Arsenic: toxicity, oxidative stress and human disease.

Arsenic (As) is a toxic metalloid element that is present in air, water and soil. Inorganic arsenic tends to be more toxic than organic arsenic. Examples of methylated organic arsenicals include monomethylarsonic acid [MMA(V)] and dimethylarsinic acid [DMA(V)]. Reactive oxygen species (ROS)-mediated oxidative damage is a common denominator in arsenic pathogenesis. In addition, arsenic induces morphological changes in the integrity of mitochondria. Cascade mechanisms of free radical formation derived from the superoxide radical, combined with glutathione-depleting agents, increase the sensitivity of cells to arsenic toxicity. When both humans and animals are exposed to arsenic, they experience an increased formation of ROS/RNS, including peroxyl radicals (ROO•), the superoxide radical, singlet oxygen, hydroxyl radical (OH•) via the Fenton reaction, hydrogen peroxide, the dimethylarsenic radical, the dimethylarsenic peroxyl radical and/or oxidant-induced DNA damage. Arsenic induces the formation of oxidized lipids which in turn generate several bioactive molecules (ROS, peroxides and isoprostanes), of which aldehydes [malondialdehyde (MDA) and 4-hydroxy-nonenal (HNE)] are the major end products. This review discusses aspects of chronic and acute exposures of arsenic in the etiology of cancer, cardiovascular disease (hypertension and atherosclerosis), neurological disorders, gastrointestinal disturbances, liver disease and renal disease, reproductive health effects, dermal changes and other health disorders. The role of antioxidant defence systems against arsenic toxicity is also discussed. Consideration is given to the role of vitamin C (ascorbic acid), vitamin E (α-tocopherol), curcumin, glutathione and antioxidant enzymes such as superoxide dismutase, catalase and glutathione peroxidase in their protective roles against arsenic-induced oxidative stress.

Oral cavity complications in oncological and hemato-oncological patients.

BACKGROUND: Oral cavity injuries are very significant complications in the treatment of oncological and hemato-oncological patients. Preventive and curative interventions and patient education reduce the risk of complications and their consequences. A working group of authors from professional groups prepared recommendations for care. PURPOSE: A basic summary of recommended interventions to prevent and treat oral cavity injuries in daily practice, defined on the basis of expert societies guidelines, trials, literature data and proven practice and on the consensus opinions of the authors group members. RESULTS: Preventive measures and patient education are essential in the approach to dealing with oral injuries in chemotherapy, radiotherapy, risky targeted treatment and osteonecrosis of the jaw. Local care products are an important element of care, in case of infections, their antimicrobial action is essential, in case of graft-versus-host disease or in connection with targeted oncological therapy, corticoids are used. CONCLUSION: The recommended procedures contribute to the reduction of the development, severity and consequences of oral complications in oncological and hemato-oncological patients.

Digital intervention increases influenza vaccination rates for people with diabetes in a decentralized randomized trial.

People with diabetes (PWD) have an increased risk of developing influenza-related complications, including pneumonia, abnormal glycemic events, and hospitalization. Annual influenza vaccination is recommended for PWD, but vaccination rates are suboptimal. The study aimed to increase influenza vaccination rate in people with self-reported diabetes. This study was a prospective, 1:1 randomized controlled trial of a 6-month Digital Diabetes Intervention in U.S. adults with diabetes. The intervention group received monthly messages through an online health platform. The control group received no intervention. Difference in self-reported vaccination rates was tested using multivariable logistic regression controlling for demographics and comorbidities. The study was registered at clinicaltrials.gov: NCT03870997. A total of 10,429 participants reported influenza vaccination status (5158 intervention, mean age (±SD) = 46.8 (11.1), 78.5% female; 5271 control, Mean age (±SD) = 46.7 (11.2), 79.4% female). After a 6-month intervention, 64.2% of the intervention arm reported influenza vaccination, vers us 61.1% in the control arm (diff = 3.1, RR = 1.05, 95% CI [1.02, 1.08], p = 0.0013, number needed to treat = 33 to obtain 1 additional vaccination). Completion of one or more intervention messages was associated with up to an 8% increase in vaccination rate (OR 1.27, 95% CI [1.17, 1.38], p < 0.0001). The intervention improved influenza vaccination rates in PWD, suggesting that leveraging new technology to deliver knowledge and information can improve influenza vaccination rates in high-risk populations to reduce public health burden of influenza. Rapid cycle innovation could maximize the effects of these digital interventions in the future with other populations and vaccines.

The ETA receptor antagonist, BMS-182874, reduces acute hypoxic pulmonary hypertension in pigs in vivo.

OBJECTIVE: Elevated levels of the potent vasoactive peptide endothelin (ET), have been found in pathophysiological conditions associated with pulmonary hypertension. In this study, we have investigated the effects of the ETA receptor antagonist, BMS-182874, on hypoxic pulmonary hypertension in pigs. METHODS: Pigs were subjected to acute, intermittent 15-min periods of hypoxia (FiO2 0.1). Following a first hypoxia establishing hypoxic baseline values, vehicle or BMS-182874 (10 or 30 mg/kg) was administered i.v. before a second hypoxic period. In separate groups of animals, the effects of the nitric oxide synthase inhibitor N omega-nitro-L-arginine (L-NNA) in combination with BMS-182874 (10 mg) during repeated hypoxia were investigated. The ET-1-blocking properties of BMS-182874 were studied in vivo by infusion of ET-1 during normoxia and in vitro using isolated porcine pulmonary arteries. RESULTS: The hypoxia-evoked increase in mean pulmonary artery pressure was reduced by administration of BMS-182874 (10 mg/kg i.v.; from 42 +/- 8 to 34 +/- 4 mmHg, P < 0.05 and 30 mg/kg i.v.; from 38 +/- 4 to 30 +/- 5 mmHg, P < 0.05). In addition, BMS-182874 at 30 mg/kg reduced the pulmonary vascular resistance during hypoxia (from 7.4 +/- 1.5 to 5.3 +/- 1.1 mmHg.min.l-1 P < 0.05). The hemodynamic response to repeated hypoxia was reproducible in control animals and unaffected by the cyclo-oxygenase inhibitor diclophenac (3 mg/kg). Infusion of L-NNA alone resulted in an augmented pulmonary vasoconstriction during hypoxia; pulmonary arterial pressure from 35 +/- 6 to 43 +/- 9 mmHg; P < 0.05 and vascular resistance from 7.2 +/- 1.1 to 9.9 +/- 1.8 mmHg.min.l-1; P < 0.05. L-NNA in combination with BMS-182874 (10 mg/kg) resulted in a hypoxic pulmonary vasoconstriction of similar magnitude as hypoxic baseline. In addition, BMS-182874 reduced the hemodynamic response to ET-1 in normoxic pigs and competitively antagonized the vasoconstrictor effect of ET-1 in isolated porcine pulmonary arteries. CONCLUSIONS: The non-peptide, selective ETA receptor antagonist, BMS-182874, reduces hypoxic pulmonary vasoconstriction in pigs. The reduction in pulmonary vascular response to hypoxia following BMS-182874 is at least partly independent of nitric oxide.

Increased expression of the lactate dehydrogenase M subunit in myocardial regions with decreased thallium uptake.

OBJECTIVE: In ischaemic heart disease, the heart muscle is subjected to repeated episodes of regional ischaemia or to a constant underperfusion. The purpose of the present investigation was to study the myocardial metabolic adaptation to this stress. METHODS: Eighteen male patients with ischaemic heart disease were studied by biopsies taken from the left ventricular septum during bypass surgery. Citrate synthase, total lactate dehydrogenase and its H and M subunits, coenzyme Q10, and myoglobin were determined in all biopsies. Concentrations of ATP, ADP, and AMP were determined and energy charge calculated in the biopsies from the patients with ischaemic heart disease. Biopsies from the septal region of hearts obtained from brain dead kidney and liver donors were used as reference and preoperative myocardial thallium scintigraphy was performed in the patients with ischaemic heart disease to relate the myocardial biochemical markers to thallium uptake at the biopsy site. RESULTS: Myocardial activities of citrate synthase as well as contents of coenzyme Q10 and myoglobin in patients with ischaemic heart disease were not different from those of the reference group, and no linear relation was found between these three markers on the one hand and thallium uptake on the other. The energy charge was directly related and the M subunit of lactate dehydrogenase inversely related to the thallium uptake. CONCLUSION: The results suggest an absence of adaptation to ischaemia in terms of increased myocardial oxidative capacity and O2 transport and storage capacity. Furthermore, it is indicated that a stressed energy metabolism with increasing severity of ischaemic heart disease enhances anaerobic metabolism and induces a shift in myocardial lactate dehydrogenase subunit fractions.

The endothelin antagonist bosentan: hemodynamic effects during normoxia and hypoxic pulmonary hypertension in pigs.

In this study, we investigated the hemodynamic effects and receptor-blocking properties of the nonselective endothelin antagonist bosentan in pigs during normoxia and acute hypoxia. Hypoxic pulmonary hypertension was induced by decreasing the fraction of inhaled oxygen to 0.1. In a control group of pigs, hemodynamic parameters proved to be stable through 2 hours of hypoxia. Infusions of endothelin-1, endothelin-3, and sarafotoxin 6c into the pulmonary artery resulted in pulmonary and systemic vasoconstriction during normoxia, whereas endothelin administration during hypoxic pulmonary hypertension resulted in pulmonary vasodilation. After administration of bosentan, the vasopressor effect of endothelin-1 during normoxia was significantly attenuated and the pulmonary vasodilatory effect of endothelin-1 during hypoxia was reduced. Furthermore, the development of hypoxic pulmonary hypertension was significantly reduced by bosentan. In contrast, bosentan did not influence the pulmonary vasopressor response to the thromboxane mimic U-46619. We therefore conclude that vasopressor endothelin receptors seem to be activated by endogenous endothelin released during hypoxia, leading to an increase in the pulmonary vascular tone.

Short ischemia causes endothelial dysfunction in porcine coronary vessels in an in vivo model.

BACKGROUND: The aim of this study was to evaluate the effects of a short period of ischemia (10 mins) and a prolonged period of ischemia (60 mins) followed by reperfusion on coronary flow changes induced by acetylcholine (ACh), adenosine (ADO), and endothelin (ET). METHODS: The left anterior descending coronary artery in anesthetized pigs was occluded for 10 or 60 minutes followed by 120 minutes reperfusion. Thereafter, the flow changes in the left anterior descending coronary artery were studied after intracoronary infusion of ACh, ADO, and ET. RESULTS: Short-term ischemia (10 minutes) caused a decrease in vasodilatation, but not the vasoconstriction response to ACh. Prolonged ischemia (60 minutes) impaired ADO induced vasodilatation and aggravated ET evoked vasoconstriction. CONCLUSIONS: The present findings suggest that a short period of ischemia (10 minutes) causes disturbances of the endothelial regulation of coronary vascular tone and that this endothelial regulation is more sensitive, and precedes changes in vascular smooth muscle function after ischemia and reperfusion.

Surviving resuscitation: successful repair of cardiac rupture.

An 83-year-old man was found unconscious and was successfully resuscitated. Progressive cardiac failure developed. After 42 hours of observation echocardiography revealed cardiac tamponade and a discontinuity in the left atrial wall. Exploration showed a laceration of the left atrium at the junction of the left pulmonary veins, which was closed with a direct suture on cardiopulmonary bypass. The postoperative course was uneventful.

The effect of cardiotomy suction on the brain injury marker S100beta after cardiopulmonary bypass.

BACKGROUND: An increase of S100beta in serum during cardiopulmonary bypass (CPB) has been interpreted as a sign of brain injury. Cardiotomy suction may cause fat embolization, and its role in the S100beta increase was examined. METHODS: Twenty coronary artery operation patients were randomly assigned to two groups, 10 with suction during CPB to cardiotomy reservoir (CR), 10 to cell saving device (CS). S100beta was measured (immunoassay) in blood from the patients and from cell saving device after processing. In 7 additional patients S100beta was measured in the cell saving device before processing and directly from the wound at sternotomy. RESULTS: Before anesthesia, serum S100beta was 0.03+/-0.06 microg/L. At the end of CPB it was 2.47+/-1.31 microg/L and 0.44+/-0.27 microg/L (CR vs CS; p < 0.001). S100beta was 33+/-12 microg/L in CS reservoir and 42+/-18 microg/L in blood from the wound. CONCLUSIONS: Most serum S100beta after CPB with cardiotomy suction may be of extracerebral origin. S100beta after CPB with cell saving device was the same as after off-pump operation. The interpretation that an increase in S100beta during CPB in patients reflects cerebral injury must be questioned.

Arterial patch angioplasty for reconstruction of proximal coronary artery stenosis.

BACKGROUND: Ostium patch angioplasty and reconstruction with an onlay patch consisting of pericardium or the saphenous vein is an alternative surgical technique for patients with proximal coronary artery stenosis. Previously described surgical techniques comprise anterior or posterior approaches. In this article we report our experience of using a segment of the proximal right internal mammary artery as an onlay patch for surgical angioplasty. METHODS: Between June 1997 and April 1999, 18 patients (9 men and 9 women) were subjected to surgical patch angioplasty of the left main coronary artery, 3 patients had an additional angioplasty performed on the proximal right coronary artery. The first 12 patients were operated with a posterior incision technique, and six subsequent patients by a new technique performed through an oblique incision into the left main stem after transsection of the ascending aorta. RESULTS: All patients had an uneventful postoperative course, and were fully rehabilitated without clinical symptoms of ischemic heart disease at mean follow-up of 10 months (range 1-23 months). Postoperative catheterization after six days showed excellent results with a widely open and funnel-shaped neoostium. CONCLUSIONS: The use of a proximal segment of the right internal mammary artery as an onlay patch for reconstructing proximal coronary artery lesions is safe with no complications. Although the posterior approach may be used to obtain excellent results, transsection of the ascending aorta gives an optimal visualization and mobilization of the left main coronary artery when performing surgical angioplasty.

Increase in serum S100A1-B and S100BB during cardiac surgery arises from extracerebral sources.

BACKGROUND: Elevated levels of serum S100B after coronary artery bypass grafting may arise from extracerebral contamination. Serum S100B content was analyzed in several tissues, and the two dimers S100A1-B and S100BB were analyzed separately in blood. METHODS: Serum, shed blood, marrow, fat, and muscle were studied in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass using suction either to the cardiotomy reservoir (group 1, n = 10) or to a cell-saving device (group 2, n = 10), or operated on off-pump (group 3, n = 10). RESULTS: Serum S100B was sixfold higher in group 1 than in groups 2 and 3, which were identical. The same ratio between S100A1-B and S100BB was found in all groups. When compared with serum, S100B was 10(2) to 10(4) times higher in marrow, fat, muscle tissue, and shed blood. CONCLUSIONS: Separate analysis of S100A1-B and S100BB did not distinguish between S100B of cerebral and extracerebral origin. The concept that S100B only originates in astroglial and Schwann cells is wrong. Fat, muscle, and marrow in mediastinal blood contain high levels of S100B. Cardiopulmonary bypass caused no increase in S100B.

Neuropeptide Y Y1 receptors in vascular pharmacology.

The existence of neurogenic mediator candidates apart from noradrenaline and acetylcholine involved in the control of vascular tone has attracted enormous attention during the past few decades. One such mediator is neuropeptide Y (NPY), which is co-localized with noradrenaline in sympathetic perivascular nerves. Stimulation of sympathetic nerves in vitro and in vivo causes non-adrenergic vasoconstriction which can be blocked by experimental manipulations that inhibit NPY mechanisms. Thus, the vasopressor response to stimulation of sympathetic nerves can be attenuated by chemical or surgical sympathectomy, treatment with reserpine or other pharmacological agents, and tachyphylaxis to NPY or by NPY antagonists. The NPY field was long plagued by a lack of specific antagonists, but with the recently developed, selective, non-peptide and stable NPY antagonists it has now become possible to study subtypes of this receptor family. For instance, it has become clear that the NPY Y1 receptor mediates most of the direct peripheral effects of NPY on vascular tone. These antagonists promise to stimulate NPY research and will likely unravel the true significance of NPY in cardiovascular control under physiological conditions as well as in pathophysiological states.

The endothelin ETB receptor antagonist BQ-788 reduces the pulmonary vasodilator effect of endothelin-1 during acute hypoxia in pigs.

Pigs were subjected to acute, intermittent hypoxia (fraction of inhaled O2 0.1, n = 10). The increase in mean pulmonary artery pressure during hypoxia was not altered after i.v. administration of the selective endothelin ETB receptor antagonist BQ-788 (N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma-methylleucyl-D -1- methoxycarbonyltryptophanyl-D-norleucine) (1 mg). However, the vasodilatory effect of endothelin-1 (25 ng/kg per min) infused into the pulmonary artery during hypoxia was attenuated by BQ-788. The present results suggest that the pulmonary vasodilator effect of exogenously administered endothelin-1 during acute hypoxia is mediated by endothelin ETB receptors in the pig. Furthermore, endothelin ETB receptor antagonism with BQ-788 does not influence the pulmonary vascular response to acute hypoxia.

Is endothelin-1 release at reperfusion of the ischaemic human heart due to cold-induced displacement of endothelin from binding sites?

Following reperfusion of ischaemic human hearts subjected to cold (4 degrees C) cardioplegia during coronary bypass surgery, there was an increase in cardiac outflow of endothelin-1 but not the pro-peptide big endothelin-1. Furthermore, specific endothelin-1 binding in human lung membrane preparations was displaced by incubation in buffer medium at 4 degrees C. The present results thus indicate that cold-induced displacement of endothelin-1 binding, rather than increased synthesis, may explain the cardiac release of endothelium-1 following ischaemia during heart surgery in which cold cardioplegia has been used.

Hemostatic disturbances associated with implantation of an artificial heart.

Coagulation and platelet parameters have been assessed following implantation of a Jarvik 7 artificial heart. Initially an ongoing intravascular coagulation could not be overcome with heparin and coumarin. The in vivo formation of thromboxane A2 (as monitored by measurement of the major urinary metabolite) was increased 3-4 fold. Administration of aspirin every second to third day reduced the thromboxane formation dramatically. In parallel to this, the intravascular coagulation subsided, the demand for heparin decreased considerably and the clinical condition of the patient improved. These events provide evidence for a direct link between thromboxane formation and the coagulation cascade. The thromboxane formation was insufficiently suppressed around the 110th postoperative day. Two weeks later the patient suffered a cerebral embolus, followed by a bleeding in the embolized area. This case illustrates the applicability of antiplatelet treatment when the need for efficient antithrombotic treatment is especially pronounced. Aspirin, however, is not the ideal drug for this purpose.

Release patterns of CK-MB and mitochondrial CK following myocardial ischaemia.

Following myocardial damage as in acute myocardial infarction (AMI) or open heart surgery, the tissue damage might result in a release of mitochondrial CK (CK-MIT). The presence of this CK isoenzyme in serum may be detected after chromatographic separation of CK-activity on Sephacryl S-200. By combining chromatographic separation of CK-MB with immunologic inhibition of CK-M, both CK-MB and CK-MIT can be estimated in serum. Using this procedure changes in enzyme activities were studied in ten patients with AMI and twelve patients subjected to open heart surgery using cardioplegia. Following AMI CK-MB peaked about 24 h after onset of ischaemic symptoms. CK-MIT increased similarly and reached a plateau after 24 h where it remained during an additional 24-36 h. At peak CK-MB concentration, the corresponding CK-MIT activity was about 22% of the CK-MB activity. Following cardiac surgery there was a rapid release of CK-MB with a peak about 5 h after release of aortic cross-clamping, and with a simultaneous CK-MIT activity amounting to 19% of the CK-MB activity. In conclusion, CK-MIT is released into serum following myocardial ischaemia. Its appearance has time characteristics similar to that of other mitochondrial enzymes. The CK-B method does not specifically determine CK-B, but non-CK-M, which in cardiac ischaemia at peak serum CK-MB concentrations includes about 20% CK-MIT.

Influence of percutaneous transluminal coronary angioplasty on cardiac release of endothelin, neuropeptide Y and noradrenaline.

In the present study, the cardiac outflow of endothelin, noradrenaline and neuropeptide Y was investigated in 13 patients undergoing first time coronary angioplasty (PTCA) due to stenosis of the left anterior descending coronary artery. During PTCA there was an increase in the coronary sinus levels of endothelin but no detectable changes in neuropeptide Y or noradrenaline concentrations. It is therefore concluded that endothelial damage rather than myocardial ischaemia is the cause of endothelin release during PTCA.

In vitro flow characteristics of the Jarvik-7 prosthesis with respect to filling pressure, stroke frequency, and systolic duration.

The Jarvik-7 total artificial heart (TAH), as an implantable substitute for the natural heart, has become the most widely used prosthesis. Although the performance of the Jarvik-7 prosthesis has been described experimentally as well as clinically, the interrelationship between cardiac output, filling pressure, stroke frequency and systolic duration in a wider perspective has not been reported. Our in vitro evaluation of the pump demonstrates the relation between cardiac output and right filling pressure in the range of 2-17 mm Hg with a stroke frequency varying between 60-130 beats per minute with 40% and 50% systolic duration. With respect to complete ventricular filling, a safer and wider range of right filling pressures and stroke frequencies could be employed to produce various cardiac output values at 50% systolic duration as compared to 40% systolic duration. When complete diastolic filling was present, particularly with a high stroke frequency and a low systolic duration, an increase of the left filling pressure to an extent which in a clinical situation would probably cause pulmonary oedema, was observed. By using a right Jarvik-7/70 ml ventricle and a left Jarvik-7/100 ml ventricle, this buildup of the left filling pressure was completely avoided.

Treatment of rat gliomas with recombinant retrovirus harboring Herpes simplex virus thymidine kinase suicide gene.

The retrovirus vector containing Herpes simplex virus type 1 thymidine kinase (HSVtk) gene was constructed. The vector was transfected into the packaging cell line PG13. It was shown that individual transfected cells differ in the production of recombinant retrovirus and in their susceptibility to be killed by ganciclovir. Recombinant retrovirus with a gibbon envelope was able to transduce the HSVtk gene into rat glioma cells. In vivo studies confirmed the ability of intraperitoneal ganciclovir administration to influence subcutaneous and intracerebral tumors developed after injection of C6 rat glioma cells with subsequent injection of HSVtk retrovirus producing cells.

The use of lectins identified with specific antibodies in lectin histochemistry of NZB/W F1 mouse kidney.

The affinity of Helix pomatia, peanut, Pisum sativum, soy bean, and wheat germ agglutinins to various nephron parts of NZB/W F1 mice was different and is assumed to be age dependent. The affinity of Pisum sativum agglutinin to basal membranes of small renal vessels increased with the age of NZB/W F1 mice. The wheat germ agglutinin bound to structures with alkaline phosphatase activity.