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Generation and recycling of radicals from phenolic antioxidants.

Hindered phenols are widely used food preservatives. Their pharmacological properties are usually attributed to high antioxidant activity due to efficient scavenging of free radicals. Butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA) also cause tissue damage. Their toxic effects could be due to the production of phenoxyl radicals. If phenoxyl radicals can be recycled by reductants or electron transport, their potentially harmful side reactions would be minimized. A simple and convenient method to follow phenoxyl radical reactions in liposomes and rat liver microsomes based on an enzymatic (lipoxygenase + linolenic acid) oxidation system was used to generate phenoxyl radicals from BHT and its homologues with substitutents in m- and p-positions. Different BHT-homologues display characteristic ESR signals of their radical species. In a few instances the absence of phenoxyl radical ESR signals was found to be due to inhibition of lipoxygenase by BHT-homologues. In liposome or microsome suspensions addition of ascorbyl palmitate resulted in disappearance of the ESR signal of phenoxyl radicals with concomittant appearance of the ascorbyl radical signal. After exhaustion of ascorbate, the phenoxyl radical signal reappears. Comparison of the rates of ascorbyl radical decay in the presence or absence of BHT-homologues showed that temporary elimination of the phenoxyl radical ESR signal was due to their reduction by ascorbate. Similarly, NADPH or NADH caused temporary elimination of ESR signals as a result of reduction of phenoxyl radicals in microsomes. Since ascorbate and NADPH might generate superoxide in the incubation system used, SOD was tested. SOD shortened the period, during which the phenoxyl radicals ESR signal could not be observed. Both ascorbyl palmitate and NADPH exerted sparing effects on the loss of BHT-homologues during oxidation. These effects were partly diminished by SOD. These data indicate that reduction of phenoxyl radicals was partly superoxide-dependent. It is concluded that redox recycling of phenoxyl radicals can occur by intracellular reductants like ascorbate and microsomal electron transport.

Animals↗

Application of a device to lower pulpal temperatures in vivo.

Heat generated by tooth reduction and restoration procedures may be harmful to the pulp. Water spray during those procedures aids in maintaining lowered pulpal temperatures. A device that lowers intrapulpal temperatures has been developed and tested in an animal model. The animal's pulp chamber temperatures were lowered to 15.5 degrees C and 12.4 degrees C and maintained at those temperatures for 20 min. Histological examinations disclosed no inflammatory reaction to the testing. Therefore, this device may aid in reducing the trauma of dental preparation procedures as well as other effects of lowered temperature on the biology of the dental pulp.

Animals↗

[The influence of transport on organ cultured corneas. An experimental study of porcine corneal endothelium].

BACKGROUND: To investigate the influence of transport on the quality of corneas in organ culture, based on the vitality of the corneal endothelium. METHODS: Transport was simulated for 222 porcine corneal disks. These were placed in standard transportation containers filled with organ culture medium II, kept in an incubator and then shaken on a laboratory shaker. RESULTS: Agitated corneas at all acceleration rates always showed less endothelial cell damage than corneas kept motionless. The best condition was found after maximum accelerations of 0.10 g and 0.72 g. Damage consisted predominantly of disseminated cell loss and circular cell damage. A storage temperature of 37 degrees C caused most harm to the endothelium. CONCLUSION: The reduction in endothelial damage found in corneas after agitation can be attributed to a better distribution of nutrients in the transportation container. Assuming transferability, a better quality of human grafts can be achieved by inducing slight motions of corneas in organ culture.

Animals↗

Age, risk-benefit trade-offs, and the projected effects of evidence-based therapies.

BACKGROUND: Physicians underutilize evidence-based therapies in the elderly, perhaps because of concerns about the generalizability of clinical trial results in elderly patients given that the relative efficacy of therapies may vary with age. We compared the estimated effects of age and efficacy of treatment on survival among patients with acute coronary syndromes. METHODS: Baseline risk, defined as mortality in the year after hospitalization for acute coronary syndromes, was determined for different age strata among 81,584 patients who had been discharged between April 1, 1997, and March 31, 2000, in Ontario, Canada. We calculated the relative efficacy (relative risk reduction) needed to achieve a clinically meaningful absolute survival benefit, using a number needed to treat of 50 patients for the different age strata. We also evaluated risk-benefit trade-offs in the elderly versus the young by modeling different levels of the relative efficacy and rates of fatal complication by age. RESULTS: Baseline risk (1-year all-cause mortality) was 12-fold lower in the youngest patients (age <50 years) than in oldest patients (age > or = 75 years). Given this gradient, a therapy would have to have a relative efficacy of 88% (i.e., a relative risk of 0.12) in the youngest age group, and 7% (a relative risk of 0.93) in the oldest age group, to generate a number needed to treat 50 patients. For a therapy whose relative efficacy was 25%, the fatal complication rate would have to be sevenfold greater in the oldest compared with the youngest age group to outweigh the survival benefits associated with treatment. CONCLUSION: For acute coronary syndromes, baseline mortality is so much higher for elderly patients that neither sharp reductions in the relative efficacy of therapies nor increases in the rates of serious complications are likely to negate the benefits of therapy. More attention should be paid to overall trial results and less to age-specific subgroup data, unless the latter provide very clear evidence for substantial reductions in absolute efficacy or net harm.

Aged↗

Shrimp aquaculture development and the environment in the Gulf of California ecoregion.

Beginning in the middle of the 1980s, the Gulf of California ecoregion experienced a boom in shrimp aquaculture and became the second largest producer in the western hemisphere. The moderated, but continual development of shrimp farming, in conjunction with municipal and agriculture effluents has been accompanied by concern about: (a) depletion of fishing stocks, (b) reduction of mangrove forest, (c) frequent harmful algal blooms in coastal waters and shrimp ponds, and (d) water quality deterioration. We demonstrate that environmental degradation resulted from a conjunction of factors including agriculture, untreated municipal effluents, shrimp aquaculture, increasing number of fishermen, and an absence of an effective regulatory program. We recommend the immediate implementation of an integrated coastal management program to protect the integrity of the coastal ecosystems and operate upon the principle of environmental sustainability for the different economic activities including shrimp aquaculture.

Animals↗

The temperament and character inventory in major depression.

Patients admitted for pharmacological treatment of a non-bipolar major depressive episode completed the Temperament and Character Inventory (TCI) prior to and after at least 6 weeks of treatment. Treatment with various antidepressants resulted in a 43% reduction of symptomatology. Scores on the harm avoidance dimension before and after treatment appeared to be significantly higher as compared to Dutch normative data. TCI scores did not predict response to treatment or show a change during treatment. It is concluded that, in this group of patients, the personality dimension harm avoidance is a trait factor without predictive value for antidepressant responsiveness.

Adult↗

The relevance of clinical nutrition education and role models to the practice of medicine.

Clinical nutrition is concerned with the diagnosis and treatment of diseases that affect the intake, absorption, and metabolism of dietary constituents and with the promotion of health through the prevention of diet related diseases. Adult diseases of clinical nutrition encompass the most common causes of mortality in the developed world and include obesity with its co-morbidities of hypertension, diabetes, dyslipidemias, increased risks of cardiovascular disease, some cancers, and pulmonary failure; intestinal disorders related to inadequate nutrient absorption; eating disorders; and malnutrition associated with chronic illness and surgical trauma. Scientific advances on the relationship of dietary substances to the cellular mechanisms of disease occur with regularity and frequency. Yet, despite the prevalence of nutritional disorders in clinical medicine and increasing scientific evidence on the significance of dietary modification to disease prevention, present day practitioners of medicine are typically untrained in the relationship of diet to health and disease. In the absence of reliable medical advice on nutrition, patients increasingly turn to herbal dietary supplements, costly diet schemes for weight reduction, and other unproved and potentially harmful remedies. Standardization of curricula for nutrition education of medical students and trainees and the provision of knowledgeable clinical nutrition specialist educators and role models in medical institutions is increasingly relevant to the cost-effective integration of nutritional concepts into medical practice.

Adult↗

Prevalence of and risk factors associated with Mycobacterium tuberculosis infection in prisoners, North West Frontier Province, Pakistan.

BACKGROUND: This cross-sectional study was conducted to assess the prevalence of and identify factors associated with latent Mycobacterium tuberculosis (MTB) infection in prisoners of North West Frontier Province (NWFP). METHODS: A stratified random sampling technique was used to select a sample of 425 from a total of 6607 male prisoners aged 18-60 years from the five central prisons of NWFP, Pakistan (Peshawar, Dera Ismail Khan, Haripur, Kohat, and Mardan). The selected inmates were interviewed using a structured pre-tested questionnaire; a Mantoux tuberculin skin test (TST) was also performed. Latent MTB infection status of the prisoner was determined by the size of the induration of the TST in the presence/absence of a previous BCG scar. RESULTS: Overall prevalence of latent MTB infection among prisoners was 48% (204/425). Using multiple logistic regression, a prisoner's age, educational level, smoking status, duration of current incarceration, and average accommodation area of 60 ft(2) or less in prison barracks were found to be statistically significant (P < 0.05) predictors of latent MTB infection. CONCLUSION: The high prevalence of latent MTB infection as assessed by TST in prisoners requires immediate steps be taken to identify and confirm MTB infection, and to treat and counsel those found to be positive in this setting. Efforts to halt MTB transmission in prisons should include: routine screening of prisoners on entry using sputum smear and TST for diagnosis of tuberculosis (TB) and latent MTB infection, respectively. The isolation and treatment of TB positive prisoners and chemo-prophylactic treatment of TST positives, reduction of overcrowding, education regarding the harmful effects of smoking, and intensive monitoring of those serving longer prison terms may help reduce the MTB transmission in this setting and in the community at large.

Adolescent↗

Conscious volunteers developed hypoxemia and pulmonary collapse when breathing air and oxygen at reduced lung volume.

Ventilation at maximal voluntary reduction of lung volume caused significant desaturation in some healthy subjects breathing air. Saturation rapidly returned to control levels when normal lung volume was regained. These changes are probably due to reversible airway obstruction. During the inhalation of oxygen, ventilation at maximal voluntary reduction of lung volume caused, in one subject, a reduction of arterial Po2 of 243 mmHg. Normal arterial Po2 was not immediately restored on regaining normal lung volume. Chest radiographs showed extensive atelectasis, which persisted for several hours in an ambulant subject. These changes are probably due to absorption of oxygen from alveoli beyond obstructed airways. Reduction of lung volume may be harmful for patients who are breathing oxygen. Caution is therefore necessary in the use of a subatmospheric pressure phase during artificial ventilation and during suction of the tracheobronchial tree.

Humans↗

Prolonged transient ischemia results in impaired CBF recovery and secondary glutamate accumulation in cats.

Effects of prolonged focal ischemia [middle cerebral artery occlusion (MCAO)] of 1, 2, and 4 h followed by 15-h reperfusion on CBF, extracellular amino acids, purine catabolites, evoked potentials, and infarction were studied in core (A:auditory cortex) and border zone (SF: somatosensory cortex) areas of halothane-anesthetized cats. Following MCAO, CBF reduction was severe in A (<15 ml 100 g-1 min-1) and mild to moderate in SF. Prominent elevation of glutamate and abolition of evoked potentials in A contrasted with milder and more variable disturbances in SF. After reperfusion, recovery of CBF, glutamate, and evoked potentials was fast and persistent in the 1- and 2-h groups. In the 4-h group, immediate recovery of CBF, glutamate, and evoked potentials was incomplete, and secondary deterioration of all parameters was obtained at the end of the experiments. Infarction in the 4-h group was significantly larger than in the 1- and 2-h groups. Persistent recovery of extracellular glutamate concentration and electrical function and salvage of neuronal tissue from infarction therefore seem to depend on successful restoration of CBF, which in turn depends on the magnitude and the duration of CBF reduction and of exposure to potentially harmful substances such as glutamate during the ischemic attack.

Amino Acids↗

Aspergilli and lignocellulosics: enzymology and biotechnological applications.

Aspergilli are versatile ascomycetes that are able to transform at a rapid rate a wide spectrum of lignin-related aromatic compounds. While it is clear that these fungi can degrade phenolic and polysaccharide components from lignocellulosic material, the status regarding degradation of high-molecular mass lignins is controversial. This review compiles data from the literature as well as that from the authors' laboratory with the aim of clarifying this point. The main body of evidence points towards the inability of aspergilli alone to degrade lignin free of low-molecular mass contaminants. Nevertheless, the ability of this genus to efficiently degrade hemicelluloses makes it an essential participant in the complex microbial system necessary for wood decay under natural conditions. Aspergilli are known to overproduce high levels of hemicellulolytic enzymes. Out of the large array of these enzymes that act in concert to degrade lignocellulosic material, only endoxylanases of aspergilli are described in so far as these are the main activities required for enzyme-aided bleaching. The biochemical features of the endoxylanases from Aspergillus niger are briefly described as these serve to illustrate how a complex family of isozymes is necessary to deal with the structural and chemical heterogeneity of xylans. Emphasis is placed on the biotechnological applications of lignocellulosic materials transformed by aspergilli. The key application areas are biopulping and biobleaching where a reduction in the use of environmentally harmful chemicals traditionally used in the pulp and paper industry is envisaged. Waste water treatment represents another vast application area where aspergilli have been shown to be effective not only in colour removal but also in the bioconversion of potentially noxious substances into useful bioproducts.

Aspergillus↗

Maternal heart rate and stroke volume in the pygmy goat: effects of exercise and cardiac autonomic blockade.

To determine the normal maternal heart rate and stroke volume response to exercise and the role of the autonomic nervous system in this response, pregnant and non-pregnant pygmy goats were studied at rest, during and following treadmill exercise, and after autonomic blockade. Resting heart rates, stroke volumes and cardiac outputs were 10%, 60%, and 76% higher in pregnant compared to non-pregnant animals (P less than 0.05, 0.001, and 0.001 respectively). During exercise, heart rate and stroke volume rose in both pregnant and non-pregnant animals by similar amounts. Immediately post-exercise, stroke volume in pregnant animals dropped precipitously below resting levels by 15% (P less than 0.005) but cardiac output was preserved by heart rate. This fall in stroke volume was not seen in control animals. Autonomic blockade lowered resting and exercise heart rates in both groups without changing stroke volume. The elevations in heart rate and stroke volume in pregnancy are not primarily mediated via the autonomic nervous system. Although the maternal cardiac output response to exercise appears normal, the post-exercise fall in stroke volume, presumed secondary to a reduction in preload, could potentially be harmful to both mother and fetus.

Animals↗

Is the EDRF in the cerebral circulation NO? Its release by shear and the dangers in interpreting the effects of NOS inhibitors.

Evidence from investigations of brain microcirculation (pial arterioles) reveals at least 3 different endothelium (EC) dependent mechanisms for dilation. Only one of the three can be triggered by acetylcholine (ACh) and in this vascular bed it is only this path that is dependent upon endothelial nitric oxide synthase (NOS) which produces nitric oxide (NO) from arginine. In this vascular bed the ACh sensitive path cannot be triggered by bradykinin (BK). This state of affairs appears to differ from that found in other beds or in endothelium cultured from conductance vessels. In the cerebral microcirculation there is considerable pharmacological evidence that the endothelium derived relaxing factor (EDRF) for ACh is not NO itself but may contain NO. In many experimental vascular settings the release of the NOS dependent EDRF is shear dependent. In the cerebral microcirculation there are several studies suggesting, in vivo, that this is correct. Among these are the following: (1) vessels narrow when shear is reduced after carotid ligation, and remain so along with unresponsiveness to ACh for at least ten minutes following resumption of flow. This may be important in developing stroke. The collapse is not passive due to low pressure. We know this because the narrowed vessels with their low intraluminal shear and pressure are still capable of large dilation by the NO donor, sodium nitropruside; (2) the antiplatelet effects of EC which are mediated, in part, by the EDRF for ACh are enhanced for 10 to 20 minutes following the transient increase and return of shear within these vessels. If the reverse is also true, reductions of shear may have important harmful proaggregant effects on platelets (and leukocytes) in the microvascular bed of developing infarcts. However most of the cited work depends upon pharmacological inhibitors of NOS to "prove" that NOS and an EDRF/NO are involved. In the last three years evidence in cats and rats shows that many of the NOS inhibitors also block K channels in cerebrovascular smooth muscle and that arginine, the "antidote" to the NOS inhibitors keeps the channels open. This latter work must force a reexamination of the conclusions reached in many studies.

Animals↗

Homocysteine and methylmalonic acid: markers to predict and avoid toxicity from pemetrexed therapy.

The purpose of this study was to identify predictive factors for severe toxicity caused by antifolate-chemotherapy using pemetrexed (ALIMTA, LY231514), as a model. Data on potential predictive factors for severe toxicity from pemetrexed were collected from 246 patients treated between 1995 and 1999. Multivariate stepwise regression methods were used to identify markers predictive of severe toxicity. Using a multiple logistic regression model allowed us to quantify the relative risk of developing toxicities and to generate a validated clinical hypothesis on ways to improve the safety profile of pemetrexed. Pretreatment total plasma homocysteine (tHcy) levels significantly predict severe thrombocytopenia and neutropenia with or without associated grade 3/4 diarrhea, mucositis, or infection. Pretreatment methylmalonic acid (MMA) levels significantly and independently predict grade 3/4 diarrhea and mucositis; however, these toxicities are still predicted by tHcy alone. Patients with elevated baseline levels of tHcy alone, or of both tHcy and MMA, were found to have a high risk of severe toxicity that led us to postulate that reducing tHcy would result in a reduction of severe toxicity with no harm to efficacy. This study points out for the first time the importance of pretreatment tHcy levels in predicting severe toxicity associated with an antifolate and sets the stage for a prospective clinical intervention to protect patients from pemetrexed-induced severe toxicity and possibly improve the drug's efficacy. Antifolates as a class have been associated with sporadic severe myelosuppression with gastrointestinal toxicity. Although infrequent, a combination of such toxicities can carry a high risk of mortality. This phenomenon had been unpredictable until now. Our work shows that by measuring tHcy, one can identify patients that are at risk of toxicity before treatment. Most importantly, decreasing homocysteine levels via vitamin supplementation leads to a better safety profile of pemetrexed and possibly to an improved efficacy.

Adult↗

Occupational safety and health training in Alaska.

We have eleven years of experience delivering a wide variety of worker education programs in cross-cultural settings to reduce the levels of occupational fatalities and injuries in Alaska. We published an instructional manual and informational poster for workers, on Alaska's "Right-To-Know" law regarding chemical and physical hazards. The "Job Hazard Recognition Program" curriculum for high school students has received national acclaim for being proactive in dealing with worker safety education before the student becomes a member of the work force. Adult educational programs and materials have been designed to include less lecture and formal presentation, and more practical "hands on" and on-the-job experience for specific trades and hazards. New industry specific manuals deal with hazardous waste reduction as a method to reduce harm to the employee. Difficulty in getting instructors and training equipment to rural locations is dealt with by becoming creative in scheduling classes, using locally available equipment, and finding regional contacts who support the overall program. Alternative approaches to funding sources include building on regional long-term plans and establishing complementary program objectives.

Accident Prevention↗

[Multidisciplinary treatment of primary cancer of the breast].

The prognosis of surgery for carcinoma of the breast is directly and closely related with the number of homolateral axillary lymph nodes involved. When node involvement is present, recurrences are numerous and early, this tendency being increased in accordance with the number involved. When 4 or more nodes are involved, 35 to 52% of recurrences are seen during the first 18 months, according to the differend statistics available. Such recurrences are distant in 85% of cases. This is due to the fact that carcinoma of the breast, even in its early stages, is most often a generalised disease with disseminated lesions in the form of distant micrometastases. In these cases with a poor prognosis, some form of treatment to complement surgery is necessary. Radiotherapy has proved a failure, useless and often harmful as a result of prolonged reduction in cellular immune defences. Prolonged polychemotherapy, by contrast, has shown its great, not to say astonishing, effectiveness. Continued study is thus essential.

Antineoplastic Agents↗

Drug and defibrillator interactions.

We reviewed the interactions of drugs and defibrillators, with emphasis on implantable cardioverter defibrillators. Articles were identified by searching MEDLINE from 1966 to the present; additional sources were identified from reference lists in these articles. Drugs have the potential for both beneficial and harmful interactions with electrical therapy. Beneficial interactions include reductions in the energy required to defibrillate the heart and in the occurrence of arrhythmia resulting in decreased shock frequency, prolonged device longevity, and improved patient comfort. Potentially harmful interactions include altering the detection of ventricular tachycardia; altering the pacing threshold, resulting in interference with bradycardia or antitachycardia pacing; development of incessant ventricular tachycardia; and increasing the energy required to defibrillate the heart. As the use of implantable cardioverter defibrillators increases, pharmacists should be aware of the potential for drug-device interactions.

Animals↗

Linking evidence-based medicine therapeutic summary measures to clinical decision analysis.

OBJECTIVE: Evidence-based medicine (EBM) seeks to improve clinical practice by evaluating the quality of clinical evidence and ensuring that only the "best" evidence from clinical research is used in the management of individual patients. EBM has contributed to our understanding of the meaning of the benefit and harm of treatment as reported in the literature, and it is often promoted as an aid to clinical decision making. However, EBM therapeutic summary measures reflect only a single dimension of clinical decision making. The purpose of this work is to show how EBM therapeutic summary measures can be effectively incorporated into medical decision making. DESIGN: The effective application of the therapeutic summary measures advocated by EBM requires their integration into the framework of clinical decision analysis. Clinical decision analysis involves not only the identification and specification of the probabilities of clinical events but also the assessment of their relative values or utilities. We present here several analytic models for the integration of EBM therapeutic summary measures within the framework of clinical decision analysis. MAIN RESULTS: As expected, our analysis demonstrated that treatment should never be administered if its harm is greater than its efficacy, which is generally expressed as relative risk reduction. Likewise, a diagnostic test should never be ordered if the therapeutic harm is greater than the therapeutic efficacy. Intervention is always favored if the number needed to treat to avoid one adverse outcome (NNT) is smaller than the number needed to treat to harm one individual (NNH). When faced with a choice between two therapeutic options, the action threshold above which an intervention is favored can be expressed in terms of the harm inflicted (H) as H x NNT or NNT/NNH. If a patient's preferences are taken into account as relative value judgments (RV) of adverse events relative to that of therapeutic events, the action threshold is defined as NNT x (RV/NNH). CONCLUSIONS: In the setting of clinical decision making, EBM summary measures derived from population studies can be effectively used to define diagnostic and therapeutic action thresholds that may help in the management of individual patients.

Aged↗