A Prospective, Dual-Center Trial of Circumferential Radiofrequency Ablation of Anal High-Grade Squamous Intraepithelial Lesions Demonstrate Improved Long-term Efficacy Over Historical Controls of Targeted Ablation.

BACKGROUND: Targeted ablation of anal canal high-grade dysplasia results in high recurrence over time. Circumferential radiofrequency ablation might decrease recurrence. OBJECTIVE: This study aimed to determine the safety and efficacy of circumferential radiofrequency ablation for anal high-grade dysplasia. DESIGN: This was a dual-center, prospective trial of circumferential radiofrequency ablation with a 1-year follow-up with longer follow-up data abstracted from medical records of study patients returning after trial for surveillance. Ten participants from the identically conducted pilot circumferential radiofrequency ablation trial were included to improve sample size for longer-term analysis. SETTINGS: This study included 3 surgeons at 2 sites. PATIENTS: The study included 51 patients undergoing circumferential radiofrequency ablation for anal canal high-grade dysplasia. INTERVENTION: Circumferential radiofrequency ablation of anal canal high-grade dysplasia and targeted radiofrequency ablation of recurrence. MAIN OUTCOME MEASURES: The primary outcome measures were circumferential radiofrequency ablation efficacy and associated morbidity. RESULTS: Fifty-one participants underwent circumferential radiofrequency ablation but 48 participants returned for 1 or more postprocedure high-resolution anoscopy and were evaluable. The mean age of participants was 43 years, most were male (94%), 33% were living with HIV, and 58% had 3 or more high-grade dysplasias treated. Sixty percent had no recurrence, whereas 19% had 1 recurrence, 15% had 2 recurrences, and 6% had 3 recurrences. Most recurrences (66%) developed within the first 6 months. Kaplan-Meier probability of recurrence combining both series was 19% at 3 months, 30% at 6 months, and approximately 40% after 6 months out to 30 months. Most common morbidities were pain (85.4%) lasting for a median of 21 (range, 4-91) days and bleeding (91%) lasting for a median of 21 (range, 5-87) days. Of those with pain and bleeding, 65% and 85%, respectively, described it as mild. No patients developed fistulas, stricture, or incontinence. No serious adverse events related to circumferential radiofrequency ablation occurred. Having a previous recurrence was the only significant predictor of a subsequent recurrence (HR, 28.53) for recurrence at 9 months or before. LIMITATIONS: Enrollment ended prematurely, 10 participants from the pilot study were combined to increase the sample size, and longer-term follow-up was collected retrospectively were the limitations of this study. CONCLUSIONS: Circumferential radiofrequency ablation has improved efficacy over targeted ablation but with increased pain and bleeding. See Video Abstract at http://links.lww.com/DCR/B973 . ESTUDIO PROSPECTIVO BICNTRICO SOBRE LA ABLACIN POR RADIOFRECUENCIA CIRCUNFERENCIAL DE LESIONES ANALES INTRAEPITELIALES ESCAMOSAS DE ALTO GRADO DEMOSTRANDO MAYOR EFICACIA A LARGO PLAZO CON RELACIN A CONTROLES HISTRICOS DE ABLACIN DIRIGIDA: ANTECEDENTES:La ablación dirigida de la displasia de alto grado en el canal anal proporciona como resultados una alta recidiva a largo plazo. La ablación por radiofrecuencia circunferencial podría disminuir la reincidencia.OBJETIVO:Determinar la seguridad y eficacia de la ablación por radiofrecuencia circunferencial para la displasia anal de alto grado.DISEÑO:Estudio prospectivo bicéntrico de ablación por radiofrecuencia circunferencial con un seguimiento de 1 año, en base al monitoreo prolongado de datos, obtenidos de los registros medicos, de todos los pacientes incluidos en el estudio y que fueron controlados clinicamente. Diez participantes del estudio piloto de ablación por radiofrecuencia circunferencial realizada de manera idéntica, se combinaron para mejorar el análisis del tamaño de la muestra a largo plazo.PACIENTES:Se incluyeron 51 pacientes sometidos a la ablación por radiofrecuencia circunferencial de una lesion displásica de alto grado en el canal anal.AJUSTES:Tres cirujanos en 2 centros.INTERVENCIÓN:Ablación por radiofrecuencia circunferencial de la displasia de alto grado en el canal anal y ablación por radiofrecuencia dirigida de la recidiva.PRINCIPALES MEDIDAS DE RESULTADOS:Las medidas primarias fueron la eficacia de la ablación por radiofrecuencia circunferencial y la morbilidad asociada.RESULTADOS:Cincuenta y un participantes se sometieron a la ablación por radiofrecuencia circunferencial, de los cuales, 48 regresaron para ser evaluados con ≥1 anuscopias de alta resolución, después del procedimiento. La edad media de los participantes fue de 43 años, en su mayoría hombres (94%), el 33% eran portadores de VIH y el 58% tenía ≥3 lesiones displásicas de alto grado tratadas. El sesenta por ciento no tuvo recidiva, mientras que el 19%, 15% y 6% tuvieron 1, 2 o 3 recidivas. La mayoría de las recaídas (66%) se desarrollaron dentro de los primeros 6 meses. La probabilidad de recurrencia de Kaplan-Meier combinando ambas series fue del 19 % a los 3 meses, del 30 % a los 6 meses y aproximadamente del 40 % entre los 6 y 30 meses. Los indicadores de morbilidad más frecuentes fueron, el dolor (85,4%) con una mediana de duración de 21 días (rango, 4-91) y sangrado (91%) con una mediana de duración de 21días (rango, 5-87). Aquellos pacientes con dolor (65%) y sangrado (85%) respectivamente, los describieron como leves. Ningún paciente desarrolló fístula, estenosis o incontinencia. No se produjeron eventos adversos graves relacionados con la ablación por radiofrecuencia circunferencial. Tener una recurrencia previa fue el único factor predictivo importante de una recidiva ulterior (RH 28,53) en casos de recaída a los 9 meses o antes.LIMITACIONES:Como el registro finalizó prematuramente, se agregaron 10 participantes del estudio piloto para aumentar el tamaño de la muestra. El seguimiento a largo plazo fué recopilado retrospectivamente.CONCLUSIONES:La ablación por radiofrecuencia circunferencial ha mejorado la eficacia sobre la ablación dirigida pero con dolor y sangrado mas importantes. Consulte Video Resumen en http://links.lww.com/DCR/B973 . ( Traducción-Dr. Xavier Delgadillo ).

New data on Propyrotherium (Mammalia, Pyrotheria) from the middle Eocene age (Chubut, Argentina): anatomy, age constraints, and phylogeny.

Pyrotheria is one of the most peculiar orders of South American native ungulates, whose members evolved from the early? Eocene to the late Oligocene period when they became extinct. Here, we described the most complete specimen of Propyrotherium saxeum ever found, one of the lesser-known representatives of pyrotheres that characterized the middle-late Eocene period of Patagonia (Argentina). It includes a nearly complete mandible and a tusk-like tooth of the same individual, as well as other isolated upper and lower teeth. Propyrotherium saxeum has a dental formula that includes at least P2-M3 and i2?-p3-m3 (lack of p2). It is characterized by some peculiar features of the mandible (e.g., ascending ramus longer than high, hiding the m3 and straight incisura mandibular) and dentition (e.g., cristid obliqua in p3-m3, cristid between posterior lophid and distal cingulid in m1-m3, P3-M3 and p3-m3 bilophodont, P2 and p3-m3 bi-rooted, P3-M3 three-rooted, paraconid in p3). The phylogenetic analysis reveals that Propyrotherium is more closely related to Pyrotherium and Baguatherium, differing from the previous hypothesis, and supports the monophyly of Pyrotheriidae including Carolozittelia, Griphodon, Pyrotherium, Baguatherium, and Propyrotherium. The absolute age obtained through U-Pb zircon dating of the Sarmiento Formation at Cañadón Pelado, the fossil's original locality, indicates that the fossil-bearing tuff would have been deposited between 39.65 and 40.41 Ma, with a weighted mean age of 40.03 ± 0.38 Ma (Bartonian). This implies a biochron much longer than previously thought for Propyrotherium and provides a chronological framework for the fauna of Cañadón Pelado.

Paleobiological inferences on middle Eocene native ungulates from South America: Functional morphological analysis of Notostylops and Notopithecus.

Eocene early-diverging representatives of South American extinct notungulates are traditionally considered to have been "generalists" and "non-specialized" in terms of the appendicular skeleton and locomotor behavior, as is the case with the notostylopid Notostylops, a middle Eocene iconic taxon from Patagonia (Argentina). However, they are mainly known from dental remains, and associated cranial and postcranial elements are scarce. The discovery of a nearly complete specimen attributed to N. murinus allows us to: (1) increase the knowledge of the anatomy of its appendicular skeleton; (2) identify isolated bones from several collections and suggest different taxonomic interpretations for published specimens; (3) perform a biomechanical and functional study using functional morphological analysis to infer its paleoecological attributes (e.g. posture, locomotor habit, estimated speed, and body mass); and (4) establish morphofunctional comparisons, based on possible functional ranges, with other extinct early-diverging notoungulates from the middle Eocene, such as the Notopithecid Notopithecus. Our evidence suggests that Notostylops was a medium-sized mammal (8.5-20 kg), which could achieve a dynamic digitigrade posture that allowed a scansorial secondary locomotor habit and a speed of up to 50 km/h. However, Notopithecus was a small-sized mammal (0.6-1.4 kg) with a plantigrade posture both in a static and dynamic context, terrestrial habits, and a speed of up to 35 km/h. Therefore, we conclude that these Eocene notoungulates show different locomotor capabilities, which can be associated with early niche diversifications, clearly contrasting with the "all-generalists" paradigmatic view.

MDR-1 function protects oocyte mitochondria against the transgenerational effects of nitrogen mustard exposure.

Oocytes are vulnerable to alkylating agents like nitrogen mustard (NM), which can cause mitochondrial dysfunction associated with increased oxidative stress. Because mitochondria are maternally inherited, NM exposure affects oocyte mitochondrial physiology and compromises future progeny. Multidrug resistance transporters (MDRs) are transmembrane proteins that efflux such cytotoxic substances; MDR-1 is expressed in oocyte plasma and mitochondrial membranes and protects against oxidative stress. Our objective was to investigate how loss of MDR-1 can modulate oocyte response to NM transgenerationally. Wild Type (WT) and Mdr1a mutant female mice were injected intraperitoneally with sterile saline (control) or 0.1 mg/kg NM. 48 h post-injection, females were either sacrificed for F0 studies or mated with control males to yield F1 pups. After weaning, F1 females were sacrificed or mated to yield F2 pups. Germinal vesicle oocytes were assessed for mitochondrial membrane potential and reactive oxygen species (ROS) levels. NM exposed oocytes of both genotypes exhibited significantly higher ROS than controls in F0 and F1. NM F2 oocytes of neither genotype exhibited significantly higher ROS, though variation in Mdr1a mutants led to an upward trend. NM oocytes of both genotypes exhibited significantly disrupted mitochondrial membrane potential in F0. WT regained normalcy by F1 whereas Mdr1a mutants were unable to by F2. Our data suggest that Mdr1a mutants exhibit transgenerational mitochondrial dysfunction following toxic challenge that persists, implying that MDR-1 protects against toxicant-induced mitochondrial stress. Women without functional MDR-1 exposed to environmental toxicants could therefore be at risk for passing on compromised mitochondria to future offspring.

Parasites in stranded cetaceans of Patagonia.

There is an increasing interest in parasites of marine mammals of Argentina. Here, we examined several poorly known cetaceans, i.e., 2 spectacled porpoises and 1 Burmeister's porpoise (Phocoenidae), and 1 Gray's beaked whale and 1 Cuvier's beaked whale (Ziphidae); we also updated the parasite information for 1 sperm whale (Physeteridae). These hosts strand only occasionally. We found Anisakis simplex s.l. in 2 spectacled porpoises and the Burmeister's porpoise, and recorded its distribution among the stomach chambers. Anisakis physeteris infected the sperm whale; Corynosoma cetaceum occurred in the duodenal ampulla of the Burmeister's porpoise; Corynosoma australe was found in the posterior-most region of the intestine of 1 spectacled porpoise, while another one had Tetrabothrius sp. in the anal crypts; Corynosoma bullosum and Corynosoma sp. were found in the sperm whale. The only digenean found was Pholeter gastrophilus in the Burmeister's porpoise. Merocercoids of Phyllobothrium delphini were present in the blubber of 1 spectacled porpoise, the sperm whale, and the Gray's beaked whale, while Scolex pleuronectis infected the Gray's beaked whale and 1 spectacled porpoise. No parasites were recovered from the Cuvier's beaked whale. Poor parasite-species assemblages are consistent in marine mammals of Patagonia. Given the conservation status of these hosts, the limited parasitological information gathered is valuable for conservation or management of these hosts in Patagonia.

Geometric morphometric analysis as a proxy to evaluate age-related change in molar shape variation of low-crowned Notoungulata (Mammalia).

Shape and age variation in dentition of Paleogene extinct native South American ungulates (Notoungulata) has been traditionally described using qualitative and quantitative approaches, and has played a controversial role in the systematics of several groups. Such is the case of the Notopithecidae, a group of notoungulates with low-crowned teeth, known from the middle Eocene of Patagonia (Argentina). In this group, as well as in other contemporary families, extreme morphological changes associated to increasing dental wear were originally assumed to represent taxonomic differences; thus, dozens of species were erected, clearly reflecting the difficulty of defining discrete characters. In this contribution, a total of 89 upper molars and 91 lower molars were analyzed distributed in two factors, wear and species; three species of notopithecids were considered as study case, Notopithecus adapinus, Antepithecus brachystephanus, and Transpithecus obtentus, based on the large and well-identified sample of upper and lower molars for each species. We have coupled geometric morphometric analyses with traditional comparative methods to get a better understanding and interpretation of both the changes in tooth shape contour and the link between shape and ontogeny. In addition, we evaluate the utility of this approach to identify which changes are strictly wear-related and also test the qualitative characteristics used for diagnosing and differentiating notopithecid species. Our study yielded consistent results when applying independent geometric morphometric analyses on complex structures such as brachydont molar teeth. The landmark data is highly congruent with alternative sources of evidence, such as morphological studies using discrete characters. In notopithecid species, wear is the main factor affecting molar shape, followed by species (in lower molars) and allometry; in addition, lower teeth morphology is more definitive in separating species than upper molars, a fact that entails a key point for systematic studies of Paleogene brachydont notoungulates.

Parasite communities of common dolphins (Delphinus delphis) from Patagonia: the relation with host distribution and diet and comparison with sympatric hosts.

We studied the helminths of 18 common dolphins, Delphinus delphis, from northern Patagonia. Parasites were found only in the gastrointestinal tract. Four species were in the stomach, the nematode Anisakis simplex, the acanthocephalan Corynosoma cetaceum, and the digeneans Braunina cordiformis and Pholeter gastrophilus, plus 1 digenean in the hepatopancreatic ducts, Oschmarinella rochebruni. Infection levels were low (0-155 parasites). Braunina cordiformis and C. cetaceum were the most prevalent species. Anisakis simplex was mainly concentrated in the forestomach, B. cordiformis in the main stomach, and C. cetaceum in the pyloric stomach. Component diversity was low and component evenness was intermediate. Infracommunity diversity was also low, and the mean evenness was higher than at the component community level. Low prevalence in common dolphins is consistent with parasite assemblages of other cetaceans off Patagonia. None of the parasites found is specific to this host species within the study area. We suggest that potential prey are probably important in parasite transmission in this and other dolphins from the Patagonian region.

Description of a New Temnocephala Species (Platyhelminthes) from the Southern Neotropical Region.

The genus Temnocephala is endemic to the Neotropical region. Temnocephala mexicana and Temnocephala chilensis are the only 2 temnocephalans whose known distribution ranges extend to the south beyond Parallel 40°S. No Temnocephala species has ever been recorded from the extensive area between Parallel 43°S and the southern end of the South American continent, which makes the study of the southern limit of the distribution of the genus a topic of great interest. The southernmost report corresponds to T. chilensis from the Telsen River, Chubut Province, Argentina. In March 2000, several temnocephalans were found on the freshwater anomuran crustacean Aegla neuquensis from the same locality; the specimens were identified as belonging to a new species, which is described here. This species is characterized by possessing an unusually thin-walled, narrow zone that has the appearance of a deep groove connecting the introvert to the shaft of the penial stylet; an introvert with 36 longitudinal rows of spines, each bearing 6-8 spines that are progressively smaller towards the distal end; a distal end of the introvert with a very thin, sclerotized wall without spines; a seminal vesicle that opens sub-polarly into the contractile vesicle; a pair of paranephrocytes at the level of the pharynx and a second pair at the level of the anterior portion of the anterior testes, and eggs with very long stalks. On the basis of their overall morphology, host preference, and geographical distribution, T. chilensis and the new species are closely related, so a diagnostic key for the southern species of Temnocephala is also included. The type locality of the new species is in the southern limit of the known distribution area of T. chilensis, so after this work there are 2 known species marking the southern limit of the distribution of the genus.

Uterine adenocarcinoma with generalised metastasis in a bottlenose dolphin Tursiops truncatus from northern Patagonia, Argentina.

An endometrial adenocarcinoma with areas of squamous differentiation and generalised metastasis was observed in a bottlenose dolphin Tursiops truncatus stranded in northern Patagonia in July 1997. This is the second report of a uterine adenocarcinoma in a free-living cetacean and the first in a Delphinidae. This neoplasm likely compromised reproduction for several years. In addition, the dolphin presented tattoo-like skin lesions and its digestive tract was infested by Anisakis simplex, Pseudoterranova sp., Braunina cordiformis and Corynosoma australe.

Molecular systematics of pinniped hookworms (Nematoda: Uncinaria): species delimitation, host associations and host-induced morphometric variation.

Hookworms of the genus Uncinaria have been widely reported from juvenile pinnipeds, however investigations of their systematics has been limited, with only two species described, Uncinaria lucasi from northern fur seals (Callorhinus ursinus) and Uncinaria hamiltoni from South American sea lions (Otaria flavescens). Hookworms were sampled from these hosts and seven additional species including Steller sea lions (Eumetopias jubatus), California sea lions (Zalophus californianus), South American fur seals (Arctocephalus australis), Australian fur seals (Arctocephalus pusillus), New Zealand sea lions (Phocarctos hookeri), southern elephant seals (Mirounga leonina), and the Mediterranean monk seal (Monachus monachus). One hundred and thirteen individual hookworms, including an outgroup species, were sequenced for four genes representing two loci (nuclear ribosomal DNA and mitochondrial DNA). Phylogenetic analyses of these sequences recovered seven independent evolutionary lineages or species, including the described species and five undescribed species. The molecular evidence shows that U. lucasi parasitises both C. ursinus and E. jubatus, whereas U. hamiltoni parasitises O. flavescens and A. australis. The five undescribed hookworm species were each associated with single host species (Z. californianus, A. pusillus, P. hookeri, M. leonina and M. monachus). For parasites of otarids, patterns of Uncinaria host-sharing and phylogenetic relationships had a strong biogeographic component with separate clades of parasites from northern versus southern hemisphere hosts. Comparison of phylogenies for these hookworms and their hosts suggests that the association of U. lucasi with northern fur seals results from a host-switch from Steller sea lions. Morphometric data for U. lucasi shows marked host-associated size differences for both sexes, with U. lucasi individuals from E. jubatus significantly larger. This result suggests that adult growth of U. lucasi is reduced within the host species representing the more recent host-parasite association. Intraspecific host-induced size differences are inconsistent with the exclusive use of morphometrics to delimit and diagnose species of Uncinaria from pinnipeds.

Cestodes from Hector's beaked whale ( Mesoplodon hectori ) and spectacled porpoise ( Phocoena dioptrica ) from Argentinean waters.

Single individuals of 2 little-known cetacean species, Mesoplodon hectori and Phocoena dioptrica , stranded and died on the coast of Argentina (Buenos Aires and Chubut provinces, respectively) and were studied for the presence of helminths. The cestodes found were described and illustrated using light microscopy. The following cestode taxa were recovered: Tetrabothrius ( Tetrabothrius ) hobergi n. sp. (several fragmented specimens, at least 1 gravid) and Tetrabothrius ( s.l. ) sp. 1 (several fragmented immature specimens) from M. hectori , and Tetrabothrius ( s.l. ) sp. 2 (single fragmented immature specimen) and 2 morphotypes of tetraphyllidean larvae from P. dioptrica. Tetrabothrius ( T. ) hobergi n. sp. can be distinguished from Tetrabothrius ( T. ) forsteri by the greater number of testes and larger eggs and oncospheres, from Tetrabothrius ( T. ) curilensis by the smaller testes and vitellarium, the shape and size of the ovary, and the larger oncospheres and longer embryonic hooks, and from Tetrabothrius ( T. ) sp. from Ziphius cavirostris by the narrower strobila, smaller scolex, and smaller number of testes. The generic designations of Tetrabothrius ( s.l. ) sp. 1 and Tetrabothrius ( s.l. ) sp. 2 were based on the scolex morphology. Tetrabothrius ( s.l. ) sp. 1 is closest to Tetrabothrius ( T. ) forsteri and Tetrabothrius ( Biamniculus ) innominatus based on the number of testes, while the scolex size of Tetrabothrius ( Tetrabothrius ) sp. 2 is within the variability range reported for Tetrabothrius ( T. ) forsteri . More definite identification of the 2 species was not possible due to the condition of the available material. The present study provides the first descriptions of cestodes from M. hectori and P. dioptrica , thus enriching the knowledge regarding the helminths of insufficiently studied marine mammals.