RESUMO
Asexual replication in the apicomplexan Sarcocystis neurona involves two main developmental stages: the motile extracellular merozoite and the sessile intracellular schizont. Merozoites invade host cells and transform into schizonts that undergo replication via endopolygeny to form multiple (64) daughter merozoites that are invasive to new host cells. Given that the capabilities of the merozoite vary significantly from the schizont, the patterns of transcript levels throughout the asexual lifecycle were determined and compared in this study. RNA-Seq data were generated from extracellular merozoites and four intracellular schizont development time points. Of the 6,938 genes annotated in the S. neurona genome, 6,784 were identified in the transcriptome. Of these, 4,111 genes exhibited significant differential expression between the merozoite and at least one schizont development time point. Transcript levels were significantly higher for 2,338 genes in the merozoite and 1,773 genes in the schizont stages. Included in this list were genes encoding the secretory pathogenesis determinants (SPDs), which encompass the surface antigen and SAG-related sequence (SAG/SRS) and the secretory organelle proteins of the invasive zoite stage (micronemes, rhoptries, and dense granules). As anticipated, many of the S. neurona SPD gene transcripts were abundant in merozoites. However, several SPD transcripts were elevated in intracellular schizonts, suggesting roles unrelated to host cell invasion and the initial establishment of the intracellular niche. The hypothetical genes that are potentially unique to the genus Sarcocystis are of particular interest. Their conserved expression patterns are instructive for future investigations into the possible functions of these putative Sarcocystis-unique genes. IMPORTANCE: The genus Sarcocystis is an expansive clade within the Apicomplexa, with the species S. neurona being an important cause of neurological disease in horses. Research to decipher the biology of S. neurona and its host-pathogen interactions can be enhanced by gene expression data. This study has identified conserved apicomplexan orthologs in S. neurona, putative Sarcocystis-unique genes, and gene transcripts abundant in the merozoite and schizont stages. Importantly, we have identified distinct clusters of genes with transcript levels peaking during different intracellular schizont development time points, reflecting active gene expression changes across endopolygeny. Each cluster also has subsets of transcripts with unknown functions, and investigation of these seemingly Sarcocystis-unique transcripts will provide insights into the interesting biology of this parasite genus.
Assuntos
Merozoítos , Sarcocystis , Sarcocystis/genética , Sarcocystis/crescimento & desenvolvimento , Merozoítos/crescimento & desenvolvimento , Esquizontes/genética , Esquizontes/crescimento & desenvolvimento , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Transcriptoma , Perfilação da Expressão Gênica , Reprodução Assexuada/genética , Animais , Sarcocistose/parasitologia , Sarcocistose/veterinária , Estágios do Ciclo de Vida/genéticaRESUMO
UAVs need to communicate along three dimensions (3D) with other aerial vehicles, ranging from above to below, and often need to connect to ground stations. However, wireless transmission in 3D space significantly dissipates power, often hindering the range required for these types of links. Directional transmission is one way to efficiently use available wireless channels to achieve the desired range. While multiple-input multiple-output (MIMO) systems can digitally steer the beam through channel matrix manipulation without needing directional awareness, the power resources required for operating multiple radios on a UAV are often logistically challenging. An alternative approach to streamline resources is the use of phased arrays to achieve directionality in the analog domain, but this requires beam sweeping and results in search-time delay. The complexity and search time can increase with the dynamic mobility pattern of the UAVs in aerial networks. However, if the direction of the receiver is known at the transmitter, the search time can be significantly reduced. In this work, multi-antenna channels between two UAVs in A2A links are analyzed, and based on these findings, an efficient machine learning-based method for estimating the direction of a transmitting node using channel estimates of 4 antennas (2 × 2 MIMO) is proposed. The performance of the proposed method is validated and verified through in-field drone-to-drone measurements. Findings indicate that the proposed method can estimate the direction of the transmitter in the A2A link with 86% accuracy. Further, the proposed direction estimation method is deployable for UAV-based massive MIMO systems to select the directional beam without the need to sweep or search for optimal communication performance.
RESUMO
Social grooming in the animal kingdom is common and serves several functions, from removing ectoparasites to maintaining social bonds between conspecifics. We examined whether time spent grooming with others in a highly social mammal species was associated with infection status for gastrointestinal parasites. Of six parasites detected, one (Trichuris sp.) was associated with social grooming behaviors, but more specifically with direct physical contact with others. Individuals infected with Trichuris sp. spent significantly less time grooming conspecifics than those not infected, and time in direct contact with others was the major predictor of infection status. One model correctly predicted infection status for Trichuris sp. with a reliability of 95.17% overall when the variables used were time spent in direct contact and time spent grooming others. This decrease in time spent grooming and interacting with others is likely a sickness behavior displayed by individuals with less energy or motivation for non-essential behaviors. This study emphasizes the possible links between host behavior and parasitic infections and highlights the need for an understanding of a study population's parasitic infections when attempting to interpret animal behavior.
Assuntos
Comportamento Animal/fisiologia , Chlorocebus aethiops/fisiologia , Chlorocebus aethiops/parasitologia , Trichuris/patogenicidade , Animais , Criança , Pré-Escolar , Feminino , Asseio Animal/fisiologia , Humanos , Lactente , Enteropatias Parasitárias/parasitologia , Enteropatias Parasitárias/fisiopatologia , Masculino , Reprodutibilidade dos Testes , Comportamento Social , Tricuríase/fisiopatologiaRESUMO
RATIONALE: Tick paralysis has not been reported in horses in North America. CLINICAL FINDINGS: Two American Miniature horses were examined for progressive weakness and recumbency. Numerous ticks (Dermacentor variabilis) were found on both horses. Horse 1 was recumbent (grade 5/5 gait deficit) on presentation, whereas Horse 2 was standing but ataxic (grade 4/5 gait deficit) and tetraparetic. Both horses had decreased tongue and tail muscle tone, and had normal spinal reflexes. Cerebrospinal fluid cytology was normal. Equine herpesvirus-1 testing was negative. PERTINENT INTERVENTIONS: Ticks were removed within 24 hours of presentation. Both horses were treated topically with permethrin. Supportive care included fluid therapy, treatment for corneal ulceration, and frequent repositioning during recumbency. OUTCOME: Within 48 hours of tick removal, both horses were neurologically normal. CLINICAL RELEVANCE: Ours is the first reported case of presumptive tick paralysis in horses in North America. Although rare, tick paralysis should be considered in horses presented with acute-onset weakness progressing to recumbency.
Assuntos
Dermacentor/patogenicidade , Doenças dos Cavalos/diagnóstico , Doenças dos Cavalos/terapia , Paralisia por Carrapato/veterinária , Animais , Úlcera da Córnea/terapia , Úlcera da Córnea/veterinária , Feminino , Cavalos , Inseticidas/administração & dosagem , Permetrina/administração & dosagem , Paralisia por Carrapato/diagnóstico , Paralisia por Carrapato/terapia , Resultado do Tratamento , Estados UnidosRESUMO
We reviewed 62 new cases and 18 published reports of Dracunculus infections in domestic dogs and cats to describe the epidemiology of this parasite in dogs and cats in North America. We collected host and parasite data when available, including age, sex, and breed of dog, nematode location in the host, and any clinical signs at presentation and/or description of the apparent lesion. For dogs, infections were noted in six of the AKC breed groups, but none was reported from the toy group or the miscellaneous breed class. Age of infected dogs ranged from 7â¯months to 19â¯years (median 4â¯years; average 5.3â¯years), and infection rates were similar in male and female dogs. Most nematodes were associated with the distal extremities, but worms were also found in the chest/thorax, abdomen, head, and flank. Although most infected dogs had a single worm, three dogs had two or more worms that were collected from multiple lesions. Three new cat cases, with similar lesions, presentations and seasonality, were detected in Alabama, North Carolina and Texas. Cases were reported from a wide geographic range throughout eastern North America, during every month of the year, but 72% of infections were diagnosed in the late winter to early spring (December to May). All collected worms were larvigerous females which cannot be identified to species based on morphologic characters. Thus, we attempted to amplify and sequence a portion of the cytochrome c oxidase subunit I (COI) gene for specific identification. Although 13 worms from 12 cases were available, sequences were obtained for only eight worms from seven cases. These eight worms were D. insignis, a common parasite of raccoons (Procyon lotor) and other primarily carnivorous mammals. Female worms are the most likely to be detected in dogs and cats because male worms do not emerge, parasites should be preserved in ethanol for molecular identification. Although this study used convenience sampling of available data, we found that the parasite is widespread throughout the eastern US and Canada and that Dracunculus infections in dogs are more common than is revealed in published literature. However, more research is needed to understand the epidemiology, including transmission route(s), prevalence, and distribution of this parasite.
Assuntos
Doenças do Gato/epidemiologia , Gatos/parasitologia , Doenças do Cão/epidemiologia , Cães/parasitologia , Dracunculíase/veterinária , Alabama , Animais , Canadá , Doenças do Gato/parasitologia , Doenças do Cão/parasitologia , Dracunculíase/epidemiologia , Dracunculus/isolamento & purificação , Dracunculus/patogenicidade , Feminino , Masculino , América do Norte/epidemiologia , North Carolina , TexasRESUMO
There are many known benefits of social grooming among primates, including maintenance of social relationships, removal of ectoparasites, and improved physiological condition. Recently, however, researchers have noted that social grooming and social contact may also present a significant cost by facilitating transmission of some parasites and pathogens. We investigated whether the number of social grooming partners varied based on infection status for gastrointestinal parasites. We used focal animal sampling and continuous recording to collect data on the number of grooming partners for known individual vervet monkeys (Chlorocebus aethiops). We collected non-invasive faecal samples and examined them using faecal flotation, faecal sedimentation, and immunofluorescence microscopy. We detected 6 parasites: Trichuris sp. (92%), hookworm (71%), spirurids (68%), Oesophagostomum sp. (84%), Strongyloides sp. (24%), and Entamoeba coli (92%). The number of grooming partners varied significantly based on infection with hookworm and sex. No significant relationships were detected for other parasites. Associations between host behavioural variation and some parasite taxa (specifically Trichuris, Oesophagostomum, and Entamoeba spp.) were impossible to explore due to an extremely high prevalence among hosts. This is the first report that we are aware of that has detected an association between social grooming behaviours and infection with hookworm.
Assuntos
Chlorocebus aethiops/fisiologia , Chlorocebus aethiops/parasitologia , Asseio Animal , Infecções por Uncinaria/veterinária , Doenças dos Macacos/parasitologia , Animais , Entamoeba/isolamento & purificação , Entamebíase/transmissão , Entamebíase/veterinária , Fezes/parasitologia , Feminino , Infecções por Uncinaria/parasitologia , Infecções por Uncinaria/transmissão , Masculino , Doenças dos Macacos/transmissão , Nematoides/isolamento & purificação , Infecções por Nematoides/transmissão , Infecções por Nematoides/veterinária , Comportamento Social , África do SulRESUMO
CASE DESCRIPTION: A 1-year-old castrated male dog residing in Indiana was examined because of intermittent vomiting of 4 months' duration. CLINICAL FINDINGS: The dog's condition did not resolve with medication. Diagnostic imaging revealed a possible partial obstruction at the ileocecal junction. An exploratory laparotomy was performed. The jejunum contained diffusely distributed, nodular, intramural lesions; 2 biopsy specimens were collected from representative lesions. The pancreas was grossly swollen, and pancreatitis was presumed present. No other abnormalities were observed in the abdomen. Histologic examination of the submitted biopsy specimens revealed infection with Heterobilharzia americana. TREATMENT AND OUTCOME: After diagnosis, the dog was treated with fenbendazole suspension (48 mg/kg [21.8 mg/lb], PO, q 24 h) for 10 days. This treatment was subsequently repeated 11 and 80 days later. One week after the end of the last fenbendazole treatment, several H americana eggs were detected in a fecal sample via saline sedimentation, and the dog was given praziquantel (25 mg/kg [11.4 mg/lb], PO, q 8 h) for 2 days. No gastrointestinal signs were evident 4 months after that treatment. CLINICAL RELEVANCE: The dog described in this report was the first autochthonous canine case of H americana infection in Indiana, to the authors' knowledge; this case has confirmed that the distribution of this parasite in the Midwestern United States is broader than previously known. Increased awareness of the distribution of H americana should aid veterinarians in early, noninvasive diagnosis and appropriate treatment of affected animals. Repeated treatments and recheck fecal examinations may be necessary when managing these cases.
Assuntos
Doenças do Cão/parasitologia , Doenças do Íleo/veterinária , Obstrução Intestinal/veterinária , Schistosomatidae/isolamento & purificação , Infecções por Trematódeos/veterinária , Animais , Anti-Helmínticos/uso terapêutico , Antinematódeos/uso terapêutico , Doenças do Cão/diagnóstico por imagem , Doenças do Cão/cirurgia , Cães , Fezes/parasitologia , Fenbendazol/uso terapêutico , Doenças do Íleo/diagnóstico por imagem , Doenças do Íleo/parasitologia , Valva Ileocecal/diagnóstico por imagem , Indiana , Obstrução Intestinal/diagnóstico por imagem , Obstrução Intestinal/parasitologia , Masculino , Praziquantel/uso terapêutico , Radiografia/veterinária , Schistosomatidae/classificação , Resultado do Tratamento , Infecções por Trematódeos/parasitologia , Infecções por Trematódeos/cirurgia , Vômito/veterináriaRESUMO
Giardia protozoa have been suspected to be of zoonotic transmission, including transmission from companion animals such as pet dogs to humans. Patterns of infection have been previously described for dogs and humans, but such investigations have used different time periods and locations for these two species. Our objective was to describe and compare the overall trend and seasonality of Giardia species infection among dogs and humans in the United States from 2003 through 2009 in an ecological study using public health surveillance data and medical records of pet dogs visiting a large nationwide private veterinary hospital. Canine data were obtained from all dogs visiting Banfield hospitals in the United States with fecal test results for Giardia species, from January 2003 through December 2009. Incidence data of human cases from the same time period were obtained from the CDC. Descriptive time plots, a seasonal trend decomposition (STL) procedure, and seasonal autoregressive moving-average (SARIMA) models were used to assess the temporal characteristics of Giardia infection in the two species. Canine incidence showed a gradual decline from 2003 to 2009 with no significant/distinct regular seasonal component. By contrast, human incidence showed a stable annual rate with a significant regular seasonal cycle, peaking in August and September. Different temporal patterns in human and canine Giardia cases observed in this study suggest that the epidemiological disease processes underlying both series might be different, and Giardia transmission between humans and their companion dogs seems uncommon.
Assuntos
Doenças do Cão/parasitologia , Giardia/isolamento & purificação , Giardíase/veterinária , Animais de Estimação/parasitologia , Zoonoses/parasitologia , Animais , Doenças do Cão/epidemiologia , Doenças do Cão/transmissão , Cães , Fezes/parasitologia , Giardíase/epidemiologia , Giardíase/parasitologia , Giardíase/transmissão , Humanos , Incidência , Estações do Ano , Fatores de Tempo , Estados Unidos/epidemiologia , Zoonoses/epidemiologia , Zoonoses/transmissãoAssuntos
Doenças da Aorta/diagnóstico por imagem , Doenças da Aorta/etiologia , Fístula Artério-Arterial/diagnóstico por imagem , Fístula Artério-Arterial/etiologia , Procedimentos Cirúrgicos Cardiovasculares/efeitos adversos , Átrios do Coração/diagnóstico por imagem , Doenças da Aorta/cirurgia , Fístula Artério-Arterial/cirurgia , Átrios do Coração/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , UltrassonografiaRESUMO
Estimates of the prevalence of intestinal infection of dogs with Giardia spp. in the United States vary widely. Risk factors for infection in a large sample of dogs over an extended period of time have not been well characterized. A national, electronic database of medical records was used to estimate the prevalence and identify risk factors for Giardia spp. infection among dogs visiting Banfield Pet Hospital™ located in 43 states in the United States. The overall prevalence of Giardia spp. Infection was 0.44% (95% CI: 0.43-0.45%) in approximately 2.5 million owned dogs who had a fecal flotation test performed from January 2003 to December 2009. A steady decrease in annual prevalence was observed, from a high of 0.61% in 2003 to 0.27% in 2009. Seasonal increases in prevalence were noted during the winter and summer months. Giardia spp. prevalence was highest in the Mountain region, especially Colorado (2.63%; 95% CI: 2.53-2.73%), and in puppies ≤0.5 year of age (0.63%; 95% CI: 0.61-0.64%). It was lowest for dogs of mixed breeding compared with pure breeds. Infection risk was 25-30% greater in sexually intact dogs compared to spayed and neutered dogs.
Assuntos
Doenças do Cão/diagnóstico , Giardia/isolamento & purificação , Giardíase/veterinária , Fatores Etários , Animais , Cruzamento , Doenças do Cão/epidemiologia , Doenças do Cão/parasitologia , Cães , Registros Eletrônicos de Saúde , Monitoramento Epidemiológico/veterinária , Fezes/parasitologia , Feminino , Giardíase/diagnóstico , Giardíase/epidemiologia , Giardíase/parasitologia , Hospitais Veterinários , Masculino , Análise Multivariada , Prevalência , Fatores de Risco , Estações do Ano , Fatores Sexuais , Estados Unidos/epidemiologiaRESUMO
AIMS: The aim of the study was to determine the effects of oral clotrimazole troches on the pharmacokinetics of oral and intravenous midazolam in the plasma. METHODS: We conducted a randomized, open-label, four-way crossover study in 10 healthy volunteers. Each volunteer received oral midazolam 2 mg or intravenous midazolam 0.025 mg kg(-1) with and without oral clotrimazole troches 10 mg taken three times daily for 5 days. Each study period was separated by 14 days. Serial blood samples were collected up to 24 h after oral midazolam and 6 h after intravenous midazolam. Plasma concentrations for midazolam and its metabolite 1-hydroxymidazolam were measured and fitted to a noncompartmental model to estimate the pharmacokinetic parameters. RESULTS: Ten healthy volunteers aged 21-26 years provided written informed consent and were enrolled into the study. Clotrimazole decreased the apparent oral clearance of midazolam from 57 +/- 13 l h(-1)[95% confidence interval 48, 66] to 36 +/- 9.8 l h(-1) (95% confidence interval 29, 43) (P= 0.003). These changes were accompanied by a decrease in the area under the concentration-time curve (mean difference 22 microg h(-1) l(-1), P= 0.001) and bioavailability (mean difference 0.21, P= NS). There were no significant differences in the systemic clearance of midazolam with or without clotrimazole troches. CONCLUSIONS: Oral clotrimazole troches decreased the apparent oral clearance of midazolam; no significant differences in the systemic clearance of midazolam were found.
Assuntos
Ansiolíticos/farmacocinética , Antifúngicos/farmacocinética , Clotrimazol/farmacologia , Citocromo P-450 CYP3A/metabolismo , Midazolam/farmacocinética , Administração Oral , Adolescente , Adulto , Análise de Variância , Ansiolíticos/administração & dosagem , Antifúngicos/administração & dosagem , Área Sob a Curva , Clotrimazol/administração & dosagem , Estudos Cross-Over , Interações Medicamentosas , Feminino , Humanos , Injeções Intravenosas , Masculino , Taxa de Depuração Metabólica , Midazolam/administração & dosagem , Pessoa de Meia-IdadeRESUMO
PURPOSE: We conducted a prospective, open-label study in 54 adult subjects with sickle cell disease to determine the relationship between morphine concentrations, cytochrome P450 (CYP) 2D6 genotype, and clinical outcomes. METHODS: A blood sample was obtained for genotyping and serial blood samples were drawn to measure codeine and its metabolites in the plasma before and after oral codeine sulfate 30 mg. Codeine and its metabolites were measured by liquid chromatography-tandem mass spectrometry (LC-MS). CYP2D6 genetic testing included four single nucleotide polymorphisms (SNP) indicative of three variant alleles: *17 (1023T); *29 (1659A, 3183A); and *41 (2988A) alleles. RESULTS: Thirty subjects (group I) had a mean (standard deviation) maximal morphine concentration of 2.0 (1.0) ng/ml. Morphine was not measurable in the remaining 24 subjects (group II). Nine (30%) subjects in group I and 11 (46%) subjects in group II carried a variant *17, *29, or *41 allele (p = 0.23); one (3%) subject in group I and 5 (21%) subjects in group II were homozygous for *17 or *29 allele (p = 0.07). Emergency room visits (group I 1.5 +/- 1.8 vs. group II 2.1 +/- 4.3, p = NS) did not differ based on metabolic status, but more hospital admissions (0.9 +/- 1.4 vs. 2.2 +/- 4.1, p = 0.05) were documented in patients with no measurable morphine concentrations. CONCLUSIONS: We conclude that Blacks with sickle cell disease without measurable plasma morphine levels after a single dose of codeine were not more likely to be a carrier of a single variant allele commonly associated with reduced CYP2D6 metabolic capacity; however, homozygosity for a variant CYP2D6 allele may result in reduced metabolic capacity. Furthermore, it appears that subjects without measurable morphine concentrations were more likely to be admitted to the hospital for an acute pain crisis.
Assuntos
Analgésicos Opioides/farmacocinética , Anemia Falciforme/genética , População Negra/estatística & dados numéricos , Codeína/farmacocinética , Morfina/farmacocinética , Adulto , Alelos , Analgésicos Opioides/química , Analgésicos Opioides/metabolismo , Área Sob a Curva , Codeína/química , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Feminino , Genótipo , Meia-Vida , Heterozigoto , Homozigoto , Humanos , Masculino , Taxa de Depuração Metabólica , Estrutura Molecular , Morfina/química , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Valores de ReferênciaRESUMO
INTRODUCTION: Aldosterone promotes renal fibrosis via the mineralocorticoid receptor (MR), thus contributing to hypertension-induced nephropathy. We investigated whether MR gene expression influences renal fibrosis and MR antagonist response in a two-kidney, one-clip hypertensive rat model. MATERIALS AND METHODS: Brown Norway (BN), Lewis, and ACI rats were randomised to spironolactone 20 mg/kg/day or water by gavage, starting four weeks after left renal artery clipping. Blood pressure was measured bi-weekly by tail cuff. After eight weeks of treatment, right kidneys were removed and examined for fibrosis and gene expression. Rats of each strain undergoing no intervention served as controls. RESULTS: Blood pressure increased similarly among strains after clipping and was unaffected by spironolactone. Hypertension caused the greatest renal fibrosis in BN rats (p < 0.001 by ANOVA compared to other strains). Real-time PCR analysis showed greater renal collagen type I and MR gene expression in untreated, hypertensive BN rats (both p < 0.05 compared to other strains). Spironolactone attenuated fibrosis, with similar fibrosis among strains of spironolactone-treated rats. CONCLUSION: Hypertension-induced renal fibrosis was greatest in rats with the highest MR gene expression. Spironolactone abolished inter-strain differences in fibrosis. Our data suggest that MR genotype may influence aldosterone-induced renal damage, and consequently, renal response to aldosterone antagonism.
Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Hipertensão/complicações , Hipertensão/genética , Rim/efeitos dos fármacos , Rim/patologia , Receptores de Mineralocorticoides/genética , Espironolactona/farmacologia , Aldosterona/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Fibrose , Hidroxiprolina/metabolismo , Masculino , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Receptores de Mineralocorticoides/metabolismo , Espironolactona/administração & dosagem , Sístole/efeitos dos fármacosAssuntos
Derivação Gástrica/efeitos adversos , Fístula Gástrica/diagnóstico , Ventrículos do Coração , Ponte Cardiopulmonar/métodos , Evolução Fatal , Fístula/diagnóstico , Fístula/cirurgia , Derivação Gástrica/métodos , Fístula Gástrica/cirurgia , Gastroscopia/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos , Obesidade Mórbida/diagnóstico , Obesidade Mórbida/cirurgia , Complicações Pós-Operatórias/cirurgia , Reoperação , Fatores de TempoRESUMO
STUDY OBJECTIVE: To determine whether beta-blocker dose influences cardiac collagen turnover and the effects of spironolactone on cardiac collagen turnover in patients with heart failure. DESIGN: Prospective clinical study. SETTING: Two heart failure centers. PATIENTS: Eighty-eight spironolactone-naïve patients with heart failure who were taking beta-blockers. INTERVENTION: In a subset of 29 patients, spironolactone was started at 12.5 mg/day, with the dosage titrated to 25 mg/day if tolerated. MEASUREMENTS AND MAIN RESULTS: Venous blood samples were collected from each patient. Serum procollagen type I and type III aminoterminal peptides (PINP and PIIINP) were determined by radioimmunoassay and compared between the 25 patients receiving low doses (< 50% of recommended target dose) and the 63 patients receiving high doses (> or = 50% of recommended target dose) of beta-blockers. Patients receiving low-dose beta-blockers had higher mean +/- SD PIIINP concentrations (6.6 +/- 3.5 vs 4.9 +/- 2.6 microg/L, p=0.03) and tended to have higher PINP concentrations (74.0 +/- 44.1 vs 57.1 +/- 28.6 microg/L, p=0.10) compared with those receiving high doses. A repeat blood sample was collected from the 29 patients who received spironolactone after 6 months of therapy. Changes in procollagen peptides also were compared in this subset between low-dose (9 patients) and high-dose (20 patients) beta-blocker groups. Low beta-blocker doses were associated with greater reductions in concentrations of PINP (median [intraquartile range] -14.3 microg/L [-9.8 to -19.3 microg/L] vs -2.5 microg/L [5.9 to -9.8 microg/L], p=0.02) and PIIINP (-1.4 microg/L [-0.9 to -2.4 microg/L] vs 0.1 microg/L [0.9 to -1.3 microg/L], p=0.045) with spironolactone therapy than high beta-blocker doses. In addition, 100% of the patients in this subset taking low-dose beta-blockers versus only 35% taking higher doses had reductions in both markers of cardiac fibrosis. CONCLUSION: Spironolactone may benefit patients with heart failure who cannot tolerate upward titration of beta-blocker dosages, at least in terms of its effects on cardiac remodeling.
Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Diuréticos/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Fragmentos de Peptídeos/metabolismo , Pró-Colágeno/metabolismo , Espironolactona/farmacologia , Antagonistas Adrenérgicos beta/administração & dosagem , Adulto , Idoso , Atenolol/administração & dosagem , Atenolol/farmacologia , Carbazóis/administração & dosagem , Carbazóis/farmacologia , Carvedilol , Diuréticos/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Fibrose/fisiopatologia , Humanos , Masculino , Metoprolol/administração & dosagem , Metoprolol/farmacologia , Pessoa de Meia-Idade , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/efeitos dos fármacos , Pró-Colágeno/sangue , Pró-Colágeno/efeitos dos fármacos , Propanolaminas/administração & dosagem , Propanolaminas/farmacologia , Estudos Prospectivos , Radioimunoensaio , Espironolactona/administração & dosagemRESUMO
OBJECTIVE: Coronary artery bypass graft surgery carries increased risk for patients requiring dialysis compared with other groups. Little data exist comparing outcomes of on-pump and off-pump techniques in dialysis patients. This study compares outcomes of bypass grafting in dialysis patients with these two techniques at a single institution and in the United States Renal Data System (USRDS) database. METHODS: From March 1997 to April 2004, 37 patients requiring dialysis underwent bypass graft surgery at our institution. On-pump surgery was performed for 16 patients and off-pump surgery for 21. From January 1, 2001, to December 31, 2002, a total of 3922 patients in the USRDS underwent bypass graft surgery. On-pump surgery was performed for 3382 and off-pump surgery for 540. Comparisons were made between patients undergoing on-pump and off-pump bypass surgery with respect to demographics, risk factors, and outcomes. Univariate analysis, the Kaplan-Meier method, and a multivariate Cox model were used. RESULTS: Institutional analysis revealed similar patient demographics, risk factors, use of thoracic artery grafts, and number of distal anastomoses. Outcome analysis was significant for less postoperative atrial fibrillation with the off-pump technique: 37.5% on-pump and 4.8% off-pump (P = .028). USRDS data revealed all-cause survivals at 1 and 18 months of 87.5% and 59.5% for on-pump versus 88.3% and 61.9% for off-pump procedures (P = .226). In a comorbidity-adjusted Cox model, off-pump bypass grafting was associated with a 16% reduction in all-cause mortality (P = .032). CONCLUSION: Off-pump bypass grafting is uncommon in patients in the United States who require dialysis. Off- pump bypass grafting provides a morbidity benefit and is associated with a lower risk of death.
Assuntos
Ponte de Artéria Coronária , Doença das Coronárias/cirurgia , Falência Renal Crônica/terapia , Diálise Renal , Ponte de Artéria Coronária sem Circulação Extracorpórea , Doença das Coronárias/complicações , Feminino , Humanos , Falência Renal Crônica/complicações , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Estados UnidosRESUMO
Few studies describe the administration of Taxol to rats; however, rats are typically used to study the toxicity of new drugs or novel formulations. A dose finding study was conducted to determine a safe dose of Taxol following intravenous administration in rats. Male Sprague-Dawley rats received a bolus of paclitaxel 5-20 mg/kg i.v. Blood was drawn before administration and at the following times after administration: 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20 and 24 h. Plasma concentrations were determined using high performance liquid chromatography. Two rats received paclitaxel 20 mg/kg and died immediately. Nine rats received paclitaxel 10 mg/kg; seven of these rats died within 12 h and two rats were killed due to moribund conditions. Ten rats received paclitaxel 5 mg/kg with no morbidity. The following pharmacokinetics for paclitaxel in the plasma were estimated: C0, 8977 ng/ml; AUC(0 --> infinity), 7477 ng*h/ml; CL(s), 668 ml/h*kg; V(ss), 1559 ml/kg; V(z) 2557 ml/kg and t(1/2), 2.6 h. It is concluded that further pharmacokinetic studies that are rationally designed to include appropriate measures of preclinical toxicity associated with paclitaxel are needed to identify formally the safest dose in rats following intravenous administration; however, these data indicate that male Sprague-Dawley rats can safely receive Taxol in a 5 mg/kg i.v. bolus.
Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Paclitaxel/farmacocinética , Animais , Antineoplásicos Fitogênicos/sangue , Antineoplásicos Fitogênicos/toxicidade , Injeções Intravenosas , Masculino , Paclitaxel/sangue , Paclitaxel/toxicidade , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: We identified a drug-drug interaction between gemcitabine and paclitaxel in a clinical pharmacokinetic study. The purpose of the present study was to determine whether paclitaxel affected the uptake and accumulation of the parent drug gemcitabine and the formation of its metabolites after treatment of cells with gemcitabine in vitro. MATERIALS AND METHODS: The human leukemia cell line CEM was treated with 15 micoM 3H-gemcitabine, with and without paclitaxel, and the accumulation of radiolabeled gemcitabine was assessed up to one minute and one hour. Peripheral blood mononuclear cells (PMN) and hepatocytes were treated with gemcitabine, with or without paclitaxel, for specified amounts of time at three concentrations of gemcitabine, and the concentrations of gemcitabine and its metabolites were measured by liquid chromatography. RESULTS: In CEM cells, paclitaxel reduced the uptake and accumulation of gemctabine by 32% and 30%, respectively. In the hepatocytes, the mean concentrations of gemcitabine increased in the cell culture media 100%, 48% and 38% when treated with paclitaxel plus gemcitabine 5, 15 and 30 microM, respectively, compared to gemcitabine alone. The concentrations of the deaminated metabolite dFdU were significantly decreased in the cell culture media. In the PMN, the intracellular accumulation of active triphosphorylated metabolite dFdCTP was lower in cells treated with paclitaxel (up to 83%) compared to the control. CONCLUSION: Paclitaxel substantially reduced the uptake and accumulation of gemcitabine and the formation of its metabolites in vitro at clinically relevant concentrations.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Desoxicitidina/análogos & derivados , Leucemia/metabolismo , Paclitaxel/farmacologia , Transporte Biológico/efeitos dos fármacos , Desoxicitidina/administração & dosagem , Desoxicitidina/sangue , Desoxicitidina/farmacocinética , Interações Medicamentosas , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Leucemia/sangue , Leucemia/tratamento farmacológico , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Paclitaxel/administração & dosagem , Paclitaxel/sangue , Trítio , Células Tumorais Cultivadas , GencitabinaRESUMO
BACKGROUND: The short-term clinical impact of intramyocardial gene transfer (GT) of the angiogenic protein vascular endothelial growth factor-2 (VEGF-2) has been previously reported to significantly reduce Canadian Cardiovascular Society (CCS) angina class and to prolong exercise treadmill test (ETT) time. We describe the safety and long-term events (>1 year) in consecutive, nonrandomized, patients who received intramyocardial VEGF-2. METHODS: Thirty patients with intractable CCS class III or IV angina and no options for revascularization underwent direct intramyocardial GT of VEGF-2 naked DNA via limited thoracotomy at total doses of 0.2, 0.8, or 2.0 mg. Patients were followed for clinical events after 1 year by hospital records, follow-up visits or telephone contact. Due to one perioperative death, 29 patients were followed. RESULTS: At a mean follow-up of 751 +/- 102.5 days (range 459-959) there were four deaths (13.8%), five myocardial infarctions (MIs) (17.2%), and seven revascularization procedures (24.1%). There were 15 hospitalizations in 12 patients. At the end of the follow-up period no patient (0%) had CCS class IV angina, 3 patients (11.5%) had class III angina, and 23 (88.5%) had class I to II angina. There were two new diagnoses of cancer. CONCLUSION: Transthoracic intramyocardial injection of VEGF-2 is associated with an improvement of symptoms of angina in the majority of patients beyond the first year of treatment. Major clinical events such as death, MI, and repeat revascularization are uncommon during the first year but more frequent after 1 year at a rate consistent with the severity of underlying disease in this population with advanced atherosclerosis. The majority of events were the result of progression of disease in areas of the heart remote from the site of GT. A large randomized trial is planned to determine the efficacy of intramyocardial VEGF-2 injections in inoperable patients.