19 resultados para 1008
em Université de Lausanne, Switzerland
Resumo:
The ability to identify the species origin of an unknown biological sample is relevant in the fields of human and wildlife forensics. However, the detection of several species mixed in the same sample still remains a challenge. We developed and tested a new approach for mammal DNA identification in mixtures of two or three species, based on the analysis of mitochondrial DNA control region interspecific length polymorphism followed by direct sequencing. Contrary to other published methods dealing with species mixtures, our protocol requires a single universal primer pair and is not based on a pre-defined panel of species. Amplicons can be separated either on agarose gels or using CE. The advantages and limitations of the assay are discussed under different conditions, such as variable template concentration, amplicon sizes and size difference among the amplicons present in the mixture. For the first time, this protocol provides a simple, reliable and flexible method for simultaneous identification of multiple mammalian species from mixtures, without any prior knowledge of the species involved.
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PURPOSE OF REVIEW: This article presents an overview of the common and various kinds of pupillary disorders that can be encountered in an outpatient setting. RECENT FINDINGS: The dorsal midbrain is a site where lesions may produce either an afferent or an efferent pupillary defect. The classic pupillary syndrome secondary to a dorsal midbrain lesion is bilateral light-near dissociation. Another recognized deficit is bilateral mydriasis. Recent reports have documented unilateral mydriasis, unilateral light-near dissociation, and a relative afferent pupillary defect without visual loss in association with lesions of the dorsal midbrain. These are rare syndromes. SUMMARY: Careful history and examination can often identify and localize the pupillary disorder, as well as guide appropriate evaluation.
Resumo:
La manifestation est sans doute la forme la plus commune d'expression politique, tant dans les pays démocratiques, où sa légitimité le dispute avec plus ou moins de bonheur aux formes plus conventionnelles de participation comme le vote, que dans les pays non démocratiques, où elle accompagne les tentatives de révolte et de renversement.Dans cet ouvrage de synthèse, les auteurs proposent une analyse sociologique et historique de ce mode d'action politique, avec ses normes et ses règles, ses légendes et ses mythes, ses épisodes glorieux et ses heures sombres.Mais surtout, au-delà de l'interrogation classique sur la place de la manifestation dans le répertoire d'action contemporain et dans les luttes politiques, c'est aussi à une analyse au plus près des manifestants eux-mêmes et de «ce qui les fait courir» que cet ouvrage nous invite.
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Question Does a land-use variable improve spatial predictions of plant species presence-absence and abundance models at the regional scale in a mountain landscape? Location Western Swiss Alps. Methods Presence-absence generalized linear models (GLM) and abundance ordinal logistic regression models (LRM) were fitted to data on 78 mountain plant species, with topo-climatic and/or land-use variables available at a 25-m resolution. The additional contribution of land use when added to topo-climatic models was evaluated by: (1) assessing the changes in model fit and (2) predictive power, (3) partitioning the deviance respectively explained by the topo-climatic variables and the land-use variable through variation partitioning, and (5) comparing spatial projections. Results Land use significantly improved the fit of presence-absence models but not their predictive power. In contrast, land use significantly improved both the fit and predictive power of abundance models. Variation partitioning also showed that the individual contribution of land use to the deviance explained by presence-absence models was, on average, weak for both GLM and LRM (3.7% and 4.5%, respectively), but changes in spatial projections could nevertheless be important for some species. Conclusions In this mountain area and at our regional scale, land use is important for predicting abundance, but not presence-absence. The importance of adding land-use information depends on the species considered. Even without a marked effect on model fit and predictive performance, adding land use can affect spatial projections of both presence-absence and abundance models.
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In the Cape Caribou River allochthon (CCRA), metaigneous and gneissic units occur as a shallowly plunging synform in the hanging wall of the Grand Lake thrust system (GLTS), a Grenvillian structure that forms the boundary between the Mealy Mountains and Groswater Bay terranes. The layered rocks of the CCRA are cut by a stockwork of monzonite dykes related to the Dome Mountain suite and by metadiabase-amphibolite dykes that probably form part of the ca. 1380 Ma Mealy swarm. The mafic dykes appear to postdate much of the development of subhorizontal metamorphic layering within the lower parts of the CCRA. The uppermost (least metamorphosed) units of the CCRA, the North West River anorthosite-metagabbro and the Dome Mountain monzonite suite, have been dated at 1625 +/- 6 and 1626 +/- 2 Ma, respectively. An amphibolite unit that concordantly underlies the anorthosite-metagabbro and is intruded discordantly by monzonite dykes has given metamorphic ages of 1660 +/- 3 and 1631 +/- 2 Ma. Granitoid gneisses that form the lowest level of the CCRA have given a migmatization age of 1622 +/- 6 Ma. The effects of Grenvillian metamorphism become apparent in the lower levels of the allochthon where gneisses, amphibolite, and mafic dykes have given new generation zircon ages of 1008 +/- 2, 1012 +/- 3, and 1011 +/- 3 Ma, respectively. A posttectonic pegmatite has also given zircon and monazite ages of 1016(-3)(+7) and 1013 +/- 3 Ma, respectively. Although these results indicate new growth of Grenvillian zircon, this process was generally not accompanied by penetrative deformation or melting. Thus, the formation of gneissic fabrics and the overall layered nature of the lower CCRA are a result primarily of Labradorian (1660-1620 Ma) tectonism and intrusion, and probably reflect early movement on an ancestral GLTS. Grenvillian heating and metamorphism (up to granulite facies) was strongly concentrated towards the base of the CCRA and probably occurred during northwestward thrusting of the allochthon over the Groswater Bay terrane.
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BACKGROUND: A high dietary protein intake has been shown to blunt the deposition of intrahepatic lipids in high-fat- and high-carbohydrate-fed rodents and humans. OBJECTIVE: The aim of this study was to evaluate the effect of essential amino acid supplementation on the increase in hepatic fat content induced by a high-fructose diet in healthy subjects. DESIGN: Nine healthy male volunteers were studied on 3 occasions in a randomized, crossover design after 6 d of dietary intervention. Dietary conditions consisted of a weight-maintenance balanced diet (control) or the same balanced diet supplemented with 3 g fructose · kg(-1) · d(-1) and 6.77 g of a mixture of 5 essential amino acids 3 times/d (leucine, isoleucine, valine, lysine, and threonine) (HFrAA) or with 3 g fructose · kg(-1) · d(-1) and a maltodextrin placebo 3 times/d (HFr); there was a washout period of 4 to 10 wk between each condition. For each condition, the intrahepatocellular lipid (IHCL) concentration, VLDL-triglyceride concentration, and VLDL-[(13)C]palmitate production were measured after oral loading with [(13)C]fructose. RESULTS: HFr increased the IHCL content (1.27 ± 0.31 compared with 2.74 ± 0.55 vol %; P < 0.05) and VLDL-triglyceride (0.55 ± 0.06 compared with 1.40 ± 0.15 mmol/L; P < 0.05). HFr also enhanced VLDL-[(13)C]palmitate production. HFrAA significantly decreased IHCL compared with HFr (to 2.30 ± 0.43 vol%; P < 0.05) but did not change VLDL-triglyceride concentrations or VLDL-[(13)C]palmitate production. CONCLUSIONS: Supplementation with essential amino acids blunts the fructose-induced increase in IHCL but not hypertriglyceridemia. This is not because of inhibition of VLDL-[(13)C]palmitate production. This trial was registered at www.clinicaltrials.gov as NCT01119989.
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SUMMARYIn order to increase drug safety we must better understand how medication interacts with the body of our patients and this knowledge should be made easily available for the clinicians prescribing the medication. This thesis contributes to how the knowledge of some drug properties can increase and how to make information readily accessible for the medical professionals. Furthermore it investigates the use of Therapeutic drug monitoring, drug interaction databases and pharmacogenetic tests in pharmacovigilance.Two pharmacogenetic studies in the naturalistic setting of psychiatric in-patients clinics have been performed; one with the antidepressant mirtazapine, the other with the antipsychotic clozapine. Forty-five depressed patients have been treated with mirtazapine and were followed for 8 weeks. The therapeutic effect was as seen in other previous studies. Enantioselective analyses could confirm an influence of age, gender and smoking in the pharmacokinetics of mirtazapine; it showed a significant influence of the CYP2D6 genotype on the antidepressant effective S-enantiomer, and for the first time an influence of the CYP2B6 genotype on the plasma concentrations of the 8-OH metabolite was found. The CYP2B6*/*6 genotype was associated to better treatment response. A detailed hypothesis of the metabolic pathways of mirtazapine is proposed. In the second pharmacogenetic study, analyses of 75 schizophrenic patients treated with clozapine showed the influence of CYP450 and ABCB1 genotypes on its pharmacokinetics. For the first time we could demonstrate an in vivo effect of the CYP2C19 genotype and an influence of P-glycoprotein on the plasma concentrations of clozapine. Further we confirmed in vivo the prominent role of CYP1A2 in the metabolism of clozapine.Identifying risk factors for the occurrence of serious adverse drug reactions (SADR) would allow a more individualized and safer drug therapy. SADR are rare events and therefore difficult to study. We tested the feasibility of a nested matched case-control study to examine the influence of high drug plasma levels and CYP2D6 genotypes on the risk to experience an SADR. In our sample we compared 62 SADR cases with 82 controls; both groups were psychiatric patients from the in-patient clinic Königsfelden. Drug plasma levels of >120% of the upper recommended references could be identified as a risk factor with a statistically significant odds ratio of 3.5, a similar trend could be seen for CYP2D6 poor metaboliser. Although a matched case-control design seems a valid method, 100% matching is not easy to perform in a relative small cohort of one in-patient clinic. However, a nested case-control study is feasible.On the base of the experience gained in the AMSP+ study and the fact that we have today only sparse data indicating that routine drug plasma concentration monitoring and/or pharmacogenetic testing in psychiatry are justified to minimize the risk for ADR, we developed a test algorithm named "TDM plus" (TDM plus interaction checks plus pharmacogenetic testing).Pharmacovigilance programs such as the AMSP project (AMSP = Arzneimittelsicherheit in der Psychiatrie) survey psychiatric in-patients in order to collect SADR and to detect new safety signals. Case reports of such SADR are, although anecdotal, valuable to illustrate rare clinical events and sometimes confirm theoretical assumptions of e.g. drug interactions. Seven pharmacovigilance case reports are summarized in this thesis.To provide clinicians with meaningful information on the risk of drug combinations, during the course of this thesis the internet based drug interaction program mediQ.ch (in German) has been developed. Risk estimation is based on published clinical and pharmacological information of single drugs and alimentary products, including adverse drug reaction profiles. Information on risk factors such as renal and hepatic insufficiency and specific genotypes are given. More than 20'000 drug pairs have been described in detail. Over 2000 substances with their metabolic and transport pathways are included and all information is referenced with links to the published scientific literature or other information sources. Medical professionals of more than 100 hospitals and 300 individual practitioners do consult mediQ.ch regularly. Validations with comparisons to other drug interaction programs show good results.Finally, therapeutic drug monitoring, drug interaction programs and pharmacogenetic tests are helpful tools in pharmacovigilance and should, in absence of sufficient routine tests supporting data, be used as proposed in our TDM plus algorithm.RESUMEPour améliorer la sécurité d'emploi des médicaments il est important de mieux comprendre leurs interactions dans le corps des patients. Ensuite le clinicien qui prescrit une pharmacothérapie doit avoir un accès simple à ces informations. Entre autres, cette thèse contribue à mieux connaître les caractéristiques pharmacocinétiques de deux médicaments. Elle examine aussi l'utilisation de trois outils en pharmacovigilance : le monitorage thérapeutique des taux plasmatiques des médicaments (« therapeutic drug monitoring »), un programme informatisé d'estimation du risque de combinaisons médicamenteuses, et enfin des tests pharmacogénétiques.Deux études cliniques pharmacogénétiques ont été conduites dans le cadre habituel de clinique psychiatrique : l'une avec la mirtazapine (antidépresseur), l'autre avec la clozapine (antipsychotique). On a traité 45 patients dépressifs avec de la mirtazapine pendant 8 semaines. L'effet thérapeutique était semblable à celui des études précédentes. Nous avons confirmé l'influence de l'âge et du sexe sur la pharmacocinétique de la mirtazapine et la différence dans les concentrations plasmatiques entre fumeurs et non-fumeurs. Au moyen d'analyses énantiomères sélectives, nous avons pu montrer une influence significative du génotype CYP2D6 sur l'énantiomère S+, principalement responsable de l'effet antidépresseur. Pour la première fois, nous avons trouvé une influence du génotype CYP2B6 sur les taux plasmatiques de la 8-OH-mirtazapine. Par ailleurs, le génotype CYP2B6*6/*6 était associé à une meilleure réponse thérapeutique. Une hypothèse sur les voies métaboliques détaillées de la mirtazapine est proposée. Dans la deuxième étude, 75 patients schizophrènes traités avec de la clozapine ont été examinés pour étudier l'influence des génotypes des iso-enzymes CYP450 et de la protéine de transport ABCB1 sur la pharmacocinétique de cet antipsychotique. Pour la première fois, on a montré in vivo un effet des génotypes CYP2C19 et ABCB1 sur les taux plasmatiques de la clozapine. L'importance du CYP1A2 dans le métabolisme de la clozapine a été confirmée.L'identification de facteurs de risques dans la survenue d'effets secondaire graves permettrait une thérapie plus individualisée et plus sûre. Les effets secondaires graves sont rares. Dans une étude de faisabilité (« nested matched case-control design » = étude avec appariement) nous avons comparé des patients avec effets secondaires graves à des patients-contrôles prenant le même type de médicaments mais sans effets secondaires graves. Des taux plasmatiques supérieurs à 120% de la valeur de référence haute sont associés à un risque avec « odds ratio » significatif de 3.5. Une tendance similaire est apparue pour le génotype du CYP2D6. Le « nested matched case-control design » semble une méthode valide qui présente cependant une difficulté : trouver des patients-contrôles dans le cadre d'une seule clinique psychiatrique. Par contre la conduite d'une « nested case-control study » sans appariement est recommandable.Sur la base de notre expérience de l'étude AMSP+ et le fait que nous disposons que de peux de données justifiant des monitorings de taux plasmatiques et/ou de tests pharmacogénétiques de routine, nous avons développé un test algorithme nommé « TDMplus » (TDM + vérification d'interactions médicamenteuses + tests pharmacogénétique).Des programmes de pharmacovigilances comme celui de l'AMSP (Arzneimittelsicherheit in der Psychiatrie = pharmacovigilance en psychiatrie) collectent les effets secondaires graves chez les patients psychiatriques hospitalisés pour identifier des signaux d'alertes. La publication de certains de ces cas même anecdotiques est précieuse. Elle décrit des événements rares et quelques fois une hypothèse sur le potentiel d'une interaction médicamenteuse peut ainsi être confirmée. Sept publications de cas sont résumées ici.Dans le cadre de cette thèse, on a développé un programme informatisé sur internet (en allemand) - mediQ.ch - pour estimer le potentiel de risques d'une interaction médicamenteuse afin d'offrir en ligne ces informations utiles aux cliniciens. Les estimations de risques sont fondées sur des informations cliniques (y compris les profils d'effets secondaires) et pharmacologiques pour chaque médicament ou substance combinés. Le programme donne aussi des informations sur les facteurs de risques comme l'insuffisance rénale et hépatique et certains génotypes. Actuellement il décrit en détail les interactions potentielles de plus de 20'000 paires de médicaments, et celles de 2000 substances actives avec leurs voies de métabolisation et de transport. Chaque information mentionne sa source d'origine; un lien hypertexte permet d'y accéder. Le programme mediQ.ch est régulièrement consulté par les cliniciens de 100 hôpitaux et par 300 praticiens indépendants. Les premières validations et comparaisons avec d'autres programmes sur les interactions médicamenteuses montrent de bons résultats.En conclusion : le monitorage thérapeutique des médicaments, les programmes informatisés contenant l'information sur le potentiel d'interaction médicamenteuse et les tests pharmacogénétiques sont de précieux outils en pharmacovigilance. Nous proposons de les utiliser en respectant l'algorithme « TDM plus » que nous avons développé.
Resumo:
La manifestation est sans doute la forme la plus commune d'expression politique, tant dans les pays démocratiques, où sa légitimité le dispute avec plus ou moins de bonheur aux formes plus conventionnelles de participation comme le vote, que dans les pays non démocratiques, où elle accompagne les tentatives de révolte et de renversement.Dans cet ouvrage de synthèse, les auteurs proposent une analyse sociologique et historique de ce mode d'action politique, avec ses normes et ses règles, ses légendes et ses mythes, ses épisodes glorieux et ses heures sombres.Mais surtout, au-delà de l'interrogation classique sur la place de la manifestation dans le répertoire d'action contemporain et dans les luttes politiques, c'est aussi à une analyse au plus près des manifestants eux-mêmes et de «ce qui les fait courir» que cet ouvrage nous invite.
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Food allergy can result in considerable morbidity, impact negatively on quality of life, and prove costly in terms of medical care. These guidelines have been prepared by the European Academy of Allergy and Clinical Immunology's (EAACI) Guidelines for Food Allergy and Anaphylaxis Group, building on previous EAACI position papers on adverse reaction to foods and three recent systematic reviews on the epidemiology, diagnosis, and management of food allergy, and provide evidence-based recommendations for the diagnosis and management of food allergy. While the primary audience is allergists, this document is relevant for all other healthcare professionals, including primary care physicians, and pediatric and adult specialists, dieticians, pharmacists and paramedics. Our current understanding of the manifestations of food allergy, the role of diagnostic tests, and the effective management of patients of all ages with food allergy is presented. The acute management of non-life-threatening reactions is covered in these guidelines, but for guidance on the emergency management of anaphylaxis, readers are referred to the related EAACI Anaphylaxis Guidelines.
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Historical references to the emergence of the current concept of ADHD typically cite descriptions from medical textbooks by Weikard (1775) and Crichton (An inquiry into the nature and origin of mental derangement: Comprehending a concise system of the physiology and pathology of the human mind and a history of the passion and their affects. Cardell Jr and Davies, Londres, 1798) on attention disorders, poems of Hoffman on hyperactive and impulsive behaviors (Der Struwwelpeter. Frankfurt am Main, Literarische Anstalt, 1843), as well as the work of Still (Lancet 1:1008-1012, 1077-1082, 1163-1168, 1902a, Lancet 159(4102):1008-1013, 1902b, Lancet 159(4103):1077-1082, 1902c, Lancet 159(4104):1163-1168, 1902d) on impulsive behaviors and defective moral regulation of behavior. The notion of "instability" developed by French physicians between 1887 and 1910 is rarely mentioned and often ignored. Writings from this period show that in France, the emergence of the concept of ADHD according to modern terminology comes from the notion of "mental instability" introduced in the 1890s under the leadership of Désiré-Magloire Bourneville at the Hospital Bicêtre in Paris, based on his observations of children and adolescents who had been labeled "abnormal" and placed in medical and educational institutions. In the early twentieth century, elaborating on the observations of Bourneville, Jean Phillipe and Georges Paul-Boncour showed the presence of a subgroup of "unstable" children who suffered from a disease entity in its own right within the population of "abnormal" schoolchildren (the terminology of the time). This new pathological entity included symptoms of hyperactivity, impulsivity and inattention, corresponding to today's classic triad of ADHD symptoms. While noting the lack of behavioral inhibition, clinical descriptions of Bourneville, Philip and Paul-Boncour also considered the notion of "moral disorder" which at that time played an important role in psychopathology. This resulted in some degree of confusion between impulsive symptoms and major behavioral disturbances often associated with ADHD.
Resumo:
Mutations of the TP53 and Ki-ras genes have been reported to be of prognostic importance in colorectal carcinomas. An increased intracellular concentration of the p53 protein, although not identical to, is sometimes seen in tumours with TP53 mutation and has been correlated with poor prognosis in some tumour types. Previous colorectal cancer studies, addressing the prognostic importance of Ki-ras mutation and TP53 aberrations, yielded contradictory results. The aim of this study was to determine in a clinically and therapeutically homogeneous group of 122 sporadic Dukes' B colorectal carcinomas with a median follow-up of 67 months (3-144 months) whether or not p53 protein expression, TP53 mutation and K-ras mutation correlated with prognosis. p53 staining was performed by immunohistochemistry, using the monoclonal antibody DO7 on paraffin-embedded tissue. Mutations in exons 5-8 of the TP53 gene and in codons 12 and 13 of the K-ras gene were assayed in paraffin-embedded tissue by the single-strand conformation polymorphism (SSCP) assay. Nuclear p53 staining was found in 57 (47%) tumours. Aberrant migration patterns indicating mutation of the TP53 gene were found in 39 (32%) tumours. Forty-six carcinomas (38%) showed a mutation of the Ki-ras codons 12 or 13. In a univariate analysis, patients with wild-type TP53 status showed a trend towards better survival, compared with those with mutated TP53 (log-rank test, P = 0.051). Likewise, tumours immunohistochemically positive for p53 showed a worse prognosis than p53-negative tumours (P = 0.010). The presence or absence of mutations in Ki-ras did not correlate with prognosis (P = 0.703). In multivariate analysis, only p53 immunoreactivity emerged as an independent marker for prognosis hazard ratio (HR) = 2.16, 95% confidence interval (CI) 1.12-4.11, P = 0.02). Assessment of p53 protein expression is more discriminative than TP53 mutation to predict the outcome of Dukes' stage B tumours and could be a useful tool to identify patients who might benefit from adjuvant therapy.
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Portal vein embolization (PVE) has been developed to increase the size of the future remnant liver (FRL) left in place after major hepatectomy, thus reducing the risk of postoperative liver insufficiency. PVE consist in embolizing preoperatively portal branches of the segments that will be resected. Indication is based on preoperative measurements of the FRL by computed tomography and its ratio with either the theoretical liver volume or by direct measurement of the functional liver volume. After PVE, the volume and function of the FRL increases in 3 to 6 weeks, permitting extensive resections in patients otherwise contraindicated for liver resection. The PVE technique is variable from one center to another; however n-butyl-cyano-acrylate provides an interesting compromise between hypertrophy rate and procedure risk.
Resumo:
A simple and sensitive LC-MS method was developed and validated for the simultaneous quantification of aripiprazole (ARI), atomoxetine (ATO), duloxetine (DUL), clozapine (CLO), olanzapine (OLA), sertindole (STN), venlafaxine (VEN) and their active metabolites dehydroaripiprazole (DARI), norclozapine (NCLO), dehydrosertindole (DSTN) and O-desmethylvenlafaxine (OVEN) in human plasma. The above mentioned compounds and the internal standard (remoxipride) were extracted from 0.5 mL plasma by solid-phase extraction (mix mode support). The analytical separation was carried out on a reverse phase liquid chromatography at basic pH (pH 8.1) in gradient mode. All analytes were monitored by MS detection in the single ion monitoring mode and the method was validated covering the corresponding therapeutic range: 2-200 ng/mL for DUL, OLA, and STN, 4-200 ng/mL for DSTN, 5-1000 ng/mL for ARI, DARI and finally 2-1000 ng/mL for ATO, CLO, NCLO, VEN, OVEN. For all investigated compounds, good performance in terms of recoveries, selectivity, stability, repeatability, intermediate precision, trueness and accuracy, was obtained. Real patient plasma samples were then successfully analysed.
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In terrestrial snakes, many cases of intraspecific shifts in dietary habits as a function of predator sex and body size are driven by gape-limitation - and hence, are most common in species that feed on relatively large prey, and exhibit a wide body-size range. Our data on seasnakes reveal an alternative mechanism for intraspecific niche partitioning, based on sex-specific seasonal anorexia induced by reproductive activities. Turtle-headed seasnakes (Emydocephalus annulatus) on coral reefs in the New Caledonian Lagoon feed entirely on the eggs of demersal-spawning fishes. DNA sequence data (cytochrome b gene) on eggs that we palpated from stomachs of 37 snakes showed that despite this ontogenetic-stage specialization, the prey come from a taxonomically diverse array of species including damselfish (41% of samples, at least 5 species), blennies (41%, 4 species) and gobies (19%, 5 species). The composition of snake diets shifted seasonally (with damselfish dominating in winter but not summer), presumably reflecting seasonality of fish reproduction. That seasonal shift affects male and female snakes differently, because reproduction is incompatible with foraging. Adult female seasnakes ceased feeding when they became heavily distended with developing embryos in late summer, and males ceased feeding while they were mate-searching in winter. The sex divergence in foraging habits may be amplified by sexual size dimorphism; females grow larger than males, and larger snakes (of both sexes) feed more on damselfish (which often lay their eggs in exposed sites) than on blennies and gobies (whose eggs are hidden within narrow crevices). Specific features of reproductive biology of coral-reef fish (seasonality and nest type) have generated intraspecific niche partitioning in these seasnakes, by mechanisms different from those that apply to terrestrial snakes.