was strongly increased in human osteoarthritic cartilage. CONCLUSIONS: SSAO was expressed as an active form in rat and human cartilage. The results suggest the involvement of SSAO in rat chondrocyte terminal differentiation via a modulation of the glucose transport. In man, the increased SSAO activity detected in osteoarthritic patients may trigger hypertrophy and cartilage degeneration.

Fractures of the distal humerus operated on using the Lambda® plate: report of 75 cases at 9.5 years follow-up.

INTRODUCTION: The study sought to assess the functional results and complications of osteosynthesis using the Lambda(®) plate (Zimmer, Étupes, France) in treating fracture of the distal extremity of the humerus. MATERIALS AND METHODS: The initial series comprised 115 patients (116 fractures), treated between 1992 and 2008. Forty-one (mainly foreigners) were lost to follow-up. The final series thus comprised 74 patients (75 fractures): 44 female and 30 male, with a mean age of 46±23 years (range, 16-95 years), 22 (29%) being aged 65 years or over. According to AO classification, 22 of the fractures of the distal extremity of the humerus (29%) were diaphyseal-metaphyseal, corresponding to a particular grade of type A2, 12 (16%) were type A2 or A3, six (8%) type B, and 35 (47%) type C. Eight were open fractures: seven grade 1 and one grade IIa on Gustilo's classification. The Lambda(®) plate is an inverted Y shape, with a stem of up to ten holes and sectile arms that can be remodeled to adapt perfectly to the type of fracture and the shape of the distal end of the humerus. A posterior approach was used in all cases: in 26 cases, an extra-articular transolecranal approach and otherwise a transtricipital approach, either vertical for diaphyseal-metaphyseal fracture or inverted V for type-C fracture. RESULTS: Mean follow-up was 115±64 months (range, 24-227 months). There were no cases of infection, non-union of olecranial osteotomy or disassembly of the internal fixation; there was, on the other hand, one case of non-union of the lateral condyle and one of the distal extremity of the humerus, two cases of dysesthesia in the ulnar nerve territory and one in the radial nerve territory (following preoperative paralysis), and four cases of stiffness requiring surgical arthrolysis between 6 and 12 months postoperatively. At follow-up, mean active elbow flexion was 133°±13° (range, 90°-150°) and active extension -12°±14° (range, -45°-0°). Mean elbow flexion range of motion exceeded 100° in 58 patients (77%), was between 50° and 100° in 16 (21%) and was less than 50° in one. Mean Mayo Elbow Performance Score (MEPS) was 97±7 points (range, 40-100), and mean Quick DASH Score (converted as a score out of 100) was 10±18 (range, 0-54). There were 67 excellent results (MEPS, 90-100 points), five good (75-89), two moderate and one poor. The 35 type-C fractures displayed no significant differences from the series as a whole (P=1.24 for MEPS). CONCLUSION: Osteosynthesis using the Lambda(®) plate gave excellent medium-term results in terms of both fixation stability and recovery of elbow function after fracture of the distal extremity of the humerus, even in elderly osteoporotic patients. LEVEL OF EVIDENCE: Level IV: retrospective study.

Medial facet patelloplasty in patellar instability associated with patellofemoral dysplasia: a report of 26 cases.

INTRODUCTION: Numerous procedures may be used in the surgical treatment of patellar instability. We have noticed that certain types of patellar instability result in a bulge (or protrusion) of the distal medial facet of the patella which can hinder recentering in the trochlear groove. HYPOTHESIS: In certain patellofemoral dysplasias, trimming down of this bulge (patelloplasty) as long as it is associated with a "à la carte surgery" program, can improve stability, centering and lateral patellar tilt. PATIENTS AND METHODS: This retrospective series included 23 patients (26 knees), 13 women and 10 men, mean age 25.9±9.01 years old (15-52) operated between 1997-2008. Patellar dislocation had occurred at least once in all knees, and at least twice in 16 knees. The mean preoperative Kujala score was 79.1±6.1 points (68-91). There was a bulge on the medial facet of the patella in all cases, in particular on skyline views associated with the usual criteria for patellofemoral dysplasia. Patelloplasty was associated in all cases with resection of the lateral patellar retinaculum and anteromedialization of the tibial tubercle (7 were lowered) and four Albee trochleoplasties. RESULTS: Recurrent dislocation occurred in one case (4.7%). Nineteen patients (22 knees) were followed up for a mean 7.53±3.27 years (2-13 years). The mean postoperative Kujala score was 91.8±7.9 points (70-100) and the subjective results in 19/22 (86.5%) knees were satisfactory or very satisfactory. On skyline views, 21 patellae (95.5%) were well centered and one (4.5%) still presented with lateral tilt. There was no osteoarthritis in 15 knees (68%). CONCLUSION: In selected cases, patelloplasty of the medial facet of the patella has no particular morbidity at intermediate follow-up. Associated with other surgical procedures, the rate of satisfaction of patients is very high and especially encouraging. LEVEL OF EVIDENCE: Level IV, retrospective cohort study.

Posterior approach and dislocation rate: a 213 total hip replacements case-control study comparing the dual mobility cup with a conventional 28-mm metal head/polyethylene prosthesis.

INTRODUCTION: Dislocation is a frequent complication of total hip arthroplasties (THA) especially in older patients, especially when using a posterior approach. In these cases, dual mobility (DM) cups developed by Gilles Bousquet in 1975 can be indicated to reduce this complication risk. HYPOTHESIS: Dual mobility cups reduce the rate of dislocation in primary total hip arthroplasty using posterior approach in a single-surgeon series. AIM: Test this hypothesis in a controlled study to compare the rate of dislocation in primary total hip arthroplasties done in patients over 50 years old either with a dual mobility cup or a conventional metal-on-polyethylene 28-mm diameter head. PATIENTS AND METHODS: Two consecutive series of primary total hip replacements were performed by a single surgeon using a posterolateral approach. The piriformis tendon was left intact. The DM series included 105 patients who underwent arthroplasty between January 2005 and June 2007 with a dual mobility cup (60 women and 45 men, mean age 76.6±5.65 years old [53-93]). The control series (S series) included 108 patients who underwent arthroplasty (56 women and 52 men, mean age 74.2±5.9 years old [53-87]) with a conventional 28-mm polyethylene cup between January 2003 and June 2005. All hip replacements included a 28-mm metal-polyethylene cup and a 12-14-mm Morse taper. Both groups were comparable for gender, diagnosis, body mass index, type of anesthesia and ASA score distribution. All patients included in this series had a minimum follow-up of 1 year. RESULTS: There were no dislocations in the DM series and five early dislocations (before the third month) in the S series for a rate of 4.63%. Although the rate of dislocation was higher in the S series (4.63% vs 0%), the difference was barely significant (P=0.0597). DISCUSSION: This study comparing the incidence of dislocations after THA with conventional or dual mobility cups, shows that even using a posterior approach and in older patients, dual mobility cups increase stability with no postoperative dislocations. Although results are barely significant, a larger series should confirm the benefit of this implant. In this series, morbidity was not increased with dual mobility cups. LEVEL OF EVIDENCE: Level III: retrospective case-control study.

Dating the demise: neandertal extinction and the establishment of modern humans in the southern Caucasus.

This paper considers the recent radiometric dating (14C-AMS, TL, ESR) of 76 late Middle and early Upper Paleolithic samples from Ortvale Klde Rockshelter, located in the Republic of Georgia. We present a critical evaluation of each date based on its stratigraphic and archaeological context, its pretreatment and contamination history, and its resulting accuracy and precision, the goal being to establish a sound chronology for the site. Only by systematically identifying aberrant dates within a data set and isolating them from further analysis can we hope to understand cultural and biological phenomena on an accurate temporal scale. Based on the strict discard protocol outlined here, we omit 25% of the dated samples from the analysis. The remaining data speak to the lengthy tenure of Neandertals in the region, but also to their relatively rapid demise and the establishment of modern human populations approximately 38-34 ka 14C BP (42-39 kacalBP(Hulu)). We compare these chronometric data with those from the neighboring sites of Bronze and Dzudzuana caves, as well as Mezmaiskaya Cave, located in the northern Caucasus. While the lack of key contextual information limit our ability to subject these other data sets to the same critical evaluation procedure, they provide the first interregional temporal assessment of the Middle to Upper Paleolithic "transition," the results of which suggest an initial expansion of modern humans into the southern Caucasus followed by expansion along the Black Sea coast and into the northern Caucasus.

Harmonization of strategies for the validation of quantitative analytical procedures: a SFSTP proposal part IV. Examples of application.

A harmonized approach for the validation of analytical methods based on accuracy profile was introduced by a SFSTP commission on the validation of analytical procedure. This fourth and last document aims at illustrating this methodology and the statistics used. Therefore the validation of real case methods are proposed such as methods for the quality control of drugs, for the quantitation of impurities in drug substances, for bioanalysis or for the determination of nutriments. Furthermore, different types of analytical methods are used in order to demonstrate the applicability of the proposed approach to a wide range of methods such as liquid chromatography (LC-UV, LC-MS), spectrophotometry or ELISA.

Limitation of adipose tissue enlargement in rats chronically treated with semicarbazide-sensitive amine oxidase and monoamine oxidase inhibitors.

Inhibition of semicarbazide-sensitive amine oxidases (SSAO) and monoamine oxidases (MAO) reduces fat deposition in obese rodents: chronic administration of the SSAO-inhibitor semicarbazide (S) in combination with pargyline (MAO-inhibitor) has been shown to reduce body weight gain in obese Zucker rats, while (E)-2-(4-fluorophenethyl)-3-fluoroallylamine, an SSAO- and MAO-B inhibitor, has been reported to limit weight gain in obese and diabetic mice. Our aim was to state whether such weight gain limitation could occur in non-obese, non-diabetic rats and to extend these observations to other amine oxidase inhibitors. Prolonged treatment of non-obese rats with a high dose of S (900 micromol kg(-1) day(-1)) reduced body weight gain and limited white adipose tissue enlargement. When chronically administered at a threefold lower dose, S also inhibited SSAO activity but not fat depot enlargement, suggesting that effects other than SSAO inhibition were involved in adipose tissue growth retardation. However, combined treatment of this lower dose of S with pargyline inhibited SSAO, MAO, energy intake, weight gain and fat deposition. Adipocytes from treated rats exhibited unchanged insulin responsiveness but impaired antilipolytic responses to amine oxidase substrates. Phenelzine clearly inhibited both MAO and SSAO when tested on adipocytes. Obese rats receiving phenelzine i.p. at 17 micromol kg(-1) day(-1) for 3 weeks, exhibited blunted MAO and SSAO activities in any tested tissue, diminished body weight gain and reduced intra-abdominal adipose tissue. Their adipocytes were less responsive to lipogenesis activation by tyramine or benzylamine. These observations suggest that SSAO inhibition is not sufficient to impair fat deposition. However, combined MAO and SSAO inhibition limits adiposity in non-obese as well as in obese rats.

Harmonization of strategies for the validation of quantitative analytical procedures. A SFSTP proposal--part III.

In the first two documents [Ph. Hubert, J.J. Nguyen-Huu, B. Boulanger, E. Chapuzet, P. Chiap, N. Cohen, P.A. Compagnon, W. Dewé, M. Feinberg, M. Lallier, M. Laurentie, N. Mercier, G. Muzard, C. Nivet, L. Valat, J. Pharm. Biomed. Anal. 36 (2004) 579-586; Ph. Hubert, J.J. Nguyen-Huu, B. Boulanger, E. Chapuzet, P. Chiap, N. Cohen, P.A. Compagnon, W. Dewé, M. Feinberg, M. Lallier, M. Laurentie, N. Mercier, G. Muzard, C. Nivet, L. Valat, E. Rozet, J. Pharm. Biomed. Anal., in press], a recent SFSTP Commission on the validation of analytical procedure has introduced a harmonized approach for the validation of analytical procedures. In order to complete this guide, the statistical methodology allowing to correctly conclude about the validity of a procedure is proposed in this third part of the guide. Indeed all the steps to obtain the decision tool namely the accuracy profile are described and illustrated step by step by a numerical example. This tool, based on the concept of total error (bias+standard deviation) build with a beta-expectation tolerance interval, allows to easily take the right decision and simultaneously minimizing the risk of the future use of the analytical procedure.

Harmonization of strategies for the validation of quantitative analytical procedures. A SFSTP proposal--part II.

As reported in a previous paper, the main objective of the new commission of the Société Française des Sciences et Techniques Pharmaceutiques (SFSTP) was the harmonisation of approaches for the validation of quantitative analytical procedures. In a series of meetings, members of this Commission have first tried to review the objectives of analytical methods and the objectives of validation methods and to recommend the use of two-sided beta-expectation tolerance intervals for total error of validation samples (accuracy profile) in the acceptance/rejection of analytical method in validation phase. In the context of the harmonization, the other objectives were: (i) to propose a consensus on the norms usually recognized, while widely incorporating the ISO terminology; (ii) to recommend to validate the analytical procedure accordingly to the way it will be used in routine; (iii) to elaborate a rational, practical and statistically reliable strategy to assure the quality of the analytical results generated. This strategy has been formalised in a guide and the three latter objectives made by the Commission are summarised in the present paper which is the second part of summary report of the SFSTP commission. The SFSTP guide has been produced to help analysts to validate their analytical methods. It is the result of a consensus between professionals having expertise in analytical and/or statistical fields. The suggestions presented in this paper should therefore help the analyst to design and perform the minimum number validation experiments needed to obtain all the required information to establish and demonstrate the reliability of its analytical procedure.

Harmonization of strategies for the validation of quantitative analytical procedures. A SFSTP proposal--Part I.

This paper is the first part of a summary report of a new commission of the Société Française des Sciences et Techniques Pharmaceutiques (SFSTP). The main objective of this commission was the harmonization of approaches for the validation of quantitative analytical procedures. Indeed, the principle of the validation of theses procedures is today widely spread in all the domains of activities where measurements are made. Nevertheless, this simple question of acceptability or not of an analytical procedure for a given application, remains incompletely determined in several cases despite the various regulations relating to the good practices (GLP, GMP, ...) and other documents of normative character (ISO, ICH, FDA, ...). There are many official documents describing the criteria of validation to be tested, but they do not propose any experimental protocol and limit themselves most often to the general concepts. For those reasons, two previous SFSTP commissions elaborated validation guides to concretely help the industrial scientists in charge of drug development to apply those regulatory recommendations. If these two first guides widely contributed to the use and progress of analytical validations, they present, nevertheless, weaknesses regarding the conclusions of the performed statistical tests and the decisions to be made with respect to the acceptance limits defined by the use of an analytical procedure. The present paper proposes to review even the bases of the analytical validation for developing harmonized approach, by distinguishing notably the diagnosis rules and the decision rules. This latter rule is based on the use of the accuracy profile, uses the notion of total error and allows to simplify the approach of the validation of an analytical procedure while checking the associated risk to its usage. Thanks to this novel validation approach, it is possible to unambiguously demonstrate the fitness for purpose of a new method as stated in all regulatory documents.

Degree of sex reversal as related to plasma steroid levels in genetic female chickens (Gallus domesticus) treated with Fadrozole.

The objectives of this work were to determine whether or not plasma levels of testosterone and estradiol reflect the various grades of sex reversal in genetic female chickens treated with Fadrozole (CGS 16949 A), a nonsteroidal aromatase inhibitor, and whether gonadal aromatase activity and plasma levels of testosterone and estradiol in treated females can or not be modified by post-hatch treatments with Fadrozole or Fadrozole + testosterone. Eggs were injected with 1 mg Fadrozole on day 4 of incubation. In females having developed sex-reversed gonads, endocrine parameters (estradiol and testosterone) at and after 13 weeks of age were indicative of the degree of sex reversal, with, for example, sex-reversed females with two testes having the highest levels of testosterone and the lowest levels of estradiol. Among these females, eight (from a total of 13) produced ejaculates with scarce and abnormal spermatozoa. Some motility was observable in the ejaculates from five of them. None of the post-hatch treatments had a significant effect on plasma levels of testosterone or estradiol (measured at 3-week intervals from week 4 to week 28 post-hatch) or on gonadal aromatase activity (measured at 12 and 28 weeks). In conclusion, these results indicate that plasma levels of testosterone and estradiol at and after 13 weeks of age are valuable indicators of the degree of sex reversal in female chickens treated with Fadrozole prior to gonadal sex differentiation. In pre-cited conditions, post-natal treatments with either Fadrozole or Fadrozole + testosterone had no apparent effect on the degree of sex reversal in these birds. Finally, the occurrence of ejaculates with motile although scarce and abnormal spermatozoa, revealed that epididymes and ducti deferens can develop and become functional in sex-reversed female chickens.

Biometry of the radial head: biomechanical implications in pronation and supination.

The aim of this study was to perform biometry of the proximal extremity of the radius and to characterize the shape of the radial head. Knowledge of the size and shape of the radial head is necessary for the creation of a radial head prosthesis that is anatomically and biomechanically correct. Twenty-seven measurements, focused on the proximal extremity, were done on 96 radii. The shape of the radial head was determined by the difference between the maximum diameter and the minimum diameter. We considered the shape to be circular when the difference was less than 1 mm, and elliptical when the difference was greater than 1 mm. The shape of the radial head was compared with the neck/diaphysis angle. Fifty-seven percent of radial heads were elliptical and 43% were circular. When the head was elliptical the maximum diameter was 22 mm +/-2.9 and the minimum diameter was 20 mm +/-2.8 ( P<0.001). When the head was circular the maximum diameter was 21.2 mm +/-2.4 and the minimum diameter was 20.4 mm +/-2.4 ( P<0.14). The angle between the neck and the diaphysis varied with regard to the shape of the radial head. It was 166.75 degrees +/-3 for the circular heads and 168.62 degrees +/-3.2 for the elliptical heads ( P<0.01). The biomechanics of the circular shape and the elliptical shape are different, involving an adaptation of the angle between the neck and the radial diaphysis. This difference must be taken in consideration in the design of a radial head prosthesis.

Sex reversal and aromatase in chicken.

Aromatase inhibitors administered before sexual differentiation of the gonads can induce sex reversal in female chickens. To analyze the process of sex reversal, we have followed for several months the changes induced by Fadrozole, a nonsteroidal aromatase inhibitor, in gonadal aromatase activity and in morphology and structure of the female genital system. Fadrozole was injected into eggs on day four of incubation, and its effects were examined during the embryonic development and for eight months after hatching. In control females, aromatase activity in the right and the left gonad was high in the middle third of embryonic development, and then decreased up to hatching. After hatching, aromatase activity increased in the left ovary, in particular during folliculogenesis, whereas in the right regressing gonad, it continued to decrease to reach testicular levels at one month. In treated females, masculinization of the genital system was characterized by the maintenance of the right gonad and its differentiation into a testis, and by the differentiation of the left gonad into an ovotestis or a testis; however, in all individuals, the left Müllerian duct and the posterior part of the right Müllerian duct were maintained. In testes and ovotestes, aromatase activity was lower than in gonads of control females (except in the right gonad as of one month after hatching) but remained higher than in testes of control and treated males. Moreover, in ovotestes, aromatase activity was higher in parts displaying follicles than in parts devoid of follicles. The main structural changes in the gonads during sex reversal were partial (in ovotestes) or complete (in testes) degeneration of the cortex in the left gonad, and formation of an albuginea and differentiation of testicular cords/tubes in the two gonads. Testicular cords/tubes transdifferentiated from ovarian medullary cords and lacunae whose epithelium thickened and became Sertolian. Transdifferentiation occurred all along embryonic and postnatal development; thus, new testicular cords/tubes were continuously formed while others degenerated. The sex reversed gonads were also characterized by an abundant fibrous interstitial tissue and abnormal medullary condensations of lymphoid-like cells; in the persisting testicular cords/tubes, spermatogenesis was delayed and impaired. Related to aromatase activity, persistence of too high levels of estrogens can explain the presence of oviducts, gonadal abnormalities and infertility in sex reversed females.

Expression of AMH, SF1, and SOX9 in gonads of genetic female chickens during sex reversal induced by an aromatase inhibitor.

Aromatase inhibitors administered prior to histological signs of gonadal sex differentiation can induce sex reversal of genetic female chickens. Under the effects of Fadrozole (CGS 16949A), a nonsteroidal aromatase inhibitor, the right gonad generally becomes a testis, and the left gonad a testis or an ovotestis. We have compared the expression pattern of the genes encoding AMH (the anti-Müllerian hormone), SF1 (steroidogenic factor 1), and SOX9 (a transcription factor related to SRY) in these sex-reversed gonads with that in control testes and ovaries, using in situ hybridization with riboprobes on gonadal sections. In control males, the three genes are expressed in Sertoli cells of testicular cords; however, only SOX9 is male specific, since as observed previously AMH and SF1 but not SOX9 are expressed in the control female gonads. In addition to testicular-like cords, sex-reversed gonads present many lacunae with a composite, thick and flat epithelium. We show that during embryonic and postnatal development, AMH, SF1 and SOX9 are expressed in the epithelium of testicular-like cords and in the thickened part but not in the flattened part of the epithelium of composite lacunae. AMH and SF1 but not SOX9 are expressed in follicular cells of ovotestes. Coexpression of the three genes, of which SOX9 is a specific Sertoli-cell marker, provides strong evidence for the transdifferentiation of ovarian into testicular epithelium in gonads of female chickens treated with Fadrozole.

Sex reversal and aromatase in the European pond turtle: treatment with letrozole after the thermosensitive period for sex determination.

In the European pond turtle (Emys orbicularis), gonadal sex differentiation is temperature-dependent. The temperature sensitive period (TSP) of gonadogenesis lies between stages 16 and 22 of embryonic development. Previous studies have shown that embryos incubated at 30 degrees C, a temperature yielding 100% phenotypic females, can be sex reversed by treatments with an aromatase inhibitor administered during TSP or even somewhat after TSP (as of stage 22+). The goal of the present study was to determine whether the ovary still retains male potential at later stages of embryonic development and whether the induced male characters persist after hatching. For this purpose, eggs of E. orbicularis were treated with letrozole, a nonsteroidal aromatase inhibitor, at or as of stages 23, 24 or 25, then gonadal aromatase activity in each individual and the related gonadal structure were studied at hatching (stage 26) and for one year after hatching. Two kinds of treatments were carried out: 1) repeated applications of 10 microg of letrozole in ethanolic solution onto the eggshell; and 2) a single injection of 10 microg of letrozole in olive oil. Similar results were obtained with either application or injection of the aromatase inhibitor. In treatments as of or at stage 23, individuals with gonadal aromatase activity lower than 20 fmoles/hour/gonad had ovotestes, i.e., 22% of the treated individuals. At hatching, the inner part of these ovotestes contained testicular cords and also mixed lacunae presenting various degrees of transdifferentiation of the epithelium into a Sertolian epithelium. The cortex was maintained, although some germ cells degenerated within it. These processes continued after hatching. However, at 12 months, gonads were still ovotestes displaying some follicles with a growing oocyte in the remaining parts of the cortex. In treatments as of or at stages 24 or 25, only a few individuals were masculinized. One had ovotestes; in others, the cortex was absent in some parts and when it was present oocytes were degenerating. These results show that in the European pond turtle, differentiation of ovotestes from ovaries can be induced by treatment with an aromatase inhibitor starting at late stages of embryonic development (between the end of TSP and hatching), although such differentiation is less frequent as embryonic development proceeds. Sex reversal persists for at least one year after hatching. J. Exp. Zool. 290:490-497, 2001.

Comparative morphology and paleobiology of Middle Pleistocene human remains from the Bau de l'Aubesier, Vaucluse, France.

The discovery of later Middle Pleistocene human remains from the Bau de l'Aubesier, France reinforces an evolutionary model of the gradual accumulation of Neandertal-derived facial and dental features during the Middle Pleistocene of the northwestern Old World. The pronounced maxillary incisor beveling of Aubesier 4 helps to extend the antiquity of nondietary use of the anterior dentition. The interproximal "toothpick" groove on the Aubesier 10 molar increases the sample for these lesions. The pathological loss of the mandibular dentition of Aubesier 11 indicates advanced antemortem masticatory impairment, at a level previously undocumented before the Late Pleistocene. These remains support a view of later Middle Pleistocene humans able to support debilitated individuals despite the considerable use of their bodies to accomplish routine activities.