A procedure for identifying significant environmental aspects in sea ports.

A new methodology has been designed to identify and rank the significant environmental aspects in sea ports. The main objective of the Strategic Overview of Significant Environmental Aspects (SOSEA) is to help port managers to identify significant environmental aspects and to reinforce the awareness about them in order to prioritise work in environmental management. Developed in close collaboration with port environmental managers and tested in a set of ports, it is a user-friendly tool that can be applied in approximately half a working day. It is based on ISO 14001 vocabulary and requirements and it can be considered as the base for the implementation of any Environmental Management System for port communities.

The Self Diagnosis Method. A new methodology to assess environmental management in sea ports.

A methodology has been designed to assess the performance of the environmental management in sea ports. The Self Diagnosis Method, developed by two research teams and about sixty sea ports, allows the comparison of the current environmental situation with that corresponding to previous years and the assessment of the opportunities for improvement. The main objective is to review the management activities and procedures that affect the environment and the way the port authority handles significant environmental aspects. It has been designed as a "first level" tool: it can be applied in approximately six hours by a non-expert user. It is based on the ISO 14001 vocabulary, requirements and structure, and it can be considered as a first step in the voluntary implementation of an environmental management system for port communities.

The influence of diet upon liver function tests and serum lipids in healthy male volunteers resident in a Phase I unit.

AIM: To investigate the effect of diet upon liver function tests and serum lipids within the restricted environment of a Phase I unit. METHODS: An open randomized three-way crossover study was designed with subjects consuming three types of diet. The diets comprised, a balanced normal calorie diet, a high-carbohydrate high-calorie diet and a high-fat high-calorie diet. Each diet was consumed in a randomized sequence over 8 days with a recovery period of 14 days between periods. The blood concentrations of various laboratory parameters were measured at intervals throughout each dietary period and during the recovery periods. RESULTS: Blood transaminase activity and triglyceride concentrations increased significantly whilst subjects consumed a high-carbohydrate high-calorie diet but not when fed either a high-fat high-calorie diet or a balanced normal calorie diet. CONCLUSIONS: The rises in transaminases and triglycerides were caused by the carbohydrate content of the diet rather than its calorific value. Sucrose rather than starch was the carbohydrate which caused the rise in transaminases and triglycerides. The importance of controlling diet in Phase I studies is stressed.

Carboxyl residues in the active site of human phenol sulfotransferase (SULT1A1).

The carboxyl-specific amino acid modification reagent, Woodward's reagent K (WK), was utilized to characterize carboxyl residues (Asp and Glu) in the active site of human phenol sulfotransferase (SULT1A1). SULT1A1 was purified using the pMAL-c2 expression system in E. coli. WK inactivated SULT1A1 activity in a time- and concentration-dependent manner. The inactivation followed first-order kinetics relative to both SULT1A1 and WK. Both phenolic substrates and adenosine 3'-phosphate 5'-phosphosulfate (PAPS) protected against the inactivation, which suggests the carboxyl residue modification causing the inactivation took place within the active site of the enzyme. With partially inactivated SULT1A1, both V(max) and K(m) changed for PAPS, while for phenolic substrates, V(max) decreased and K(m) did not change significantly. A computer model of the three-dimensional structure of SULT1A1 was constructed based on the mouse estrogen sulfotransferase (mSULT1E1) X-ray crystal structure. According to the model, Glu83, Asp134, Glu246, and Asp263 are the residues likely responsible for the inactivation of SULT1A1 by WK. According to these results, five SULT1A1 mutants, E83A, D134A, E246A, D263A, and E151A, were generated (E151A as control mutant). Specific activity determination of the mutants demonstrated that E83A and D134A lost almost 100% of the catalytic activity. E246A and D263A also decreased SULT1A1 activity, while E151A did not change SULT1A1 catalytic activity significantly. This work demonstrates that carboxyl residues are present in the active site and are important for SULT1A1 catalytic activity. Glu83 and E134 are essential amino acids for SULT1A1 catalytic activity.

Topical and systemic absorption of sodium pyrithione following topical application to the nails of the rhesus monkey.

A study was performed to investigate the local penetration into the nail, the systemic absorption into the rest of the body, and the routes of excretion of sodium pyrithione following topical application to the nail. Approximately 20 microliters of a film-forming 3% sodium 14C-pyrithione solution was applied once daily to 5 fingernails and 5 toenails of 4 rhesus monkeys for 6 or 7 days. Following dose removal on study day 7, 2 animals were sacrificed, and the treated nails were analyzed for radioactivity. The other 2 monkeys received the topical dose for 1 more day and were monitored during the postdosing period. Sodium 14C-pyrithione was absorbed slowly into and across the nail following topical application, with the nails serving as reservoirs for the drug. Further evidence of the slow movement of sodium pyrithione across the nail was provided by peak plasma 14C equivalents obtained on day 9, 1 day after the last dose had been removed from the nails. Only slight drug concentrations were measurable in plasma, with no radioactivity observed beyond day 12. The urinary excretion data exhibited a delay in peak urinary excretion (days 8 and 9), and an elimination half-life of 2 days, so that approximately 90% of the absorbed drug was eliminated within 1 week following treatment. Including a minor excretion pathway through the feces, total excretion as a percent of dosage was 8.5%, indicating that less than 10% of the applied topical dose of sodium pyrithione was absorbed systemically.(ABSTRACT TRUNCATED AT 250 WORDS)

Interspecies comparison of the pharmacokinetics of aldose reductase inhibitors.

The pharmacokinetics of three aldose reductase inhibitors (ARIs) were evaluated in various species, including rat, dog, cynomolgus monkey, rhesus monkey, chimpanzee, and man. The three ARIs (AL01567, AL01576, and AL01750) were administered intravenously as a single dose to all species except rat, which was dosed orally with AL01750, and man, who was dosed orally with AL01567 and AL01576. Plasma drug concentrations were measured by HPLC or liquid scintillation spectrometry and various pharmacokinetic parameters (clearance, CL; Vd, volume of distribution; and t1/2) were calculated from the data. Overall the pharmacokinetics of the three compounds were quite similar, each being characterized by low CL, intermediate Vd, and long t1/2. For AL01576, mean CL ranged from 0.21 ml/min/kg in cynomolgus monkey to 0.91 ml/min/kg in dog, mean Vd from 0.66 liter/kg in cynomolgus monkey to 2.4 liters/kg in dog and man and mean t1/2 from 29 hr in dog to 72 hr in man. Mean CL of AL01567 ranged from 0.14 ml/min/kg in man to 1.4 ml/min/kg in dog, mean Vd from 0.45 liter/kg in rat to 3.5 liters/kg in dog and mean t1/2 from 22 hr in rhesus monkey to 63 hr in man. Mean CL of AL01750 ranged from 0.13 ml/min/kg in chimpanzee to 1.3 ml/min/kg in dog, mean Vd from 0.40 liter/kg in rat to 1.8 liters/kg in dog and mean t1/2 from 12 hr in rhesus monkey to 62 hr in chimpanzee. For all three drugs, CL and Vd corrected for body weight were quite similar in all species except dog, whose CL and Vd were two- to fourfold greater than the other animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of the aldose reductase inhibitor imirestat following topical ocular administration.

The pharmacokinetics of imirestat following topical ocular administration were evaluated in a series of studies in rabbits and dogs. Following single topical doses to both albino and pigmented rabbits, imirestat was subject to rapid uptake into the cornea followed by an initial rapid decline and then very slow elimination, with a t1/2 of approximately 130 hr. Drug was rapidly absorbed into aqueous humor, with concentrations declining to nondetectable levels by 12 hr. Imirestat was retained in the lens following topical dosing similar to that in cornea, with an apparent elimination t1/2 of 140 hr. Vitreous humor concentrations of drug were detectable for up to 72 hr after dosing. There was no apparent difference in the disposition of the drug between albino and pigmented rabbits. Bioavailability following topical dosing increased with dose, although not in a linear fashion. Formulation pH did not have an appreciable effect on ocular bioavailability. There was detectable systemic absorption following topical dosing, with plasma concentrations in rabbit being 50 to 75% of that observed following an equivalent intravenous dose. However, drug levels in the dosed eyes were significantly higher than in contralateral undosed eyes. Multiple dosing of imirestat for 6 weeks resulted in accumulation of drug in rabbit lens. Concentrations were higher in lens cortex than lens nucleus, with the time course for accumulation being different for the two. Our data suggest that imirestat penetrates into ocular tissue following topical dosing and is retained in lens and cornea, potential sites of action for the drug.

Disposition of the aldose reductase inhibitor AL01576 in rats.

The disposition of the aldose reductase inhibitor AL01576 was studied in rats following intravenous and oral dosing. Single 4-mg/kg intravenous bolus and oral doses of [14C] AL01576 were administered and levels of radioactivity in blood, excreta, and various tissues were determined over a 168-h period. The decline of radioactivity in blood was quite similar for the two routes of administration, with an apparent half-life of approximately 30 h. At 120 to 144 h, a second, slower elimination phase began that was not fully characterized in the 168-h duration of the study. The HPLC analysis of plasma samples revealed intact AL01576 as the only compound in plasma. The mean plasma parent and radioactivity concentrations are in agreement; suggesting the absence of or an insignificant amount of metabolite in the plasma. The urinary and fecal excretion rate data showed a kinetic pattern similar to that of blood radioactivity. Fecal excretion was the primary route of elimination following both intravenous and oral dosing, accounting for 59% of the administered intravenous dose and 61% of the oral dose. Urinary excretion accounted for 32% of the intravenous dose and 29% of the oral dose. Negligible amounts of radioactivity were recovered as expired 14CO2. Experiments with bile-duct cannulated rats confirmed that the major route of elimination of the drug is biliary excretion. The pattern of distribution of [14C] AL01576 in tissues was quite similar following the two routes of administration. Tissue radioactivity concentration peaked at 4 h (the first sampling time) following both routes of administration in all tissues except the GI tract.(ABSTRACT TRUNCATED AT 250 WORDS)

Naloxone enhances myocardial responses to isoproterenol in dog isolated heart-lung.

Intracoronary injection of naloxone produces rapid local increases in myocardial performance. The role of beta-adrenergic activation in this response was investigated. Naloxone was injected into the left anterior descending artery (LAD) of anesthetized dogs with the adjacent circumflex territory serving as control. Naloxone increased the contractile state locally in the LAD region. Pretreatment with propranolol eliminated the regional inotropic response. An isolated heart-lung model was set up, and isoproterenol dose responses were determined. When repeated after naloxone, contractile (dP/dt) responses to isoproterenol were both augmented and prolonged. In a third study imipramine was used to determine whether naloxone might act by reducing neuronal uptake of the isoproterenol. Imipramine extended the effect of isoproterenol temporally but did not alter the peak response. Adding naloxone increased the peak response to isoproterenol and maintained it above the extended imipramine response. The data support the concept that the blockade of opiate receptors facilitates adrenergic activity mediated by myocardial beta 1-receptors 1) directly through postsynaptic mechanisms, 2) indirectly through beta 2-mediated release of norepinephrine, or 3) via interference with nonneuronal disposal mechanisms.

The interaction of endogenous opiates with autonomic circulatory control in the dog.

The intravenous injection of either methionine or leucine enkephalin sharply reduces blood pressure, peak left ventricular pressure, and peak LV dP/dt in anesthetized dogs. The magnitude of the hypotensive response increases in proportion to the severity of the preceding surgical stress. The peptides are relatively ineffective after only simple surgical procedures but become highly effective when the autonomic balance is shifted toward sympathetic dependence after more complicated procedures or following bilateral carotid occlusion. The greater the animal's dependence upon sympathetic outflow to maintain blood pressure, the more effective is the opiate peptide. This suggests that the peripherally administered opiates may act by opposing existing adrenergic tone. Such antagonism of adrenergic tone during circulatory shock may help to explain some of the benefit of opiate receptor blockade in this condition. The rapid decline in blood pressure can be demonstrated in response to a variety of the proenkephalin-A derived peptides expected to circulate during physiological stresses. Based on a comparison of the responses to a series of peptides, the hypotensive effect is most likely mediated through activating opiate receptors of the delta subtype.

The role of the renal lymphatics in fluoride handling.

The role of the renal lymphatics in the handling of fluoride ion by the canine kidney was studied during IV sodium fluoride infusion. It was found that renal lymph and renal venous plasma have similar fluoride concentrations and that there was less fluoride in lymph than in arterial plasma. Fluoride did not alter renal lymphatic flow rate over a wide range of plasma fluoride concentrations.

Head position training with the cerebral palsied child: an application of biofeedback techniques.

A biofeedback training system has been developed for providing the cerebral palsied child with precise auditory and visual information regarding the spatial position of his head. The child actively practices correcting his head position by using feedback delivered through a mercury-switch device called a head position trainer. Twelve children have received clinical training and results are discussed in terms of feedback-sensitive, feedback-trained and feedback-learned, the results of treatment dictating the classification. It is concluded that the head position trainer is an effective sensory aid for the cerebral palsied child in the development of head control and position awareness. It is proposed that this system has excellent potential use as an adjunct to regular therapy programming in that it provides additional daily practice time and an objective method of recording the child's progress.

Biofeedback--background and applications to physical rehabilitation.

This paper presents a brief background to biofeedback applications including biofeedback techniques related to physical rehabilitation, and in particular, that of the cerebral palsied. Relevant literature is noted and there is an overview of 3 years research investigating the use of biofeedback in the management of cerebral palsied children. A theoretical framework for using biofeedback to ameliorate motor problems with the physically disabled in general is presented. The areas of investigation are head position, joint position, electromyography, spinal rotation, weight-bearing, response-feedback toys, jaw closure, and postural alignment. The results of these various programs indicate a preliminary outcome classification of feedback-sensitive, feedback trained, and feedback-learned. All children were feedback-sensitive, the majority could be trained, and several cases demonstrated a learned carry-over response. In conclusion, biofeedback training offers the advantages of therapy in natural training settings, and direct involvement of the patient.

A study of weight transmission through the knee joint with applied varus and valgus loads.

An electromechanical device is described which permits measurement of the amount of weight borne on each compartment of the knee during varying amounts of lateral angulation. A lateral angulation of only 3 degrees in either direction completely unloaded the opposite condyle. The correction to be obtained by tibial osteotomy of varus or valgus knee deformity should permit the mechanical axis of the extremity to pass the tibial spines on the side opposite the deformity. An angular deviation of 3 degrees more than that required to restore the mechanical axis to normal position is sufficient.