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We construct small-amplitude periodic water waves with multiple critical layers. In addition to waves with arbitrarily many critical layers and a single crest in each period, multimodal waves with several crests and troughs in each period are found. The setting is that of steady two-dimensional finite-depth gravity water waves with vorticity. [ABSTRACT FROM AUTHOR]

Abstract: In this paper we show that the hydrodynamic problem for three-dimensional water waves with strong surface-tension effects admits a fully localised solitary wave which decays to the undisturbed state of the water in every horizontal direction. The proof is based upon the classical variational principle that a solitary wave of this type is a critical point of the energy, which is given in dimensionless coordinates by subject to the constraint that the momentum is fixed; here is the fluid domain, ϕ is the velocity potential and is the Bond number. These functionals are studied locally for η in a neighbourhood of the origin in . We prove the existence of a minimiser of subject to the constraint , where . The existence of a small-amplitude solitary wave is thus assured, and since and are both conserved quantities a standard argument may be used to establish the stability of the set of minimisers as a whole. ‘Stability’ is however understood in a qualified sense due to the lack of a global well-posedness theory for three-dimensional water waves. We show that solutions to the evolutionary problem starting near remain close to in a suitably defined energy space over their interval of existence; they may however explode in finite time due to higher-order derivatives becoming unbounded. [Copyright &y& Elsevier]

PURPOSE: There is a paucity of long-term evaluations on rehabilitation of musculoskeletal disorders, e.g., neck, shoulder or back pain. The aim of this study was to assess quality of life and the effect of early multimodal rehabilitation on 91 patients with musculoskeletal pain and disability at a 5-year follow-up. METHOD: The follow-up assessment, which included questions on pain, function, quality of life, perceived health, sick leave and psychosomatic symptoms, was performed 5 years after the assessment of baseline status. RESULTS: Improvements in pain, perceived health and psychosomatic symptoms were maintained at the 5-year follow-up. In addition, improvements in function, quality of life, and level of acceptable pain were significant in comparison to baseline. At the time of the baseline assessment all patients were on sick leave (13% were on partial sick leave). At the 5-year follow-up, 58% of the patients were at work part or full time. The results show that those working differed significantly from those not working at the 5-year follow-up on almost all variables, indicating that those working enjoy better health. The most salient prognostic factors for return to work were perceived health and educational level at the time of the baseline evaluation. CONCLUSIONS: These results show that treatment improved quality of life and the effects were basically maintained at 5 years. Work capacity as reflected in return to work increased greatly (81%) at a 1-year follow-up and was substantial (58%) at the 5-year follow-up. Moreover, perceived health and educational levels were important prognostic factors. Finally, the fact that patients working reported better health underscores the probable importance of return to work. Our results imply that it may be feasible to obtain long-term benefits from such a primary care-based intervention. [ABSTRACT FROM AUTHOR]

The pharmacokinetic and pharmacodynamic properties of raclopride, a new antipsychotic, were investigated in 16 healthy men. Single 4 mg doses were administered as intravenous infusion, oral solution and 2 extended release (ER) formulations. Total plasma clearance was about 100 ml/min (6.0 L/h), of which renal clearance accounted for 0.2 ml/min, indicating extensive metabolism. The volume of distribution was 1.5 L/kg; mean absolute bioavailability was 65 to 67% following the oral solution and the ER formulations. A transient increase in plasma prolactin levels followed both the intravenous infusion and the oral solution. The ER formulations resulted in a lower increase, which appeared later. However, the area under the prolactin level curve was similar after administration of all dosage forms. The frequency and severity of the most commonly reported side effects (tiredness and restlessness) were higher after the intravenous infusion than after the ER capsules. These findings indicate that such capsules may be advantageous for clinical antipsychotic treatment with raclopride.

The possible influence of concomitant food intake on the bioavailability of the novel antidepressant zimeldine and its active metabolite norzimeldine was assessed in ten healthy female volunteers, who ingested a single dose of 200 mg zimeldine on an empty stomach and together with a standardized breakfast of 1 840 kJ. The plasma concentrations of zimeldine and norzimeldine were measured by a selective modern liquid chromatographic technique. Neither the peak concentration nor time to reach peak concentration nor elimination half-life nor the total area under the curve (AUC) of zimeldine was affected by concomitant food intake. For norzimeldine, the peak concentration showed a 10% reduction, but there was no change in any other parameter. Thus, the bioavailability of zimeldine and of its active metabolite norzimeldine is unaffected by food intake, suggesting that the drug need not be taken in a strictly defined relation to meals.

Alaproclate, a selective serotonin reuptake inhibitor, presently undergoing clinical trial for the treatment of major depressive disorders, has been shown to inhibit hexobarbital metabolism in mice. In the present study the influence of oral alaproclate on the total plasma clearance of antipyrine and on the formation of its metabolites was investigated in 10 healthy volunteers. The peak level of alaproclate was reached after about 1.5 h, and after a distribution phase, its plasma elimination half-life was between 3.0 and 3.5 h. Antipyrine tests were performed before treatment, during the first four doses and after the seventh dose of alaproclate 200 mg/day. During treatment, total plasma antipyrine clearance and the clearance for production of all antipyrine metabolites were reduced by 30%, indicating non-selective inhibition of oxidative drug-metabolizing enzyme activity in man by alaproclate. After the last dose of alaproclate, antipyrine plasma clearance and the clearance to its metabolites returned to control values. In order to allow more detailed evaluation of the results, the time course of the clearances for production of metabolites was investigated. This revealed that the extent of inhibition of metabolite formation by alaproclate was dependent on the plasma alaproclate level, indicating a rapidly reversible inhibition.

Deuterium labelled delta 1-tetrahydrocannabinol was administered intravenously (5.0 mg) and by smoking (10.0 mg) to five heavy and four light marihuana users. All subjects smoked an estimated amount of 8.6-9.9 mg delta 1-tetrahydrocannabinol. The plasma levels of delta 1-tetrahydrocannabinol were followed for 48 hours and in two subjects fof 72 hours after administration. The systemic availability after inhalation calculated from the area under curve values was in the range of 27 +/- 10% for the heavy users and 14 +/- 1% for the light users. There was little difference between the groups with regard to the amount of smoked delta 1-tetrahydrocannabinol or plasma levels and area under curve values obtained after i.v. administration. Thus, it seems likely that the statistically significant difference in systemic availability of smoked delta 1-tetrahydrocannabinol was due to a more efficient smoking by the heavy users. It is also indicated that heavy users prefer slightly higher delta 1-tetrahydrocannabinol plasma levels than light users. Based on the area under curve values after i.v. administration, a plasma clearance of 760-1190 ml min-1 was calculated. The elimination half-life of delta 1-tetrahydrocannabinol is more than 20 hours. The present results do not suggest that tolerance or sensitivity to delta 1-tetrahydrocannabinol in heavy users is readily achieved.

The use of placebo in controlled clinical trials is a very difficult matter from an ethical point of view. Scientifically it offers probably the best way of obtaining fast and valid conclusions, thus promoting medical progress for the benefit of future patients. On the other hand, some patients may stand the risk of obtaining a suboptimal therapy in a placebo-controlled trial. In general, this latter aspect must be given precedence. Therefore the use of placebo control should be minimized and other control methods encouraged. However, in certain well-defined instances the use of a placebo control can be justified, provided the ethical implications can be handled.

The tolerability and pharmacokinetics of remoxipride were studied in 18 healthy normal male volunteers. Increasing oral doses of 0.5-100 mg were given to eight male volunteers in one study (study I). In addition, an intravenous (IV) infusion of 20 mg remoxipride and a 20 mg oral dose were given in an open crossover study to ten males (study II). Remoxipride was well tolerated with respect to cardiovascular effects, clinical chemistry, body temperature and adverse effects in all subjects. Following IV administration, remoxipride plasma concentrations declined exponentially in five subjects and biexponentially in the remaining five. The mean apparent volume of distribution was 0.5 l/kg (SD = 0.10) and the mean half-life 4.1 h (range 2.6-6.6). The recovery of unchanged remoxipride in urine was 10-36%, and the mean renal clearance was 32 ml/min (SD = 13). Remoxipride was a low clearance drug with a total plasma clearance of about 120 ml/min (SD = 41). The mean oral bioavailability was 96%. There was a linear relationship between the peak plasma concentration as well as the area under the concentration versus time curve and the administered dose. A transient increase in plasma prolactin concentrations occurred but there were no effects on plasma growth hormone levels.