Middle-age abolishes cardioprotection conferred by thioredoxin-1 in mice.

Thioredoxin-1 (Trx1) has cardioprotective effects on ischemia/reperfusion (I/R) injury, although its role in ischemic postconditioning (PostC) in middle-aged mice is not understood. This study aimed to evaluate if combining two cardioprotective strategies, such as Trx1 overexpression and PostC, could exert a synergistic effect in reducing infarct size in middle-aged mice. Young or middle-aged wild-type mice (Wt), transgenic mice overexpressing Trx1, and dominant negative (DN-Trx1) mutant of Trx1 mice were used. Mice hearts were subjected to I/R or PostC protocol. Infarct size, hydrogen peroxide (H2O2) production, protein nitration, Trx1 activity, mitochondrial function, and Trx1, pAkt and pGSK3ß expression were measured. PostC could not reduce infarct size even in the presence of Trx1 overexpression in middle-aged mice. This finding was accompanied by a lack of Akt and GSK3ß phosphorylation, and Trx1 expression (in Wt group). Trx1 activity was diminished and H2O2 production and protein nitration were increased in middle-age. The respiratory control rate dropped after I/R in Wt-Young and PostC restored this value, but not in middle-aged groups. Our results showed that Trx1 plays a key role in the PostC protection mechanism in young but not middle-aged mice, even in the presence of Trx1 overexpression.

Relation between periodontal disease and arterial stiffness.

BACKGROUND AND OBJECTIVE: Periodontal disease has been described as playing a role in the atherosclerosis process, and its relation with intimal thickness and vascular endothelial function (EF) has been investigated. The present study sought to determine whether there are differences in parameters of arterial stiffness and EF between patients with and without severe periodontal disease (SPD). MATERIAL AND METHODS: Patients referred to the School of Dentistry University of Buenos Aires, were assessed. Demographic characteristics, atherogenic risk factors and concomitant pathologies were recorded. Patients with known cardiovascular pathology were excluded. Using carotid Doppler ultrasound an operator assessed arterial stiffness parameters: compliance, elastic modulus (EM), ß stiffness index (ßSI) and vascular EF by brachial artery flow-mediated dilatation. The patients were divided into two groups: with and without SPD. RESULTS: Forty patients were included; 60% were women; 15 were in the SPD group and 25 in the group without SPD. Respective results of the studied variables were: age 56.53 ± 17.58 vs. 51.12 ± 12.97 years (NS); probing depth 2.53 ± 1.30 (95% CI 1.81-3.25) vs. 1.25 ± 0.51 (95% CI 1.31-1.73) p = 0.02; clinical attachment level 4.80 ± 2.00 (95% CI 3.69-5.91) vs. 1.72 ± 0.93 (95% CI 1.33-2.11) p = 0.001; intimal thickness 0.10 ± 0.17 (95% CI 0.095-0.11) vs. 0.82 ± 0.18 (95% CI 0.074-0.98) (NS); EM 48.33 ± 12.53 vs. 38.86 ± 7.69 (p = 0.005); ßSI 4.21 ± 1.03 vs. 3.64 ± 1.02 (p = 0.004); EF 16.13 ± 5.02 vs. 22.76 ± 4.50 (p = 0.0003). Correlation between: EM and clinical attachment level r = 0.58 (p < 0.001), ßSI and clinical attachment level r = 0.66 (p < 0.001), EF and clinical attachment level 0.59 (p < 0.001). CONCLUSIONS: Parameters of arterial stiffness and EF were worse in patients with SPD and correlated moderately with clinical attachment level. Correlation with compliance and EF was negative.

Impaired cardiac mitochondrial function and contractile reserve following an acute exposure to environmental particulate matter.

BACKGROUND: It has been suggested that mitochondrial function plays a central role in cardiovascular diseases associated with particulate matter inhalation. The aim of this study was to evaluate this hypothesis, with focus on cardiac O2 and energetic metabolism, and its impact over cardiac contractility. METHODS: Swiss mice were intranasally instilled with either residual oil fly ash (ROFA) (1.0 mg/kg body weight) or saline solution. After 1, 3 or 5 h of exposure, O2 consumption was evaluated in heart tissue samples. Mitochondrial respiration, respiratory chain complexes activity, membrane potential and ATP content and production rate were assessed in isolated mitochondria. Cardiac contractile reserve was evaluated according to the Langendorff technique. RESULTS: Three hours after ROFA exposure, tissue O2 consumption was significantly decreased by 35% (from 1180 +/- 70 to 760 +/- 60 ng-at O/min g tissue), as well as mitochondrial rest (state 4) and active (state 3) respiration, by 30 and 24%, respectively (control state 4: 88 +/- 5 ng-at O/min mg protein; state 3: 240 +/- 20 ng-at O/min mg protein). These findings were associated with decreased complex II activity, mitochondrial depolarization and deficient ATP production. Even though basal contractility was not modified (control: 75 +/- 5 mm Hg), isolated perfused hearts failed to properly respond to isoproterenol in ROFA-exposed mice. Tissue O2 consumption rates positively correlated with cardiac contractile state in controls (r2 = 0.8271), but not in treated mice (r2 = 0.1396). GENERAL SIGNIFICANCE: The present results show an impaired mitochondrial function associated with deficient cardiac contractility, which could represent an early cardiovascular alteration after the exposure to environmental particulate matter.

Lithotomy's prohibition and referral to experts in medical oaths of hippocratic stemma. / Prohibición de la litotomía y derivación a expertos en los juramentos médicos de la genealogía hipocrática.

OBJECTIVE: The aim is to analyse how the Hippocratic Oath's commitments of not cutting for stone and referral to experts was modified in medical oaths of Hippocratic stemma from different time periods. METHODS: Nineteen oaths of Hippocratic stemma were studied: 4 Medieval, 2 Modern, and 13 Contemporary. They were selected according to: name of the oath when it includes the word «Hippocratic¼ or because their authors recognized having based their oaths on the Hippocratic Oath. Their historical significance and representativity regarding time period, renowned medical schools, and importance and reliability of the sources was also taken into consideration. RESULTS: Four oaths prohibit cutting for stone (one Medieval, 2 Modern, one Contemporary); 4 oaths mention seeking consultation about patients (all Contemporary); 3 mention not performing criminal operations (all Contemporary); 8 do not mention these commitments (3 Medieval, 5 Contemporary). CONCLUSION: The commitment of the Hippocratic Oath of not cutting for stone and referral to experts has been modified mainly in Contemporary oaths. The original commitment seems to have been split into 2 tendencies: those that mention obtaining consultation, and those that refer to not performing criminal operations. Due to the bioethics movement in the second half of the 20th century, referring patients that exceed the physician's limitations to more skilled colleagues constitutes an ethical obligation. Thus, it should be a commitment present in every Contemporary oath.

[Analysis of the ethical principles in medical oaths used by medical schools of Argentina in relation to the Hippocratic Oath]. / Análisis de los principios eticos en juramentos médicos utilizados en las Facultades de Medicina de la Argentina en relación al Hipocratico.

Medical oaths have consulted the source of all Medical Ethics through centuries. Since the 60s a new consensus on ethics was sought to apply to the new medical problems. The consensus was on the basic principles: beneficence, non-maleficence, justice and respect for the patient's autonomy with its two rules of confidentiality and veracity. The Hippocratic Oath specifies the principles of beneficence and non-maleficence and the rule of confidentiality. They are included in the texts used in different Medical Schools of the United States, Canada and the United Kingdom. The purpose of this analysis is to determine which of those ethical principles are included in the Argentinian Medical Oaths. At present, out of the ten Faculties of Medicine that use a formula, six choose the Declaration of Geneva and the rest use their own texts. No schools use the Hippocratic Oath. Neither of the five different Oaths include the four principles. The rule of confidentiality is the one most frequently mentioned followed by the principles of beneficence and justice. The principles of non-maleficence and of respect for the patient's autonomy, in general, and the rule of veracity, in particular, are not indicated. Revision of the Medical Oaths used in Argentina, is basically for the ethical revision suggested, in order to include all the ethical principles strongly agreed upon.

[Exogenous adenosine and postischemic dysfunction in the isolated rabbit heart]. / Adenosina exógena y disfuncion postisquémica en el corazon aislado de conejo.

It is recognized that adenosine lessens the systolic alterations of the postischemic ventricular dysfunction ("stunned myocardium"), but little is known about the drug's effects on the diastolic phase of the cardiac cycle. The aim of this work was to determine the effect of adenosine when it was administered: a) before ischemia and during reperfusion, and b) from the early reperfusion period to the end of the experiment on the systolic and diastolic function of the "stunned myocardium". An additional objective was to determine whether adenosine modifies the release of creatine phosphokinase (CPK) and lactate dehydrogenase (LDH), in the "stunned myocardium". Rabbit isolated isovolumic hearts were perfused according to Langendorff's technique, and subjected to 15 minutes global ischemia and 30 minutes reperfusion. A small latex balloon was inserted into the left ventricle via the left atrium which allowed to measure the ventricular end-diastolic pressure (diastolic stiffness) and calculate the developed pressure, the maximal rate of pressure generation and maximal rate of pressure decay (+dP/dtmax and -dP/dtmax), the ratio between these two variables (+P/-P), and the time constant of isovolumic relaxation (tau, Tau). The adenosine administered both before the ischemia period, and at the beginning of reperfusion, attenuated the systolic and diastolic stiffness alterations without modifying the isovolumic relaxation. The administration of adenosine did not diminish the CPK and LDH release significantly when it was given before the ischemia period or the beginning of reperfusion.

[Confidentiality in medical oaths: (When the white crow becomes gray...)]. / Confidencialidad en los juramentos médicos (cuando el cuervo blanco se vuelve gris...).

Confidentiality, together with the ethical principles of beneficence and non-maleficence, is the most important rule in Medical Oaths at the present time. However, the scientific-technical advances in medicine have made this rule one of the most controversial ones because of its exceptions. In consequence, the aim of the present paper is to comparatively analyze the rule of confidentiality in Medical Oaths of different places, times, origins and in different versions of the Hippocratic Oath in order to determine what should be kept a secret and with what degree of commitment (absolute or "prima facie"). Of the thirty six analyzed Oaths, twenty-seven manifest this rule and nine do not. No relation was found between the manifestation of this rule and the place, time, origin and different versions of the Hippocratic Oath. Most pledges suggest not to reveal what has been seen or heard during the medical act, the same as in the Hippocratic Oath. Seven texts point out that confidentiality should be absolute and four give exceptions in connection with beneficence and justice principles and the moral duty of causing no damage to third parties. Two pledges specify protection of privacy. In conclusion, today confidentiality is considered to be a moral duty for the benefit of the patient and out of consideration for his autonomy; however, at the present time in medicine the duty of keeping absolute secrecy is being reconsidered.

[Effect of enalaprilat on postischemic systolic and diastolic dysfunction (stunned myocardium) on the isolated rabbit heart]. / Efecto del enalaprilato sobre la disfunción postisquémica sistólica y diastólica ("miocardio atontado") en el corazón aislado de conejo.

The aim was to determine: 1) whether Enalaprilat (0.08 mg/kg/min) administration: a) before ischemia or b) at the beginning of reperfusion improved the postischemic systolic and diastolic dysfunction ("stunned myocardium") and attenuated the "hyperfunction" phase at the beginning of reperfusion; and 2) whether creatine kinase (CPK), and lactate dehydrogenase (LDH) activities, and lactate release are involved in the protective effects of Enalaprilat. An isolated isovolumic rabbit heart preparation was used as experimental model and subjected to 15 minutes of ischemia followed by 30 minutes of reperfusion, without (group 1), and with Enalaprilat before the ischemia (group 2) and at the beginning of reperfusion (group 3). Left ventricular developed pressure, and end diastolic pressure (diastolic stiffness) were measured and the time constant of isovolumic relaxation (t, Tau) and the ratio between +dP/dtmax and -dP/dtmax were calculated. For the determinations of lactate release and CPK and LDH activities in the perfusate, samples were taken from the coronary effluent for spectrophotometrical measurements. In comparison to the stunned group (group 1) both Enalaprilat preischemia (group 2) and postischemia (group 3) exerted a significant protective effect on the postischemic recovery of contractile state and diastolic stiffness, and attenuated the "hypercontractile" phase in both groups. However Enalaprilat failed to improve myocardial relaxation. Lactate release was also attenuated, but the enzyme activities were not modified.

[The activation of A1 adenosine receptors attenuates myocardial stunning in the rabbit]. / La activación de los receptores A1 de adenosina atenúa el atontamiento de miocardio en el conejo.

Hearts exposed to a prolonged period of ischemia (> or = 30 minutes) present smaller infarct size when reperfused in the presence of adenosine. However, when the period of ischemia is shorter, the infarct areas are not very significant, but a postischemic ventricular dysfunction persists. The objective of this study was to determine the effect of adenosine, (administered only during reperfusion) on systolic and diastolic alterations present in postischemic ventricular dysfunction, as well as to determine whether A1 receptors participate in this effect. Isolated isovolumic rabbit hearts were subjected to 15 minutes of global ischemia followed by 30 minutes of reperfusion. Before ischemia and during reperfusion ventricular function was evaluated. In the control group, the left ventricular developed pressure (LVDP) reached 56 +/- 2% of recovery at 30 minutes of reperfusion. The administration of adenosine improved LVDP 75 +/- 3% (P < 0.05 vs. control). However, when adenosine was given in presence of an A1 receptor selective antagonist (DPCPX), LVDP reached 50 +/- 2% (P < 0.05 vs. control). In the control group, left ventricular end diastolic pressure (LVEDP) (diastolic stiffness), increased 293 +/- 4%, at 30 minutes of reperfusion. Only a 15 +/- 8% (P < 0.05 vs. control) increase in LVEDP was observed with adenosine. Reperfusion with adenosine plus DPCPX did not attenuate an increase of 493 +/- 9% (P < 0.05 vs. control) in diastolic stiffness. Adenosine administered from the beginning of reperfusion attenuated both systolic alterations and diastolic stiffness in postischemic dysfunction. This effect was abolished by DPCPX, suggesting an important role for the A1 receptors in adenosine protection.

[Effect of nifedipine on cardiac chronotropism in conscious dogs]. / Acción de la nifedipina sobre el cronotropismo cardíaco en perros conscientes.

The effect of nifedipine (NIF) was studied in intact conscious dogs with and without autonomic blockade. Maximal decrease of systolic arterial pressure (delta P, in mmHg), maximal increase of heart rate (delta F, in beats/min), the ratio delta F/delta P, and the time elapsed between delta F and delta P (delta t) were measured after the acute administration of the drug. Two intravenous doses of NIF (50 and 150 micrograms/kg) were administered either alone or after sympathetic and parasympathetic blockade. Group Ia: 50 micrograms/kg of NIF alone. The delta F/delta P and delta T were 3.8 +/- 0.4 and 11.3 +/- 2.2 sec respectively. Group Ib: 150 micrograms/kg of NIF alone. The delta F/delta P and delta T were 2.4 +/- 0.2 and 15 +/- 3 sec respectively. Group IIa: 2 mg/kg of propranolol + 150 micrograms/kg of NIF. The delta F/delta P and delta T were 0.84 +/- 0.4 and 16 +/- 5 sec respectively. Group IIIa: 0.2 mg/kg of atropine + 2 mg/kg of propranolol + 50 micrograms/kg of NIF. In this group left systolic ventricular pressure decreased about 14 mmHg, but the heart rate (HR) was not modified. Group IIIb: 0.2 mg/kg of atropine + 2 mg/kg of propranolol + 150 micrograms/kg of NIF. In this group, left systolic ventricular pressure decreased about 18 mmHg but the HR was not modified. We conclude that acute administration of NIF decreases systolic ventricular pressure and increases HR. The reflex tachycardia is partially abolished by 2 mg/kg of propranolol, and completely abolished by sympathetic and parasympathetic blockade.(ABSTRACT TRUNCATED AT 250 WORDS)

[Time course of the myocardial infarction in the rabbit]. / Cronodinamia del infarto de miocardio en el conejo.

The histopathologic evolution of myocardial infarct and of areas distant from infarct in rabbit hearts was studied. The left coronary artery of 55 rabbits was ligated, and rabbits were sacrificed at 2, 4, 6, 8, 12, 14, 16, 18, 26, 35 and 56 days post-ligature (n = 5 per group). Two rabbits were used as control and two were sham operated. The hearts were excised, cut in slices and stained with hematoxilin-eosin, Masson's trichrome and picrosirius red. Histological evaluation was semi-quantitative (scale: 0 to +++). At day 2, presence of neutrophils was +++, disappearing completely at day 6. Fibroblast proliferation increased from day 4 to day 14 post-occlusion. Coagulation necrosis in medial myocardium during the first week was +++. Subendocardic myocytolysis was evident from day 2 up to day 56 post-infarction. During the second week, proliferation of lymphocytes and macrophages (+++), granulation tissue formation (+++), and incipient traces of fibrosis that peaked at day 35 were observed. Cicatrization was complete at day 56 (+++). In areas far from infarction (right ventricle and septum), proliferation of fibroblasts was observed at day 2, and perivascular, interstitial and endocardic fibrosis at day 16. In conclusion, myocardial infarction in rabbits, unlike myocardial infarction in human beings, is characterized by early presence of fibroblasts and subendocardic fibrosis, and quick increase and precocious disappearance of neutrophils. An interesting finding was the early proliferation of fibroblasts in normal areas far from infarct.

[Analysis of the ethical principles of beneficence and no harm in medical oaths in relation with the Hippocratic one]. / Análisis de los principios éticos de beneficencia y de no-maleficencia en los juramentos médicos, en relación con el hipocrático.

The principles of beneficence and no-maleficence, already set forth in the Hippocratic Oath, have been the foundation of medical ethics for the last twenty-five centuries. The principle of beneficence is currently maintained in most wordings of the pledges of medical schools of the United States, Canada and Argentina; it is not the same with the principle of non-maleficence. The aim of this paper is to determine whether these principles are described in medical oaths at different times. These principles did not remain in an oaths. Of twenty-nine analyzed texts, nine describe both principles simultaneously, eleven only mention beneficence; three only express non-maleficence, and six indicate neither of them. Most wordings that describe these principles are modifications of the Hippocratic Oath. Two contemporary wordings describe the achievement of the greatest benefit with minimum harm. Two current wording also subordinate the principle of beneficence to the principle of respect for the patient's autonomy, and eight wordings indicate not only patients' benefit in particular but that of society in general. It is not possible to ignore that it is no enough to fulfill only these two principles. Physicians should encourage the development of patients' responsibility in managing their own health and respect their autonomy.

Doctor-patient sexual relationships in medical oaths.

BACKGROUND: Doctor-patient sexual relationship is considered to be unfair because the first party would be abusing the second party's vulnerability. The prohibition of this relationship is noted in the Hippocratic oath. Currently, a reprise of the use of oaths in medical schools can be observed. AIM: To determine whether the prohibition has been maintained and how its expression has varied in the oaths during different periods. METHODS: 50 oaths were studied: 13 ancient-medieval and 37 modern-contemporary. Of the 50 texts, 19 were versions of the original oaths. The oaths that pointed out the prohibited doctor-patient relationship referred to any sexual aspect or included paragraphs that began as the Hippocratic oath does were noted. RESULTS: Of the 24 (48%) texts that expressed the prohibition, 8 (62%) were ancient-medieval and 16 (43%) were modern-contemporary. Some expressly call it Hippocratic oath, many use general terminology (corruption or vice) and others describe it in association with other commitments (abortion and euthanasia). CONCLUSIONS: The clause on the prohibition of the doctor-patient sexual relationship in Hippocratic oath was included to be for legal, economic and social reasons at the time. That the clause is found mostly in the ancient-medieval oaths can be attributed to the influence of the original. This commitment is generalised and associated with others by contemporary formulas. Currently, sexual relationships are the subject of legal and ethical analysis and their inclusion in the oaths is being debated.

Dissociation between myocardial relaxation and diastolic stiffness in the stunned heart: its prevention by ischemic preconditioning.

The effects of myocardial stunning and ischemic preconditioning on left-ventricular developed pressure and end-diastolic pressure (diastolic stiffness) as well as on coronary-perfusion pressure were examined in isolated isovolumic rabbit hearts. The isovolumic relaxation was evaluated, and the time constant of pressure decay during the isovolumic period was calculated. Our experimental protocol comprised: 1) myocardial stunning-global ischemia (15 min) followed by reperfusion (30 min); 2) myocardial stunning-global ischemia (20 min) followed by reperfusion (30 min); and 3) ischemic preconditioning--a single cycle of brief global ischemia and reperfusion (5 min each), before a second ischemic period, of 20-min duration. There was no effect upon systolic and diastolic parameters when 15 and 20 minutes of ischemia were evaluated. In both stunned groups the left ventricular developed pressure first recovered to near control values, but then stabilized at only 60% of the control values. Whereas the isovolumic relaxation time constant was increased after 5 min of reperfusion, and return to control values at late reperfusion, the end diastolic pressure remained elevated during the entire period. Values of dP/dV calculated at common pressure levels, were used as a second index of diastolic stiffness. They were increased after stunning, as also was the coronary perfusion pressure. When the heart was preconditioned with a single episode of ischemia, the systolic and diastolic alterations were completely abolished. We thus concluded that diastolic abnormalities incurred by myocardial stunning consist in both an increase in diastolic stiffness and an early impairment of isovolumic relaxation.(ABSTRACT TRUNCATED AT 250 WORDS)