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1.
J Evol Biol ; 31(2): 267-276, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29194826

RESUMO

Females are predicted to alter sex allocation when ecological, physiological and behavioural variables have different consequences on the fitness of male and female offspring. Traditionally, tests of sex allocation have examined single causative factors, often ignoring possible interactions between multiple factors. Here, we used a multifactorial approach to examine sex allocation in the viviparous skink, Niveoscincus ocellatus. We integrated a 16-year observational field study with a manipulative laboratory experiment to explore whether the effects of the maternal thermal environment interact with the resources available to females for reproduction to affect sex allocation decisions. We found strong effects of temperature on sex allocation in the field, with females born in warm conditions and males in cold conditions; however, this was not replicated in the laboratory. In contrast, we found no effect of female resource availability on sex allocation, either independently, or in interaction with temperature. These results corresponded with an overall lack of an effect of resource availability on any of the life history traits that we predicted would mediate the benefits of differential sex allocation in this system, suggesting that selection for sex allocation in response to resource availability may be relatively weak. Combined, these results suggest that temperature may be the predominant factor driving sex allocation in this system.


Assuntos
Lagartos/fisiologia , Reprodução , Processos de Determinação Sexual , Razão de Masculinidade , Animais , Feminino , Alimentos , Luz , Masculino , Temperatura , Viviparidade não Mamífera
2.
Knee Surg Sports Traumatol Arthrosc ; 24(2): 540-5, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26658571

RESUMO

PURPOSE: To compare arthroscopic and open Latarjet performed by a single shoulder surgeon with learning curve analysis METHODS: A comparative and learning curve analysis was carried out on a prospectively gathered database of 2 consecutive series of patients treated with arthroscopic and open Latarjet procedures performed by a single shoulder surgeon between 2008 and 2014. The database included patient characteristics, ISIS scores, operative time, intra- and postoperative complications, graft and screws positioning, as well as pre- and postoperative Walch-Duplay scores. RESULTS: Sixty-four patients were included in the study, 28 in the arthroscopic group and 36 in the open group with similar age, sex ratio and preoperative ISIS score. Operative time was significantly higher in the arthroscopic group (146 versus 81 min, p = 0.001), and although no intra-operative complications were recorded in either group, there were significantly more postoperative complications in the arthroscopic group (29 vs. 11 %, p = 0.03). Screw placement was more accurate in the open group, and postoperative Walch-Duplay score did not show any significant difference between the groups (88 points in the arthroscopic group and 91 points in the open group). The arthroscopic Latarjet learning curve analysis showed that the need for conversion ceased after the first 10 patients and that surgical time came close to that of open procedure after 20 procedures. CONCLUSIONS: In this study, 10 arthroscopic Latarjet procedures were needed to overcome the need for conversion, and 20 procedures to achieve equal operating time to the open technique. Even though functional outcome and patient satisfaction were similar in both techniques, complications, screw placement inaccuracy, persistent apprehension and recurrences still remain higher with the arthroscopic technique. LEVEL OF EVIDENCE: Retrospective comparative analysis, Level III.


Assuntos
Artroscopia/métodos , Transplante Ósseo/métodos , Competência Clínica , Instabilidade Articular/cirurgia , Curva de Aprendizado , Escápula/cirurgia , Articulação do Ombro/cirurgia , Adulto , Idoso , Artroscopia/efeitos adversos , Transplante Ósseo/efeitos adversos , Feminino , Humanos , Instabilidade Articular/complicações , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Recidiva , Estudos Retrospectivos
3.
Philos Trans A Math Phys Eng Sci ; 373(2045)2015 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-26032317

RESUMO

We present our estimates of the thickness and volume of the Arctic Ocean ice cover from CryoSat-2 data acquired between October 2010 and May 2014. Average ice thickness and draft differences are within 0.16 m of measurements from other sources (moorings, submarine, electromagnetic sensors, IceBridge). The choice of parameters that affect the conversion of ice freeboard to thickness is discussed. Estimates between 2011 and 2013 suggest moderate decreases in volume followed by a notable increase of more than 2500 km(3) (or 0.34 m of thickness over the basin) in 2014, which could be attributed to not only a cooler summer in 2013 but also to large-scale ice convergence just west of the Canadian Arctic Archipelago due to wind-driven onshore drift. Variability of volume and thickness in the multiyear ice zone underscores the importance of dynamics in maintaining the thickness of the Arctic ice cover. Volume estimates are compared with those from ICESat as well as the trends in ice thickness derived from submarine ice draft between 1980 and 2004. The combined ICESat and CryoSat-2 record yields reduced trends in volume loss compared with the 5 year ICESat record, which was weighted by the record-setting ice extent after the summer of 2007.

4.
Rev Med Suisse ; 10(455): 2398-402, 2014 Dec 17.
Artigo em Francês | MEDLINE | ID: mdl-25752009

RESUMO

Evolution of shoulder arthroplasty has led to mainly three types of implants: hemiarthroplasty, total shoulder arthroplasty and reverse shoulder arthroplasty. There is yet no clear consensus about indications for the different existing types of prothesis. The aim of this article is therefore to bring together and clarify the indications found in the current literature. Hemiarthroplasty, historically the first widely used implant, has lost much ground to total shoulder arthroplasty, and keeps its place only for specific situations. Total shoulder arthroplasty is mainly used for centered glenohumeral osteoarthritis, whereas reverse shoulder arthroplasty is indicated for most situations in which the rotator cuff or tuberoties are deficient.


Assuntos
Artroplastia de Substituição , Prótese Articular , Articulação do Ombro/cirurgia , Árvores de Decisões , Humanos
5.
Int J Clin Pract ; 67(11): 1163-72, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23714173

RESUMO

Erectile dysfunction (ED) and cardiovascular disease (CVD) share risk factors and frequently coexist, with endothelial dysfunction believed to be the pathophysiologic link. ED is common, affecting more than 70% of men with known CVD. In addition, clinical studies have demonstrated that ED in men with no known CVD often precedes a CVD event by 2-5 years. ED severity has been correlated with increasing plaque burden in patients with coronary artery disease. ED is an independent marker of increased CVD risk including all-cause and especially CVD mortality, particularly in men aged 30-60 years. Thus, ED identifies a window of opportunity for CVD risk mitigation. We recommend that a thorough history, physical exam (including visceral adiposity), assessment of ED severity and duration and evaluation including fasting plasma glucose, lipids, resting electrocardiogram, family history, lifestyle factors, serum creatinine (estimated glomerular filtration rate) and albumin:creatinine ratio, and determination of the presence or absence of the metabolic syndrome be performed to characterise cardiovascular risk in all men with ED. Assessment of testosterone levels should also be considered and biomarkers may help to further quantify risk, even though their roles in development of CVD have not been firmly established. Finally, we recommend that a question about ED be included in assessment of CVD risk in all men and be added to CVD risk assessment guidelines.


Assuntos
Doenças Cardiovasculares/diagnóstico , Disfunção Erétil/etiologia , Papel do Médico , Adulto , Cardiologia , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/fisiopatologia , Endotélio Vascular/fisiologia , Disfunção Erétil/mortalidade , Disfunção Erétil/fisiopatologia , Medicina Geral , Humanos , Masculino , Pessoa de Meia-Idade , Padrões de Prática Médica , Medição de Risco , Comportamento de Redução do Risco
6.
Mol Genet Metab Rep ; 31: 100868, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35782607

RESUMO

We have developed a fast and accurate method that uses a small volume of sample to determine over 25 of the typically reported amino acids in human plasma. Samples were prepped with a single step using a spin filter to remove proteins, avoiding the decreased sensitivity from dilution in acid precipitation. Using a reverse phase (RP) High Performance Liquid Chromatography (HPLC) system with O-phthaldehyde (OPA) as the pre-column derivatization reagent, and UV detection at 338 nm, we did a direct comparison with the most common ion exchange/ninhydrin method used in clinical labs on the same plasma samples with 95% concurrence, analysis of amino acid standard solutions returned 99% concurrence. With a sample preparation time of 30 min, utilizing less than 25 µl of sample and with a chromatography run of 30 min, this method can substantially increase access to analysis in both clinical and research laboratories using instruments that are more widely available. Synopsis: We describe a rapid and easily deployed method for sensitive amino measurement in biological samples.

7.
J Geophys Res Space Phys ; 127(10): e2022JA030751, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36591320

RESUMO

Dropout events are dramatic decreases in radiation belt electron populations that can occur in as little as 30 minutes. Loss to magnetopause due to a combination of magnetopause shadowing and outward radial transport plays a significant role in these events. We examine the dropout of relativistic electron populations during the October 2012 geomagnetic storm using simulated electron phase space density, evaluating the contribution of different processes to losses across the magnetopause. We compare loss contribution from outward transport calculated using a standard empirical radial diffusion model that assumes a dipolar geomagnetic field to an event-specific radial diffusion model evaluated with a non-dipolar geomagnetic field. We additionally evaluate the contribution of Shabansky type 1 particles, which bounce along magnetic field lines with local equatorial maxima, to the loss calculated during this event. We find that the empirical radial diffusion model with a dipolar background field underestimates the contribution of radial diffusion to this dropout event by up to 10% when compared to the event-specific, non-dipolar radial diffusion model. We additionally find that including Shabansky type 1 particles in the initial electron phase space density, that is, allowing some magnetic field lines distorted from the typical single-minima configuration in drift shell construction, increases the calculated loss by an average of 0.75%. This shows that the treatment of the geomagnetic field significantly impacts the calculation of electron losses to the magnetopause during dropout events, with the non-dipolar treatment of radial diffusion being essential to accurately quantify the loss of outer radiation belt populations.

8.
Rev Med Suisse ; 7(322): 2489-93, 2011 Dec 21.
Artigo em Francês | MEDLINE | ID: mdl-22288288

RESUMO

Posterior glenohumeral dislocation is rare, accounting for less than 3% of all shoulder dislocations. Main etiologies are direct or indirect trauma, seizure and electrocution. The diagnosis is missed in 50 to 80% of the cases on initial presentation because of the rather subtle clinical signs compared to anterior dislocation and inadequate imaging. An unreduced posterior dislocation can lead to severely impairing complications such as recurrent instability, arthritis or avascular necrosis, requiring open reduction and complex surgery with a lower rate of success. The purpose of this article is to highlight and clarify the challenges when confronted with posterior dislocation in order to avoid misdiagnosis. Furthermore it aims to propose an adequate and comprehensible management from the initial diagnosis to the treatment.


Assuntos
Luxação do Ombro/diagnóstico , Luxação do Ombro/terapia , Algoritmos , Humanos , Radiografia , Luxação do Ombro/etiologia , Articulação do Ombro/diagnóstico por imagem
9.
Nat Commun ; 12(1): 3553, 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34117233

RESUMO

Lightning superbolts are the most powerful and rare lightning events with intense optical emission, first identified from space. Superbolt events occurred in 2010-2018 could be localized by extracting the high energy tail of the lightning stroke signals measured by the very low frequency ground stations of the World-Wide Lightning Location Network. Here, we report electromagnetic observations of superbolts from space using Van Allen Probes satellite measurements, and ground measurements, and with two events measured both from ground and space. From burst-triggered measurements, we compute electric and magnetic power spectral density for very low frequency waves driven by superbolts, both on Earth and transmitted into space, demonstrating that superbolts transmit 10-1000 times more powerful very low frequency waves into space than typical strokes and revealing that their extreme nature is observed in space. We find several properties of superbolts that notably differ from most lightning flashes; a more symmetric first ground-wave peak due to a longer rise time, larger peak current, weaker decay of electromagnetic power density in space with distance, and a power mostly confined in the very low frequency range. Their signal is absent in space during day times and is received with a long-time delay on the Van Allen Probes. These results have implications for our understanding of lightning and superbolts, for ionosphere-magnetosphere wave transmission, wave propagation in space, and remote sensing of extreme events.

10.
Sci Adv ; 6(41)2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33033038

RESUMO

We investigate the shape of near-Earth asteroid (101955) Bennu by constructing a high-resolution (20 cm) global digital terrain model from laser altimeter data. By modeling the northern and southern hemispheres separately, we find that longitudinal ridges previously identified in the north extend into the south but are obscured there by surface material. In the south, more numerous large boulders effectively retain surface materials and imply a higher average strength at depth to support them. The north has fewer large boulders and more evidence of boulder dynamics (toppling and downslope movement) and surface flow. These factors result in Bennu's southern hemisphere being rounder and smoother, whereas its northern hemisphere has higher slopes and a less regular shape. We infer an originally asymmetric distribution of large boulders followed by a partial disruption, leading to wedge formation in Bennu's history.

11.
Science ; 196(4292): 875-7, 1977 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-404707

RESUMO

Distribution of the enzyme aldehyde oxidase in mature Drosophilia melanogaster wing disks may allow visualization of known developmental compartments comprising (i) presumptive dorsal and ventral wing surfaces, and (ii) the presumptive anterior wing and the presumptive posterior wing.


Assuntos
Aldeído Oxirredutases/metabolismo , Drosophila melanogaster/fisiologia , Asas de Animais/fisiologia , Animais , Drosophila melanogaster/enzimologia , Drosophila melanogaster/crescimento & desenvolvimento , Larva , Mutação , Pupa , Asas de Animais/enzimologia , Asas de Animais/crescimento & desenvolvimento
12.
Science ; 210(4468): 399-404, 1980 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-17837407

RESUMO

Increasing salinity of soil and water threatens agriculture in arid and semiarid regions. By itself, the traditional engineering approach to the problem is no longer adequate. Genetic science offers the possibility of developing salt-tolerant crops, which, in conjunction with environmental manipulation, could improve agricultural production in saline regions and extend agriculture to previously unsuited regions.

13.
Science ; 247(4946): 1043-8, 1990 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-17800060

RESUMO

Studies of ecosystem processes on the Jornada Experimental Range in southern New Mexico suggest that longterm grazing of semiarid grasslands leads to an increase in the spatial and temporal heterogeneity of water, nitrogen, and other soil resources. Heterogeneity of soil resources promotes invasion by desert shrubs, which leads to a further localization of soil resources under shrub canopies. In the barren area between shrubs, soil fertility is lost by erosion and gaseous emissions. This positive feedback leads to the desertification of formerly productive land in southern New Mexico and in other regions, such as the Sahel. Future desertification is likely to be exacerbated by global climate warming and to cause significant changes in global biogeochemical cycles.

14.
Mycologia ; 111(1): 13-25, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30699058

RESUMO

The maintenance of cell shape requires finely tuned and robust vesicle trafficking in order to provide sufficient plasma membrane materials. The hyphal cells of filamentous fungi are an extreme example of cell shape maintenance due to their ability to grow rapidly and respond to the environment while keeping a relatively consistent shape. We have previously shown that two phospholipid flippases, which regulate the asymmetry of specific phospholipids within the plasma membrane, are important for hyphal growth in Aspergillus nidulans. Here, we examine the rest of the phospholipid flippases encoded by A. nidulans by obtaining single and double deletions of all four family members, dnfA, dnfB, dnfC, and dnfD. We find that deleting dnfC does not impart a noticeable phenotype, by itself or with other deletions, but that dnfD, the homolog of the essential yeast gene neo1, is important for conidiation. dnfD deletion mutants form misshapen conidiophore vesicles that are defective in metulae formation. We localize DnfD to late Golgi equivalents, where it appears just before dissociation of this organelle. We propose that DnfD functions in a trafficking process that is specifically required for the morphological changes that take place during conidiation.


Assuntos
Aspergillus nidulans/genética , Proteínas Fúngicas/fisiologia , Complexo de Golgi/enzimologia , Fosfolipídeos/fisiologia , Reprodução Assexuada , Aspergillus nidulans/enzimologia , Proteínas Fúngicas/genética , Deleção de Genes , Hifas/crescimento & desenvolvimento , Mutação , Fenótipo , Filogenia , Esporos Fúngicos
15.
J Clin Invest ; 102(10): 1824-30, 1998 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-9819368

RESUMO

In this study, we evaluated if increased sympathetic stimulation is an essential requirement for the development of neurally mediated syncope (NMS) by manipulating overall sympathetic outflow in subjects susceptible to tilt-induced syncope. Eight previously characterized patients with recurrent NMS (five females and three males; 34+/-2 yr) were recruited from the Vanderbilt Syncope Unit and eight age-matched controls underwent initial administration of clonidine (CLO) or yohimbine (YHO). This was done, prospectively, to determine doses of these agents that would increase or decrease plasma norepinephrine levels by >/= 30%. On a different day, in all subjects we determined intraarterial blood pressure, EKG and muscle sympathetic nerve activity (MSNA) both supine and during upright tilt. After this, subjects randomly received either CLO or YHO, and 3 h later another tilt was performed. After 1 wk, a similar procedure with the other drug was performed. During the two basal tilts, all the control subjects completed the study, whereas all the NMS patients developed syncope. Reduction in sympathetic tone by CLO resulted in a decreased tolerance to tilt in three out of eight controls and in all the NMS patients. In contrast, YHO not only increased basal plasma NorEpi levels and MSNA, but also prevented syncope in seven out of eight patients. In a selected population of patients, increased sympathetic activity is not a prerequisite for the development of syncope. Yohimbine-induced enhancement of sympathetic tone in patients with NMS improves orthostatic tolerance and raises the possibility that this drug may be a useful agent in the treatment of NMS.


Assuntos
Síncope Vasovagal/fisiopatologia , Ioimbina/farmacologia , Adulto , Clonidina/farmacologia , Epinefrina/sangue , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Masculino , Norepinefrina/sangue , Estudos Prospectivos , Distribuição Aleatória , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiopatologia , Síncope Vasovagal/sangue , Síncope Vasovagal/prevenção & controle , Teste da Mesa Inclinada
16.
Infect Control Hosp Epidemiol ; 28(8): 976-82, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17620247

RESUMO

BACKGROUND: Staphylococcus aureus is an important pathogen that leads to serious infections in the community and in hospitals. Evidence has shown that the prevalence of infection and colonization with drug-resistant S. aureus, such as methicillin-resistant S. aureus (MRSA) and glycopeptide intermediately susceptible S. aureus, is increasing. Authorities must be aware of the prevalence of MRSA infection and colonization in their country in order to implement and monitor infection control policies that help curtail further emergence of this pathogen. OBJECTIVES: To examine the trend of hospital-acquired MRSA infection and colonization in a tertiary care institution in Saudi Arabia during a 5-year period in order to identify specific areas at high risk for MRSA transmission, and to review our MRSA decolonization procedure and outcomes. METHODS: Surveillance data prospectively collected from January 1, 2000, through December 31, 2004, on hospital-acquired (HA) MRSA were analyzed, with an emphasis on the trend of HA-MRSA infection and colonization, areas of high transmission, risk factors, and effectiveness of the implemented decolonization policy. RESULTS: During the study period, 442 cases of HA-MRSA infection and colonization were identified. Of these, 51.2% were infections, and 48.8% were colonizations. An increasing trend in the incidence rates of infection and colonization was noticed during the study period, and most cases were identified on the surgical ward (33.3%) and medical ward (32.1%). Of the 34 infected patients who underwent systematic decolonization, 35.3% were successfully decolonized, and of the 11 who underwent topical decolonization, 63.6% were successfully decolonized. CONCLUSION: The increasing trend of HA-MRSA infections has been a noticeable global problem. We identified a gradual increase in the rates of MRSA colonization and infection in a tertiary care center Saudi Arabia and recognize the importance of abiding by strict infection control policies, including hand hygiene and proper isolation practices. Continued surveillance for MRSA and other emerging multidrug-resistant pathogens is also needed.


Assuntos
Infecção Hospitalar/epidemiologia , Resistência a Meticilina , Infecções Estafilocócicas/epidemiologia , Staphylococcus aureus/efeitos dos fármacos , Adulto , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Arábia Saudita/epidemiologia , Vigilância de Evento Sentinela
17.
J Hosp Infect ; 62(2): 207-13, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16307822

RESUMO

The aim of this study was to determine the rate, risk factors and outcomes of catheter-related bloodstream infections (CRBSIs) in patients in a paediatric intensive care unit (PICU). A prospective cohort study was performed in King Abdulaziz Medical City, Riyadh, Saudi Arabia; a 650-bed academic/tertiary care centre with a combined 10-bed medical and surgical PICU. All patients admitted to the PICU from July 2000 to February 2003 who had a central line placed were monitored for the development of bloodstream infection (BSI) from insertion until 48 h after removal. Four hundred and forty-six patients with 2493 central-line-days were documented; 273 (55%) were male and the mean age was 2.6 years. Of the 446 patients, 278 (56%) had congenital heart disease, 108 (22%) had genetic disorders and/or congenital malformations, 55 (11%) had respiratory disease, and 42 (8%) had trauma. There were 50 episodes of CRBSI in 46 patients with a rate of 20.06 per 1,000 central-line-days and a device-utilization rate of 57%. Of these 50 episodes, 24 (48%) were polymicrobial, 16 (32%) were due to Gram-negative organisms, five (10%) were due to Gram-positive organisms, and five (10%) were fungal. The most common organisms isolated were Klebsiella pneumoniae (N=12, 16%), coagulase-negative staphylococci (N=10, 14%) and Pseudomonas aeruginosa (N=8, 11%). The mean duration of line insertion was 11.8 days for CRBSI patients and 4.22 days for non-BSI patients (P<0.0001). The mean PICU stay was 30.20 days for CRBSI patients and 6.35 days for non-BSI patients (P<0.0001). BSI occurred more often in catheters inserted in the PICU compared with the operating room, and in the femoral site compared with jugular or subclavian sites (P<0.001). In multiple logistic regression analysis of the risk factors, CRBSI patients were more likely to have multiple central lines [odds ratio (OR) 9.19; 95% confidence intervals (CI): 3.76-22.43), the line was more likely to be used for total parenteral nutrition (OR: 8.69; 95% CI: 3.5-21.4), and guidewire exchange was more likely to be performed on the line. CRBSI was not associated with a higher mortality rate. The CRBSI rate in our hospital is high compared with that reported by the National Nosocomial Infection Surveillance system. This study has established a benchmark for future comparisons. Additional studies from Saudi Arabia are necessary for national comparison and development of preventive measures.


Assuntos
Cateterismo Venoso Central/efeitos adversos , Unidades de Terapia Intensiva Pediátrica , Bacteriemia/epidemiologia , Bacteriemia/etiologia , Candida/isolamento & purificação , Pré-Escolar , Estudos de Coortes , Infecção Hospitalar/epidemiologia , Infecção Hospitalar/etiologia , Feminino , Bactérias Gram-Negativas/isolamento & purificação , Bactérias Gram-Positivas/isolamento & purificação , Humanos , Lactente , Masculino , Estudos Prospectivos , Fatores de Risco , Arábia Saudita
18.
Cancer Res ; 58(1): 76-83, 1998 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-9426061

RESUMO

The goals of this work were to establish a reproducible and effective model of apoptosis in a cell line derived from advanced prostate cancer and to study the role of the caspase family of proteases in mediating apoptosis in this system. The study involved the use of the prostate cancer cell line LNCaP. Apoptosis was induced using the hydroxymethyl glutaryl CoA reductase inhibitor, lovastatin, and was evaluated by agarose gel electrophoresis of genomic DNA, morphological criteria, and terminal deoxynucleotidyl transferase-mediated nick end labeling. Caspases were studied by catalytic activity, mRNA induction, and protein processing. Lovastatin (30 microM) was an effective inducer of apoptosis, causing changes that were evident after 48 h and essentially complete after 96-120 h of treatment. These effects were prevented by the simultaneous addition of mevalonate (300 microM) to the culture medium. Lovastatin induced a proteolytic activity that was able to cleave the enzyme poly(ADP-ribose) polymerase and the substrate Z-DEVD-AFC, which is modeled after the P1-P4 amino acids of the poly(ADP-ribose) polymerase cleavage site. Caspase-7, but not caspase-3, underwent proteolytic activation during lovastatin-induced apoptosis, an effect prevented by mevalonate. Caspase-7 was the only detected interleukin 1beta converting enzyme family protease with DEVD cleavage activity that exhibited lovastatin-induced mRNA up-regulation. Again, mevalonate blocked this effect. Lovastatin-induced apoptosis also was prevented when the caspase inhibitors Z-DEVD-CH2F or Z-VAD-CH2F (100 microM) where added to the medium. These studies have identified lovastatin as a powerful inducer of apoptosis in the cell line LNCaP. Caspase activation was a necessary event for LNCaP cells to undergo apoptosis during treatment with lovastatin. Of the caspases tested, only caspase-7 underwent proteolytic activation after stimulation with lovastatin. Identification of caspase-7 as a potential mediator of lovastatin-induced apoptosis broadens our knowledge of the molecular events associated with programmed cell death in a cell line derived from prostatic epithelium.


Assuntos
Anticolesterolemiantes/farmacologia , Antineoplásicos/farmacologia , Apoptose , Caspases , Cisteína Endopeptidases/metabolismo , Lovastatina/farmacologia , Neoplasias da Próstata/patologia , Western Blotting , Caspase 7 , Cisteína Endopeptidases/efeitos dos fármacos , Cisteína Endopeptidases/genética , Fragmentação do DNA , Eletroforese em Gel de Ágar , Ativação Enzimática , Inibidores Enzimáticos/farmacologia , Humanos , Masculino , Poli(ADP-Ribose) Polimerases/metabolismo , Neoplasias da Próstata/enzimologia , RNA Mensageiro/análise , Células Tumorais Cultivadas
19.
Cancer Res ; 59(2): 382-90, 1999 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-9927051

RESUMO

We studied the molecular mechanisms of apoptosis in the prostate cancer cell line LNCaP and whether overexpression of caspase activity could force this cell line to undergo apoptosis. The inhibitor of phosphomevalonate decarboxylase, sodium phenylacetate, and the protein kinase inhibitor staurosporine induced (a) release of cytochrome c from the mitochondria to the cytosol; (b) reduction in mitochondrial transmembrane potential; (c) proteolytic processing of caspase-3 and -7 but not -2; (d) cleavage of the DEVD substrate and the death substrates poly(ADP-ribose) polymerase and DNA fragmentation factor; and (e) apoptosis. The panspecific inhibitor of caspase activation N-benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (z-VAD-FMK) prevented all of these events except release of mitochondrial cytochrome c into the cytosol. None of these apoptotic signaling events were elicited by staurosporine or sodium phenylacetate treatment of LNCaP-Bcl-2 cells that overexpress the oncoprotein Bcl-2. Because caspase-7 is activated in every model of apoptosis that we have characterized thus far, we wished to learn whether overexpression of this protease could directly cause apoptosis of LNCaP cells. By using a replication-defective adenovirus, overexpression of caspase-7 protein in both LNCaP and LNCaP-Bcl-2 cells was accompanied by induction of cleavage of the DEVD substrate and TUNEL. These studies have demonstrated that caspase-7 and -3 are critical mediators of apoptosis in LNCaP cells. Caspase-7 was proteolytically activated in every model of apoptosis that we have developed, and the overexpression of it induced apoptosis of LNCaP and LNCaP-Bcl-2 cells. Thus, adenoviral-mediated transfer of caspase-7 may offer a new effective approach for the treatment of prostate cancer.


Assuntos
Apoptose , Caspases/genética , Terapia Genética , Neoplasias da Próstata/terapia , Butiratos/farmacologia , Caspase 2 , Caspase 3 , Caspase 7 , Inibidores de Caspase , Caspases/metabolismo , Caspases/fisiologia , Grupo dos Citocromos c/metabolismo , Ativação Enzimática , Humanos , Masculino , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-bcl-2/análise , Estaurosporina/farmacologia , Células Tumorais Cultivadas
20.
Pharmacol Ther ; 24(3): 367-400, 1984.
Artigo em Inglês | MEDLINE | ID: mdl-6205409

RESUMO

PIP: Most antiandrogens appear to act by binding to the androgen receptor and competitively inhibiting the binding of testosterone and cihydrotestosterone to the receptor. Focusing on those compounds which appear to inhibit androgen receptor mediated responses, this review discusses the chemistry of those antiandrogens which have been studied to the extent that their mechanism of action is at least partially understood, outlines the mechanism of androgen action as it is currently understood and suggests how antiandrogens might fit in with this mechanism, indicates the major metabolites of several important antiandrogens, and discusses the clinical applications of several antiandrogens. Cyproterone acetate has been studied extensively as a potential male contraceptive. Although it was recognized that 100 mg of cyproterone acetate per day inhibited spermatogenesis, that dose also reduced libido and potency. Following the administration of 10 or 20 mg of cyproterone acetate per day to 15 males for 26 weeks, the following observations were made: the number of motile sperm was reduced; the quality of their motion was impaired; and the ability of the sperm to penetrate cervical mucus was decreased. Sperm density was also suppressed, but neither it nor sperm motility were inhibited to the extent necessary for contraception. Antiandrogens have been demonstrated to be beneficial in treating 5 clinical syndromes or diseases: acne, seborrhea, hirsutism with or without menstrual abnormalities; precocious puberty; benign prostatic hypertrophy; cancer of the prostate; and sexual deviates. Since 3 of these conditions are very common, effective and safe treatment would have a large market. At this time, antiandrogens are widely used in Europe for treatment of seborrhea, acne, and hirsutism and a large Veterans Administration Cooperative Study in the US was approved but has not yet been funded to compare antiandrogens with other treatments for cancer of the prostate. Studies to assess antiandrogen interaction with other hormones or drugs have been limited. Side effects in the female have been best evaluated when cyproterone acetate was administered in combination with ethinyl estradiol. In 46 women followed over 317 cycles, side effects were similar to those reported with estrogen-progestin contraceptives. Administration of 10-20 mg of cyrproterone acetate per day to males caused no significant side effects, but 100 mg or more/day has caused loss of libido, impotence, gynecomastia, tiredness, weakness, decreased efficiency, weight gain, drying and desquamation of skin over the legs, and loss of hair on the trunk and pubic area.^ieng


Assuntos
Antagonistas de Androgênios , Receptores Androgênicos/metabolismo , Receptores de Esteroides/metabolismo , Esteroides , Anormalidades Induzidas por Medicamentos , Acne Vulgar/tratamento farmacológico , Antagonistas de Androgênios/análise , Antagonistas de Androgênios/metabolismo , Antagonistas de Androgênios/uso terapêutico , Antagonistas de Androgênios/toxicidade , Animais , Ligação Competitiva , Fenômenos Químicos , Química , Anticoncepcionais Masculinos , Feminino , Hirsutismo/tratamento farmacológico , Humanos , Masculino , Hiperplasia Prostática/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Puberdade Precoce/tratamento farmacológico , Receptores Androgênicos/análise , Disfunções Sexuais Fisiológicas/tratamento farmacológico , Esteroides/análise , Esteroides/metabolismo , Esteroides/uso terapêutico , Esteroides/toxicidade
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