Up-regulation of p21(WAF1)/(CIP1) by histone deacetylase inhibitors reduces their cytotoxicity

Histone deacetylase inhibitors show promise as chemotherapeutic agents and have been demonstrated to block proliferation in a wide range of tumor cell lines. Much of this antiproliferative effect has been ascribed to the up-regulated expression of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1). In this article, we report that p21 expression was up-regulated by relatively low doses of the histone deacetylase inhibitor azelaic bishydroxamic acid (ABHA) and correlated with a proliferative arrest. Higher doses of ABHA were cytotoxic. Cells that did not up-regulate p21 expression were hypersensitive to killing by ABHA and died via apoptosis, whereas up-regulation of p21 correlated with reduced sensitivity and a block in the apoptotic mechanism, and these cells seemed to die by necrosis. Using isogenic p21(+/+) and p21(-/-) cell lines and direct inhibition of caspase activity, we demonstrate that the reduced sensitivity to killing by ABHA is a consequence of inhibition of apoptosis by up-regulated p21 expression. These data indicate the enormous potential of therapeutic strategies that bypass the cytoprotective effect of p21 and act on the same molecular targets as the histone deacetylase inhibitors.

Using a cartographic modeling language to manipulate spectral satellite imagery

Land related information about the Earth's surface is commonIJ found in two forms: (1) map infornlation and (2) satellite image da ta. Satellite imagery provides a good visual picture of what is on the ground but complex image processing is required to interpret features in an image scene. Increasingly, methods are being sought to integrate the knowledge embodied in mop information into the interpretation task, or, alternatively, to bypass interpretation and perform biophysical modeling directly on derived data sources. A cartographic modeling language, as a generic map analysis package, is suggested as a means to integrate geographical knowledge and imagery in a process-oriented view of the Earth. Specialized cartographic models may be developed by users, which incorporate mapping information in performing land classification. In addition, a cartographic modeling language may be enhanced with operators suited to processing remotely sensed imagery. We demonstrate the usefulness of a cartographic modeling language for pre-processing satellite imagery, and define two nerv cartographic operators that evaluate image neighborhoods as post-processing operations to interpret thematic map values. The language and operators are demonstrated with an example image classification task.

Prospective survey of tick paralysis in dogs

Objective To obtain information on tick paralysis in dogs, including the nature of disease, host signalment, tick-host relationship, treatment, disease progression and recovery, and preventive measures. Design A prospective survey of 577 dogs affected by tick paralysis was conducted during 1998. Forty-two veterinary clinics along the eastern coast of Australia were instructed to complete survey forms for the first 15 dogs that presented with tick paralysis during September to November. Results Five percent of dogs died from tick paralysis. Younger dogs were more likely to survive. Long coat length was associated with a greater tick burden but not greater tick size, whereas coat thickness had no bearing on either. Dogs with mild disease recovered more quickly from tick paralysis. Respiratory and gait scores reflected disease severity and were good prognostic indicators. The size of the tick did not reflect the severity of the clinical condition it induced in the host. No method of tick removal or in situ treatment improved recovery time or reduced mortality. However, the time spent in hospital was significantly less for dogs from which the live tick was manually removed. Inspiratory strider. evident in some dogs with tick paralysis, was not related to tick attachment on the neck. The use of acepromazine maleate or dexamethasone did not reduce recovery time or mortality. Increasing the dose of tick antitoxin serum (TAS) above 0.1 mL/kg had no effect on mortality or recovery time. Dogs with severe disease that received an additional dose of TAS were significantly less likely to survive. Subcutaneous use of TAS at the site of tick attachment was of no benefit in reducing mortality or time to initial clinical improvement. A registered preventative product had not been used on the majority of dogs. Clipping the coat to search for ticks did not reduce mortality. Conclusions Therapy needs to address cardiopulmonary dysfunction that may be due directly to the effect of tick toxin and not just respiratory compromise caused by progressive respiratory muscle failure.

Characterisation of Leucaena condensed tannins by size and protein precipitation capacity

The ability of differently sized condensed tannins from the genus Leucaena, a fodder tree-legume, to bind protein at different pH values was evaluated to characterise their potential biological effects. Two factors affecting the ability of condensed tannin to bind protein, its major biological activity, have been purported to be the condensed tannin size and the pH of the reaction environment. To test these hypotheses, the protein-precipitating capacities of condensed tannin extracted from four Leucaena genotypes, L leucocephala (UHK636), L pallida (CQ3439), L trichandra (CP146568) and L collinsii (OFI52/88), were assessed. Condensed tannin from L leucocephala had approximately 50% of the ability to precipitate protein on a gg(-1) basis than L pallida or L trichandra, while L collinsii gave no measurable ability to precipitate protein (reaction environment pH 5.0). Increasing or decreasing the pH of the reaction solution away from pH 5.0 (approximately the isoelectric point of the protein) reduced the ability of condensed tannin from all the species to precipitate protein, the decrease being higher at pH 2.5 than at pH 7.5. Condensed tannins from each Leucaena species were also separated by size exclusion chromatography, and the fractions examined for protein-precipitating capacity. In general, it was found that the larger-sized condensed tannin of the accessions L pallida and L trichandra could precipitate more protein than the smaller-sized condensed tannin. This pattern was not found for L leucocephala. (C) 2001 Society of Chemical Industry.

Drug targets and mechanisms of resistance in the anaerobic protozoa

The anaerobic protozoa Giardia duodenalis, Trichomonas vaginalis, and Entamoeba histolytica infect up to a billion people each year. G. duodenalis and E. histolytica are primarily pathogens of the intestinal tract, although E. histolytica can form abscesses and invade other organs, where it can be fatal if left untreated. T. vaginalis infection is a sexually transmitted infection causing vaginitis and acute inflammatory disease of the genital mucosa. T. vaginalis has also been reported in the urinary tract fallopian tubes, and pelvis and can cause pneumonia, bronchitis, and oral lesions. Respiratory infections can be acquired perinatally. T. vaginalis infections have been associated with preterm delivery, low birth weight, and increased mortality as well as predisposing to human immunodeficiency virus infection, AIDS, and cervical cancer. All three organisms lack mitochondria and are susceptible to the nitroimidazole metronidazole because of similar low-redox-potential anaerobic metabolic pathways. Resistance to metronidazole and other drugs has been observed clinically and in the laboratory. Laboratory studies have identified the enzyme that activates metronidazole, pyruvate:ferredoxin oxidoreductase, to its nitroso form and distinct mechanisms of decreasing drug susceptibility that are induced in each organism. Although the nitroimidazoles have been the drug family of choice for treating the anaerobic protozoa, G. duodenalis is less susceptible to other antiparasitic drugs, such as furazolidone, albendazole, and quinacrine. Resistance has been demonstrated for each agent and the mechanism of resistance has been investigated. Metronidazole resistance in T. vaginalis is well documented, and the principal mechanisms have been defined Bypass metabolism, such as alternative oxidoreductases, have been discovered in both organisms. Aerobic versus anaerobic resistance in T. vaginalis is discussed. Mechanisms of metronidazole resistance in E. histolytica have recently been investigated ruing laboratory-induced resistant isolates. Instead of downregulation of the pyruvate:ferredoxin oxidoreductase and ferredoxin pathway as seen in G. duodenalis and T. vaginalis, E. histolytica induces oxidative stress mechanisms, including superoxide dismutase and peroxiredoxin. The review examines the value of investigating both clinical and laboratory-induced syngeneic drug-resistant isolates and dissection of the complementary data obtained. Comparison of resistance mechanisms in anaerobic bacteria and the parasitic protozoa is discussed as well as the value of studies of the epidemiology of resistance.

Successful defibrillation of a dental patient in cardiac arrest

Cardiac arrest is a very rare event in a dental patient. However, practitioners have a duty of care to their patients if ever such an event occurs. The cardiac arrest discussed in this case report occurred in an elderly person with an implanted pacemaker whilst undergoing restorative dental treatment. Cardiac arrest was diagnosed and cardiopulmonary resuscitation instituted immediately, followed within three minutes by successful defibrillation using the School's semi-automatic defibrillator.

Induction of birth in the bandicoot (Isoodon macrourus) with prostaglandin and oxytocin

As in eutherians, maturation of the fetal pituitary and adrenal glands together with an increase in prostaglandin and mesotocin or oxytocin production initiates birth in marsupials. in this study, prostaglandin (Lutalyse) or oxytocin (Syntocinon) were administered to pregnant bandicoots at 05:00 h on the calculated day of birth and the resultant effects were filmed for analysis. The administration of prostaglandin caused the bandicoot to adopt the birth position several minutes after injection (n = 2). However, the bandicoot did not give birth for several hours. Birth occurred at a similar time of day to that observed for untreated bandicoots (n = 7), between 08:00 h and 12:00 h. After an injection of oxytocin, the bandicoot assumed the birth position and birth occurred within several minutes. The young were alive while still connected to their allantoic stalks. However, they were unable to attach to the teats and did not survive (n = 4). The induced young were the colour of venous blood and died soon after the umbilicus was separated, indicating that the cardiopulmonary system of these neonates was underdeveloped and inadequate to maintain life. The results from this study demonstrate that prostaglandin is required to prepare the bandicoot for birth, and mesotocin is required for contraction of the uterus and for birth to occur.

Conservation of the cardiostimulant effects of (-)-Norepinephrine across Ser49Gly and Gly389Arg Beta1-adrenergic receptor polymorphisms in human right atrium in vitro

OBJECTIVES The goal of this study was to determine whether the cardiostimulant effects of the endogenous beta(1)-adrenergic receptor (AR) agonist, (-)-norepinephrine are modified by polymorphic (Serine49Glycine [Ser49Gly], Glycine389Arginine [Gly389Arg]) variants of beta(1)-ARs in the nonfailing adult human heart. BACKGROUND Human heart beta(1)-ARs perform a crucial role in mediating the cardiostimulant effects of (-)-norepinephrine. An understanding of the significance of Ser49Gly and Gly389Arg polymorphisms in the human heart is beginning to emerge, but not as yet in adult patients who have coronary artery disease (CAD). METHODS The potency and maximal effects of (-)-norepinephrine at beta(1)-ARs (in the presence of beta(2)-AR blockade with 50 nM ICI 118,551 [erythro-DL-1(7-methylindan-4-yloxy)-3-isopropylamino-butan-2-ol]) for changes in contractile force and shortening of contractile cycle duration were determined in human right atrium in vitro from 87 patients undergoing coronary artery bypass grafting who were taking beta-blockers before surgery. A smaller sample of patients (n = 20) not taking beta-blockers was also investigated. Genotyping for two beta(1)-AR polymorphisms (Ser49Gly and Gly389Arg) was determined from a sample of blood taken at the time of surgery. RESULTS (-)-Norepinephrine caused concentration-dependent increases in contractile force and reductions in time to reach peak force and time to reach 50% relaxation. There were no differences in the potency or maximal effects of (-)-norepinephrine in the right atrium from patients with different Ser49Gly and Gly389Arg polymorphisms. CONCLUSIONS The cardiostimulant effects of (-)-norepinephrine at beta(1)-ARs were conserved across Ser49Gly and Gly389Arg polymorphisms in the right atrium of nonfailing hearts from patients with CAD managed with or without beta-blockers. (C) 2002 by the American College of Cardiology Foundation.

Knowledge of the national emergency telephone number and prevalence and characteristics of those trained in CPR in Queensland: baseline information for targeted training interventions

Members of the community contribute to survival from out-of-hospital cardiac arrest by contacting emergency medical services and performing cardiopulmonary resuscitation (CPR) prior to the arrival of an ambulance. In Australia there is a paucity of information of the extent that community members know the emergency telephone number and are trained in CPR. A survey of Queensland adults (n = 4490) was conducted to ascertain current knowledge and training levels and to target CPR training. Although most respondents (88.3%) could state the Australian emergency telephone number correctly, significant age differences were apparent (P < 0.001). One in five respondents aged 60 years and older could not state the emergency number correctly. While just over half the respondents (53.9%) had completed some form of CPR training, only 12.1% had recent training. Older people were more likely to have never had CPR training than young adults. Additional demographic and socio-economic differences were found between those never trained in CPR and those who were. The results emphasise the need to increase CPR training in those aged 40 and over, particularly females, and to increase the awareness of the emergency telephone number amongst older people. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

The therapeutic potential of dopamine modulators on the cardiovascular and renal systems

In the periphery, physiological dopamine increases renal blood flow, decreases renal resistance and acts on the kidney tubule to enhance natriuresis and diuresis. The loss of dopamine function may be involoved in the deterioration in kidney function associated with ageing and may have a role in the pathogenesis of hypertension and diabetes. Intravenous dopamine is used as a positive inotrope in the treatment of acute heart failure and cardiogenic shock and as a diuretic in renal failure. The clinical uses of dopamine are limited, as it must be given intravenously, and also has widespread effects. The levels of peripheral dopamine can be increased by the administration of L-dopa to increase synthesis, prodrugs to release dopamine (docarpamine, glu-dopa) or by inhibiting the breakdown of dopamine (nitecapone). Preliminary clinical trials suggest that docarpamine may be useful in patients with low cardiac output syndrome after cardiac surgery and in refractory cirrhotic ascites. Ibopamine is an agonist at dopamine D1 and D2 receptors, which may retard the progression of chronic renal failure. Gludopa is selective for the kidney thus avoiding widespread side effects. The early clinical studies with ibopamine as a diuretic in heart failure were favourable but the subsequent large mortality study showed that ibopamine increased mortality. Fenoldopam is a selective dopamine D1 receptor agonist. Intravenous fenoldopam may be useful in the treatment of hypertension associated with coronary artery bypass surgery or in hypertensive emergencies. Although our understanding of physiological and pathological roles of peripheral dopamine has been increasing rapidly in recent times, we still need more information to allow the design of clinically useful drugs that modify these roles. One priority is an orally-active selective dopamine D1 receptor agonist.

Hemodynamic and ventilatory effects of manual respiratory physiotherapy techniques of chest clapping, vibration, and shaking in an animal model

Chest clapping, vibration, and shaking were studied in 10 physiotherapists who applied these techniques on an anesthetized animal model. Hemodynamic variables (such as heart rate, blood pressure, pulmonary artery pressure, and right atrial pressure) were measured during the application of these techniques to verify claims of adverse events. In addition, expired tidal volume and peak expiratory flow rate were measured to ascertain effects of these techniques. Physiotherapists in this study applied chest clapping at a rate of 6.2 +/- 0.9 Hz, vibration at 10.5 +/- 2.3 Hz, and shaking at 6.2 +/- 2.3 Hz. With the use of these rates, esophageal pressure swings of 8.8 +/- 5.0, 0.7 +/- 0.3, and 1.4 +/- 0.7 mmHg resulted from clapping, vibration, and shaking respectively. Variability in rates and forces generated by these techniques was 80% of variance in shaking force (P = 0.003). Application of these techniques by physiotherapists was found to have no significant effects on hemodynamic and most ventilatory variables in this study. From this study, we conclude that chest clapping, vibration, and shaking 1) can be consistently performed by physiotherapists; 2) are significantly related to physiotherapists' characteristics, particularly clinical experience; and 3) caused no significant hemodynamic effects.

CPR training in households of patients with chest pain

The objectives of this study are to (1) quantify prior cardiopulmonary resuscitation (CPR) training in households of patients presenting to the Emergency Department (ED) with or without chest pain or ischaemic heart disease (IHD); (2) evaluate the willingness of household members to undertake CPR training; and (3) identify potential barriers to the learning and provision of bystander CPR. A cross-sectional study was conducted by surveying patients presenting to the ED of a metropolitan teaching hospital over a 6-month period. Two in five households of patients presenting with chest pain or IHD had prior training in CPR. This was no higher than for households of patients presenting without chest pain or IHD. Just under two in three households of patients presenting with chest pain or IHD were willing to participate in future CPR classes. Potential barriers to learning CPR included lack of information on CPR classes, perceived lack of intellectual and/or physical capability to learn CPR and concern about causing anxiety in the person at risk of cardiac arrest. Potential barriers to CPR provision included an unknown cardiac arrest victim and fear of infection. The ED provides an opportunity for increasing family and community capacity for bystander intervention through referral to appropriate training. (C) 2003 Published by Elsevier Science Ireland Ltd.

Usefulness of quantitative echocardiographic techniques to predict recovery of regional and global left ventricular function after acute myocardial infarction

The left ventricular response to dobutamine may be quantified using tissue Doppler measurement of myocardial velocity or displacement or 3-dimensional echocardiography to measure ventricular volume and ejection fraction. This study sought to explore the accuracy of these methods for predicting segmental and global responses to therapy. Standard dobutamine and 3-dimensional echocardiography were performed in 92 consecutive patients with abnormal left ventricular function at rest. Recovery of function was defined by comparison with follow-up echocardiography at rest 5 months later. Segments that showed improved regional function at follow-up showed a higher increment in peak tissue Doppler velocity with dobutamine therapy than in nonviable segments (1.2 +/- 0.4 vs 0.3 +/- 0.2 cm/s, p = 0.001). Similarly, patients who showed a > 5% improvement of ejection fraction at follow-up showed a greater displacement response to dobutamine (6.9 +/- 3.2 vs 2.1 +/- 2.3 mm, p = 0.001), as well as a higher rate of ejection fraction, response to dobutamine (9 +/- 3% vs 2 +/- 2%, p = 0.001). The optimal cutoff values for predicting subsequent recovery of function at rest were an increment of peak velocity > 1 cm/s, >5 mm of displacement, and a >5% improvement of ejection fraction with low-dose dobutamine. (C) 2003 by Excerpta Medica, Inc.

Resposta da pressão arterial ao esforço em adolescentes: influência do sobrepeso e obesidade

Artigo original Ergoespirometria

Factores que influenciam a percepção da dor pós-operatória em indivíduos submetidos a cirurgia cardíaca

Procedeu-se à investigação de factores que influenciam a percepção da dor pós-operatória em doentes submetidos a cirurgia cardíaca, usando uma amostra de 93 indivíduos sujeitos a bypass coronário no ano de 2002, no hospital de Santa Marta, 78,5% do sexo masculino e com idades compreendidas entre os 39 e os 84 anos. O questionário utilizado no estudo abrangeu os seguintes factores: demográficos, cirúrgicos, percepção da saúde geral, saúde mental, expectativas de dor, apoio, autoeficácia e satisfação com o tratamento para a dor, com médicos e enfermeiros. Quanto à dor de uma forma geral, os pacientes deste estudo revelaram uma dor média às 24 horas; uma dor um pouco mais baixa mas ainda média às 48 horas; e ao quinto dia apresentaram uma dor baixa. Através da aplicação do teste t-student, observou-se que a dor máxima e média que os pacientes revelaram nas 24 horas que precederam as 96 horas, bem como a dor geral, foi em média de menor intensidade nos homens do que nas mulheres. Análises de correlação revelaram que existe correlação entre a experiência de dor global e as várias dores avaliadas. Observaram-se também correlações entre as expectativas de dor e a intensidade de dor, o apoio e a intensidade da dor, a autoeficácia relativa à dor e a intensidade de dor, a saúde mental no pós operatório e a intensidade de dor às 96 horas, dor máxima e dor média nas últimas 24 horas e dor global. De igual modo observaram-se correlações entre a saúde mental no período pré-operatório e a intensidade de dor às 48 horas, dor máxima nas últimas 24 horas e dor global. Observaram-se ainda correlações entre a saúde geral (medida por um item) e a intensidade de dor às 24 horas, 48 horas, dor máxima nas últimas 24 horas e dor global, assim como na saúde geral percepcionada (medida por escala) e a intensidade de dor às 48 horas, dor máxima nas últimas 24 horas e dor global. Observaram-se igualmente correlações entre a satisfação com o tratamento para a dor e a intensidade de dor às 48 horas, às 96 horas, dor máxima e dor média nas últimas 24 horas e dor global. Pode afirmar-se que os sujeitos que apresentaram expectativas de dor baixas, percepcionaram maior apoio, apresentaram níveis elevados de auto-eficácia para lidar com a dor, ou que pertenciam ao sexo masculino, sentiram menos dor. De igual modo, os sujeitos que apresentaram melhor saúde mental no pré e no pós-operatório, sentiram menos dor, excepto às 24 horas onde a dor provavelmente é de índole mais física. Relativamente à percepção da saúde geral, verificou-se que os sujeitos que percepcionaram a sua saúde como boa, sentiram menos dor. Os sujeitos que expressaram maior satisfação com o tratamento, sentiram igualmente menos dor. Analisaram-se os resultados relativamente aos de outros estudos sobre dor pós-operatória em cirurgia cardíaca e propuseram-se variáveis a abordar em estudos futuros nesta temática específica.