Epidemic disease risks and implications for Veterinary Services.

Growth in the livestock sector is associated with heightened risk for epidemic diseases. The increasing spillover of new diseases from wildlife is being driven by wide-scale anthropogenic changes allowing for more frequent and closer wildlife-human and wildlife-livestock contacts. An increasing number of epidemics in livestock are associated with rapid transition of livestock systems from extensive to intensive, and local to global movement of livestock and their products through value chain networks with weak biosecurity. Major livestock epidemics in the past two decades have had substantial economic impacts, and the COVID-19 pandemic highlights the devastating socio-economic consequences that spillovers can have when not identified and controlled early in the process of emergence. This highlights the importance of Veterinary Services to integrated, whole-of-society efforts to control infectious diseases in animals. Emphasis within Veterinary Services must be placed on prevention and preparedness. The authors suggest four areas for continued improvement in Veterinary Services to meet this challenge. These are a) continued development of staff capacity for risk assessment and value chain analysis, together with improved policies and communication, b) appropriate adaptation of approaches to prevention and control in resource-poor settings, c) improved multi-sectoral and transboundary cooperation, which enables the sharing of resources and expertise, and d) systematic approaches that enable Veterinary Services to influence decisionmaking for trade, markets, business, public health, and livelihood development at the national and regional levels.

La croissance du secteur de l'élevage est associée à un risque accru de maladies épidémiques. Les changements anthropiques à grande échelle sont à l'origine du nombre croissant de maladies émergentes atteignant de nouvelles espèces réceptives (spillover) à partir de réservoirs sauvages, à la faveur de contacts plus fréquents et plus rapprochés entre la faune sauvage et les humains, d'une part, et entre la faune sauvage et les animaux domestiques, d'autre part. On considère qu'un nombre croissant d'épidémies affectant le bétail sont dues à la transition rapide des systèmes d'élevage extensif vers des systèmes intensifs, et aux mouvements du bétail et des produits de l'élevage de l'échelle locale à l'échelle mondiale par le biais de réseaux de chaînes de valeur dotés d'un faible niveau de biosécurité. Au cours des deux dernières décennies, d'importantes épidémies affectant le bétail ont eu un impact économique considérable ; en outre, la pandémie de COVID-19 a mis en évidence les conséquences socio-économiques dévastatrices des atteintes de nouvelles espèces réceptives par des agents pathogènes, lorsque ces maladies ne sont pas détectées et maîtrisées dès le processus d'émergence. Cela souligne l'importance cruciale des Services vétérinaires dans les efforts de lutte contre les maladies infectieuses chez les animaux, qui doivent être intégrés et mobiliser la société entière. Les Services vétérinaires doivent mettre un accent particulier sur la prévention et la préparation. Les auteurs proposent quatre aspects d'amélioration continue pour que les Services vétérinaires puissent relever ce défi. Il s'agit : a) du développement permanent des compétences des personnels vétérinaires en matière d'évaluation du risque et d'analyse des chaînes de valeur, et leur articulation avec de meilleures politiques et une communication plus performante ; b) une adaptation adéquate des méthodes de prévention et de contrôle dans les configurations faiblement dotées en ressources ; c) une meilleure coopération multisectorielle et transfrontalière afin de partager les ressources et les compétences ; d) des dispositifs systémiques permettant aux Services vétérinaires d'influencer les prises de décision en matière d'échanges internationaux, de marchés, de commerce, de santé publique et de développement des moyens de subsistance, à l'échelle nationale et régionale.

El crecimiento del sector pecuario está condicionado por la existencia de un mayor riesgo de enfermedades epidémicas. La creciente diseminación de nuevas enfermedades a partir de animales silvestres es consecuencia de transformaciones antrópicas a gran escala que posibilitan un contacto más frecuente y estrecho de la fauna silvestre con el ser humano y el ganado. Cada vez son más las epidemias del ganado que tienen que ver con la rápida transición de los sistemas pecuarios de un régimen de producción extensiva a otro de producción intensiva y con el paso de la dimensión local a la mundial de la circulación de animales y sus derivados a través de redes de cadenas de valor que presentan una endeble seguridad biológica. En los últimos dos decenios ha habido grandes epidemias que han afectado al ganado y tenido importantes consecuencias económicas. La pandemia de COVID-19 es un elocuente ejemplo de los devastadores efectos socioeconómicos que puede tener la extensión de un patógeno cuando no se detecta y controla en un momento lo bastante precoz del proceso de emergencia. Ello pone de relieve la importancia que revisten los Servicios Veterinarios para que toda la sociedad pueda reaccionar de forma integrada a la hora de combatir las enfermedades infecciosas de los animales. Dentro de los Servicios Veterinarios, conviene poner el acento en la prevención y la preparación. Para lograr este objetivo los autores señalan cuatro ámbitos que exigen una constante mejora: a) el desarrollo continuo de la capacidad del personal en materia de determinación de riesgos y análisis de cadenas de valor, ligado a la mejora de las políticas y la comunicación; b) la adecuada adaptación de los métodos de prevención y control en contextos de escasos recursos; c) una mejor cooperación multisectorial y transfronteriza, que permita poner en común recursos y competencias técnicas; y d) enfoques sistemáticos que hagan posible que los Servicios Veterinarios influyan en los procesos decisorios relativos al desarrollo del comercio, los mercados, las empresas, la salud pública y los medios de sustento a escala tanto nacional como regional.

[Acute treatment of pregnant women after severe trauma-a retrospective multicenter analysis]. / Akutbehandlung schwangerer Patientinnen nach schwerem Trauma ­ eine retrospektive Multicenteranalyse.

BACKGROUND: For the medical team, the management of pregnant trauma patients is a particular challenge. The aim of this study is to compile this data and to determine differences between pregnant and not pregnant trauma patients. MATERIALS AND METHODS: We carried out a retrospective data analysis from the TraumaRegister DGU® with a comparison of 102 pregnant and 3135 not pregnant women of child-bearing age (16-45 years) from 2016-2018 who were treated in a trauma center. All patients were delivered to the resuscitation room and received intensive care treatment. RESULTS: In Germany, Austria and Switzerland 3.2% of all trauma patients (102 women) were pregnant. Women with an average age of 29 years suffered most often trauma as a result of a road traffic accident. Major trauma (Injury Severity Score [ISS] ≥16 points) was seen in 24.5% of the pregnant women and 37.4% of the nonpregnant women. A computer tomography (whole body computer tomography) was carried out in 32.7% of all pregnant women but in 79.8% of the nonpregnant women. As a result of the trauma, 2.9% of the pregnant and 3.5% of the not pregnant women died. The standardised mortality rate (SMR) was 0.42 in pregnant women and 0.63 in nonpregnant women. CONCLUSION: For the first time there is data regarding incidence, trauma mechanism, prehospital and in-hospital care as well as intensive care of pregnant trauma patients in Germany, Austria and Switzerland. Further research regarding foetal outcome and trauma-related injuries in pregnant women is needed to develop an adjusted management for these patients ready to implement in trauma centres. Gynaecologists and obstetricians should be implemented in the trauma room team when needed.

[A mentalization-based perspective on childhood autism treatment]. / Perspective de prise en charge d'enfants atteints de troubles du spectre autistique par psychothérapie inspirée des thérapies basées sur la mentalisation.

Mentalization is a process by which a subject makes sense of both his own mental representations and of those around him. Disturbances in the mentalization process are found in several psychiatric disorders, notably borderline personality disorders for which mentalization-based treatments (MBT) have been developed and evaluated. Children with Autism Spectrum Disorder (ASD) display a theory of mind impairments, which corresponds to disturbances in the mentalization process. Although no MBT protocol for patients with ASD has been described in the literature, such treatment appears promising to improve theory of mind and functional outcome of these children. In this paper, we propose to discuss the theoretical ground of MBT therapeutic effect in children with ASD without intellectual disabilities and to describe a clinical protocol to test this perspective.

Impact of Modular Total Absorption Spectrometer measurements of ß decay of fission products on the decay heat and reactor ν[over ¯]_{e} flux calculation.

We report the results of a ß-decay study of fission products ^{86}Br, ^{89}Kr, ^{89}Rb, ^{90gs}Rb, ^{90m}Rb, ^{90}Kr, ^{92}Rb, ^{139}Xe, and ^{142}Cs performed with the Modular Total Absorption Spectrometer (MTAS) and on-line mass-separated ion beams. These radioactivities were assessed by the Nuclear Energy Agency as having high priority for decay heat analysis during a nuclear fuel cycle. We observe a substantial increase in ß feeding to high excited states in all daughter isotopes in comparison to earlier data. This increases the average γ-ray energy emitted by the decay of fission fragments during the first 10 000 s after fission of ^{235}U and ^{239}Pu by approximately 2% and 1%, respectively, improving agreement between results of calculations and direct observations. New MTAS results reduce the reference reactor ν[over ¯]_{e} flux used to analyze reactor ν[over ¯]_{e} interaction with detector matter. The reduction determined by the ab initio method for the four nuclear fuel components, ^{235}U, ^{238}U, ^{239}Pu, and ^{241}Pu, amounts to 0.976, 0.986, 0.983, and 0.984, respectively.

Antibody response and risk factors for seropositivity in backyard poultry following mass vaccination against highly pathogenic avian influenza and Newcastle disease in Indonesia.

A large-scale mass vaccination campaign was carried out in Java, Indonesia in an attempt to control outbreaks of highly pathogenic avian influenza (HPAI) in backyard flocks and commercial smallholder poultry. Sero-monitoring was conducted in mass vaccination and control areas to assess the proportion of the target population with antibodies against HPAI and Newcastle disease (ND). There were four rounds of vaccination, and samples were collected after each round resulting in a total of 27 293 samples. Sampling was performed irrespective of vaccination status. In the mass vaccination areas, 20-45% of poultry sampled had a positive titre to H5 after each round of vaccination, compared to 2-3% in the control group. In the HPAI + ND vaccination group, 12-25% of the population had positive ND titres, compared to 5-13% in the areas without ND vaccination. The level of seropositivity varied by district, age of the bird, and species (ducks vs. chickens).

Large ß-delayed one and two neutron emission rates in the decay of 86Ga.

Beta decay of 86Ga was studied by means of ß-neutron-γ spectroscopy. An isotopically pure ^{86}Ga beam was produced at the Holifield Radioactive Ion Beam Facility using a resonance ionization laser ion source and high-resolution electromagnetic separation. The decay of 86Ga revealed a half-life of 43(-15)(+21) ms and large ß-delayed one-neutron and two-neutron branching ratios of P1n=60(10)% and P2n=20(10)%. The ßγ decay of 86Ga populated a 527 keV transition that is interpreted as the deexcitation of the first 2+ state in the N=54 isotone 86Ge and suggests a quick onset of deformation in Ge isotopes beyond N=50.

A common polymorphism acts as an intragenic modifier of mutant p53 behaviour.

The p73 protein, a homologue of the tumour-suppressor protein p53, can activate p53-responsive promoters and induce apoptosis in p53-deficient cells. Here we report that some tumour-derived p53 mutants can bind to and inactivate p73. The binding of such mutants is influenced by whether TP53 (encoding p53) codon 72, by virtue of a common polymorphism in the human population, encodes Arg or Pro. The ability of mutant p53 to bind p73, neutralize p73-induced apoptosis and transform cells in cooperation with EJ-Ras was enhanced when codon 72 encoded Arg. We found that the Arg-containing allele was preferentially mutated and retained in squamous cell tumours arising in Arg/Pro germline heterozygotes. Thus, inactivation of p53 family members may contribute to the biological properties of a subset of p53 mutants, and a polymorphic residue within p53 affects mutant behaviour.

New half-lives of r-process Zn and Ga isotopes measured with electromagnetic separation.

The ß decays of neutron-rich nuclei near the doubly magic (78)Ni were studied at the Holifield Radioactive Ion Beam Facility using an electromagnetic isobar separator. The half-lives of (82)Zn (228±10 ms), (83)Zn (117±20 ms), and (85)Ga (93±7 ms) were determined for the first time. These half-lives were found to be very different from the predictions of the global model used in astrophysical simulations. A new calculation was developed using the density functional model, which properly reproduced the new experimental values. The robustness of the new model in the (78)Ni region allowed us to extrapolate data for more neutron-rich isotopes. The revised analysis of the rapid neutron capture process in low entropy environments with our new set of measured and calculated half-lives shows a significant redistribution of predicted isobaric abundances strengthening the yield of A>140 nuclei.

The 2006-2007 Rift Valley fever outbreak in Kenya: sources of early warning messages and response measures implemented by the Department of Veterinary Services.

The authors characterised sources of early warning messages about occurrences of Rift Valley fever (RVF) and examined the response measures that were used by the Department of Veterinary Services (DVS) to manage the 2006-2007 RVF outbreaks in Kenya. The study was conducted between November 2009 and March 2010 and it included national, provincial and district veterinary officers who were involved in the management of the outbreak. Structured questionnaires were used to collect the data. Although the majority of the respondents reported having limited capacity to implement response measures, they perceived that the measures implemented were effective. Vaccination, movement control and market closures were the main response measures implemented, particularly in districts that had cases in both livestock and humans. Vaccination, however, was implemented too late and the coverage achieved was too low to be effective. The authors suggest ways to improve the capacity of the DVS to respond to similar outbreaks in the future.

Integration of participatory approaches into surveillance systems.

Animal health surveillance is essential for protecting public health, enhancing access to international markets for animals and their products, and improving animal health, production and welfare. It is of vital importance for protecting and improving the livelihoods of diverse groups of livestock keepers and stakeholders in livestock value chains. Surveillance systems consist of sets of complementary components which generate information to inform risk assessment, decision-making and policy formulation for both national programmes and international trade. Participatory approaches have the potential to add value to surveillance systems by enhancing their performance, especially their sensitivity and timeliness, and encouraging the inclusion of marginalised groups. This paper summarises key considerations in the assessment and design of animal health surveillance and discusses how participatory approaches can be integrated into comprehensive surveillance systems, leading to a more effective overall outcome for both domestic and international purposes.

Do macromorphological features of the human placenta influence somatic and psychomotor development of the newborn and early infant? A historic question revisited.

OBJECTIVE: We examined the meaning of placental weight, form (massive and thick or extended and flat) and circumference for early somatic and psychomotor childhood development. METHODS: In this prospective study, fresh placentas (n = 265) were measured for weight and circumference and correlated with neonatal data. A subset of placentas statistically defined as 'massive' (circumference <10th percentile) and 'extended' (circumference >90th percentile) was correlated with somatic and basic psychomotor variables during the first 4 years of life. A 'medium' category (circumference 45-55th percentile) served as control. RESULTS: Placental weight correlated with birth weight (r = 0.53, p < 0.0005) and mean infantile weight until month 48 (r = 0.29, p = 0.016). Placental circumference weakly correlated with birth weight (r = 0.17, p = 0.011) but not with mean infantile weight. Placental extremes (massive, medium, extended) demonstrated significant influences only on very early somatic growth (day 1 to month 4): Massive placentas were associated with heavier and taller children (p = 0.02-0.033). Markers of early psychomotor development (first sitting, crawling, running, one- and two-word sentences) were not related with placental weight or circumference nor with extremes of placental morphology. CONCLUSION: Placental weight and circumference seem to influence very early somatic but not psychomotor development.

Isolated left ventricular noncompaction as a cause for heart failure and heart transplantation: a single center experience.

OBJECTIVES: To determine the prevalence of isolated left ventricular noncompaction (IVNC) as a cause of heart failure and heart transplantation. METHODS: There were 960 patients seen in the heart failure clinic from 1987 to 2005, with a complete evaluation including echocardiography at our center (study population, 82% men, mean age 52 years). The following data were collected: type of heart disease, age at echocardiography and at heart transplantation, and frequency of heart transplantation. Echocardiographic diagnosis of IVNC was based on our published criteria. RESULTS: The etiologies of heart failure were coronary artery disease (CAD; 37%), idiopathic dilated cardiomyopathy (33%), valvular heart disease (11%), congenital heart disease (5%), IVNC (3%), hypertensive heart disease (3%), hypertrophic cardiomyopathy (2%), myocarditis (1%), and <1% other diagnoses. Heart transplantation was performed in 253 patients (26%) due to idiopathic dilated cardiomyopathy (42%), CAD (39%), valvular heart disease (5%), congenital heart disease (5%), IVNC (2%), or other etiologies (< or =1% each). CONCLUSIONS: The most common causes for heart failure remain idiopathic dilated cardiomyopathy, CAD and valvular heart disease. Strictly using the criteria for the definition of IVNC, IVNC is a rare underlying cardiomyopathy for both, heart failure (2.7%) and heart transplantation (2%) in our center.

From individual to collective displacements in heterogeneous environments.

Animal displacement plays a central role in many ecological questions. It can be interpreted as a combination of components that only depend on the animal (for example a random walk) and external influences given by the heterogeneity of the environment. Here we treat the case where animals switch between random walks in a homogeneous 2D environment and its 1D boundary, combined with a tendency for wall-following behaviour (thigmotactism) that is treated as a Markovian process. In the first part we use mesoscopic techniques to derive from these assumptions a set of partial differential equations (PDE) with specific boundary conditions and parameters that are directly given by the individual displacement parameters. All assumptions and approximations made during this derivation are rigorously validated for the case of exploratory behaviour of the ant Messor sanctus. These PDE predict that the stationary density ratio between the 2D (centre) and 1D (border) environment only depends on the thigmotactic component, not on the size of the centre or border areas. In the second part we test this prediction with the same exploratory behaviour of M. sanctus, in particular when many ants move around simultaneously and may interact directly or indirectly. The prediction holds when there is a low degree of heterogeneity (simple square arena with straight borders), the collective behaviour is "simply" the sum of the individual behaviours. But this prediction breaks down when heterogeneity increases (obstacles inside the arena) due to the emergence of pheromone trails. Our approach may be applied to study the effects of animal displacement in any environment where the animals are confronted with an alternation of 2D space and 1D borders as for example in fragmented landscapes.

Anderson-Fabry disease: long-term echocardiographic follow-up under enzyme replacement therapy.

AIMS: Anderson-Fabry disease affects various organ systems due to glycosphingolipid accumulation. Enzyme replacement therapy (ERT) has been reported to decrease left ventricular wall thickening (LVWT) and to improve diastolic dysfunction. METHODS AND RESULTS: This prospective study included 29 patients (patients; mean age 37 +/- 13 years) with genetically, enzymatically and/or biopsy-proven Anderson-Fabry disease and long-time ERT. Data on symptoms, cardiac medications and history of hypertension were collected and all patients had comprehensive echocardiographic examination prior to ERT and at follow-up. Disease was at an early stage with a total mean Mainz severity score index of only 18.6 +/- 13.0. Prior to ERT, 79% of patients reported acroparesthesia. The median creatinine level was 121 +/- 108 mcmol/L and LVWT was present in nine patients (31%). Binary appearance of the interventricular septum was found in 20% and posterobasal fibrosis in 83%. At median follow-up of 37 months, acroparesthesia decreased to 55% (P = 0.016). There was no change in creatinine levels. The incidence of LVWT was unchanged, only an increase in interventricular septal wall thickness from 11.7 +/- 0.4 to 12.5 +/- 0.5 was observed (P = 0.009). Left atrial size and the percentage of patients with binary appearance and posterobasal fibrosis were unchanged. There was a small improvement in diastolic function (29% decrease of E/Ea; P < 0.002). CONCLUSION: Our Anderson-Fabry cohort had successful long-time ERT with impressive amelioration of subjective symptoms. Although there was not much improvement in cardiac changes apart from a slight improvement of diastolic function, at least, there was no progression of cardiac disease. For complete reversibility of cardiac changes in Anderson-Fabry disease, ERT might have to be started earlier in life and/or prescribed for a longer time.

Dynamic left ventricular outflow tract obstruction evoked by exercise echocardiography: prevalence and predictive factors in a prospective study.

AIMS: In patients without hypertrophic obstructive cardiomyopathy (HOCM), dynamic left ventricular outflow tract obstruction (DLVOTO) can cause ischaemia. Little is known about incidence and predictors of DLVOTO in patients without HOCM. METHODS AND RESULTS: In 300 patients referred for exercise echocardiography, assessment of DLVOTO at rest and with Valsalva and of the presence of systolic anterior motion of the mitral valve leaflets (SAM) was performed. Within 90 s post-exercise, wall motion, SAM, and DLVOTO were assessed again. A significant DLVOTO was defined as late-peaking Doppler velocity of >or=2.5 m/s (25 mmHg). Excluded were 7 patients with HOCM and 13 with inadequate image quality. There were 280 patients, aged 64(11) years. Coronary artery disease was found in 38% of patients; 44% were receiving beta-blocker therapy and 35% had hypertension. At rest, ejection fraction was 59 +/- 9%; left ventricular hypertrophy (LVH) was present in 21%, SAM in 16%, DLVOTO >or=25 mmHg at rest in 0.7%, and with Valsalva in 3%. At peak, echocardiographic signs of ischaemia occurred in 44%, and significant DLVOTO in 5% (13 patients). By multivariate analysis, it was found that independent predictors of significant DLVOTO at peak were chordal SAM at peak, smaller left ventricle at end-systole, higher systolic blood pressure at peak, younger age and increased septal wall thickness. Significant DLVOTO was a possible cause of symptoms and/or ischaemia in at least 6 of the 13 patients. CONCLUSION: Haemodynamically significant exercise-induced DLVOTO can occur without HOCM. Chordal SAM at peak, small, hyperdynamic left ventricles, increased septal wall thickness, and younger age are the best predictors.

Trace metal concentrations in Antarctic sea spiders (Pycnogonida, Pantopoda).

Trace metals were analysed in sea spiders collected on two Polarstern cruises in the Weddell Sea. We found a substantial interspecific heterogeneity of Cd, Cu, Ni, and Zn, indicating varying accumulation strategies and metabolic demands for essential elements. Means and 95%-confidence intervals for all 44 samples analysed are 26+/-7 mg Cd kg(-1), 38+/-22 mg Cu kg(-1), 62+/-13 mg Ni kg(-1) and 990+/-130 mg Zn kg(-1) DW. Only for Pb do we find values less than 1.0 mg kg(-1) for most collectives analysed, in good agreement with other Antarctic arthropods such as crustaceans. Our study provides further evidence for the frequently reported "Cd anomaly" in many polar arthropods. While Cu concentrations in pantopods are within the reported range for Antarctic amphipods and decapods, Ni concentrations are exceptionally high and might be part of predation defence mechanisms. These possibilities should be investigated in more detail in future studies.

Effects of polystyrene nanoparticles on the microbiota and functional diversity of enzymes in soil.

BACKGROUND: The increasing production of nanoplastics and the fragmentation of microplastics into smaller particles suggest a plausible yet unclear hazard in the natural environment, such as soil. We investigated the short-term effects (28 days) of polystyrene nanoparticles (PS-NPs) on the activity and biomass of soil microbiota, and the functional diversity of soil enzymes at environmental relevant low levels in an incubation experiment. RESULTS: Our results showed a significant decrease in microbial biomass in treatments of 100 and 1000 ng PS-NP g-1 DM throughout the incubation period. Dehydrogenase activity and activities of enzymes involved in N-(leucine-aminopeptidase), P-(alkaline-phosphatase), and C-(ß-glucosidase and cellobiohydrolase) cycles in the soil were significantly reduced at day 28 suggesting a broad and detrimental impact of PS-NPs on soil microbiota and enzymes. Leucine-aminopeptidase and alkaline-phosphatase activities tended to decrease consistently, while ß-glucosidase and cellobiohydrolase activities increased at high concentrations (e.g., PS-NP-1000) in the beginning of the incubation period, e.g., at day 1. On the other hand, basal respiration and metabolic quotient increased with increasing PS-NP application rate throughout the incubation period possibly due to increased cell death that caused substrate-induced respiration (cryptic growth). CONCLUSIONS: We herewith demonstrated for the first time the potential antimicrobial activity of PS-NPs in soil, and this may serve as an important resource in environmental risk assessment of PS-NPs in the soil environment.

Paradoxical withdrawal of reflex vasoconstriction as a cause of hemodialysis-induced hypotension.

Acute hypotension is an important complication of hemodialysis, but the underlying mechanisms remain poorly understood. Because hemorrhage-induced hypovolemia can trigger a sudden decrease in sympathetic activity resulting in bradycardia and vasodilation, we hypothesized that hemodialysis-induced hypovolemia also can trigger the same type of vasodepressor reaction, which would exacerbate the volume-dependent fall in blood pressure. We therefore measured blood pressure, vascular resistance, and sympathetic nerve activity (intraneural microelectrodes) during sessions of maintenance hemodialysis in 7 patients with and 16 patients without a history of hemodialysis-induced hypotension. During hemodialysis, blood pressure at first remained unchanged as calf resistance increased in both hypotension-resistant (from 37 +/- 4 to 49 +/- 5 U, P < 0.05) and hypotension-prone (from 42 +/- 6 to 66 +/- 12 U, P < 0.05) patients; sympathetic activity increased comparably in the subset of patients in whom it could be measured. With continued hemodialysis, calf resistance and sympathetic activity increased further in the hypotension-resistant patients, but in the hypotension-prone patients the precipitous decrease in blood pressure was accompanied by decreases in sympathetic activity, vascular resistance, and heart rate as well as symptoms of vasodepressor syncope. On an interdialysis day, both groups of patients increased vascular resistance normally during unloading of cardiopulmonary baroreceptors with lower body negative pressure and increased heart rate normally during unloading of arterial baroreceptors with infusion of nitroprusside. These findings indicate that in a group of hemodialysis patients without diabetes or other conditions known to impair autonomic reflexes, hemodialysis-induced hypotension is not caused by chronic uremic impairment in arterial or cardiopulmonary baroreflexes but rather by acute, paradoxical withdrawal of sympathetic vasoconstrictor drive producing vasodepressor syncope.

Viral oncoproteins discriminate between p53 and the p53 homolog p73.

p73 is a recently identified member of the p53 family. Previously it was shown that p73 can, when overproduced in p53-defective tumor cells, activate p53-responsive promoters and induce apoptosis. In this report we describe the generation of anti-p73 monoclonal antibodies and confirm that two previously described p73 isoforms are produced in mammalian cells. Furthermore, we show that these two isoforms can bind to canonical p53 DNA-binding sites in electrophoretic mobility shift assays. Despite the high degree of similarity between p53 and p73, we found that adenovirus E1B 55K, simian virus 40 T, and human papillomavirus E6 do not physically interact with p73. The observation that viral oncoproteins discriminate between p53 and p73 suggests that the functions of these two proteins may differ under physiological conditions. Furthermore, they suggest that inactivation of p73 may not be required for transformation.

MDM2 suppresses p73 function without promoting p73 degradation.

The newly identified p53 homolog p73 can mimic the transcriptional activation function of p53. We investigated whether p73, like p53, participates in an autoregulatory feedback loop with MDM2. p73 bound to MDM2 both in vivo and in vitro. Wild-type but not mutant MDM2, expressed in human p53 null osteosarcoma Saos-2 cells, inhibited p73- and p53-dependent transcription driven by the MDM2 promoter-derived p53RE motif as measured in transient-transfection and chloramphenicol acetyltransferase assays and also inhibited p73-induced apoptosis in p53-null human lung adenocarcinoma H1299 cells. MDM2 did not promote the degradation of p73 but instead disrupted the interaction of p73, but not of p53, with p300/CBP by competing with p73 for binding to the p300/CBP N terminus. Both p73alpha and p73beta stimulated the expression of the endogenous MDM2 protein. Hence, MDM2 is transcriptionally activated by p73 and, in turn, negatively regulates the function of this activator through a mechanism distinct from that used for p53 inactivation.