Stimulation of S91 melanoma tyrosinase activity by superpotent alpha-melanotropins

alpha-Melanocyte-stimulating hormone (alpha-MSH, alpha-melanotropin), [Nle4,D-Phe7]-alpha-MSH and related fragment analogues, Ac-[Nle4,D-Phe7]-alpha-MSH4-11-NH2 and Ac-[Nle4,D-Phe7]-alpha-MSH4-10-NH2, were studied for their ability to stimulate tyrosinase activity in Cloudman S91 mouse melanoma cells in tissue culture. All of the melanotropins stimulated tyrosinase activity in a dose-dependent manner. [Nle4,D-Phe7]-alpha-MSH was about 100 times more active than alpha-MSH as determined from the minimal effective dose (MED) required to activate the enzyme above control (basal) levels. The MED of this analogue to significantly stimulate tyrosinase activity at 24, 48 and 72 h of incubation was 10(-11) M whereas the MED of alpha-MSH was 10(-9) M at each of these times. The maximum tyrosinase activity achieved from the time of initial incubation in the presence of [Nle4,D-Phe7]-alpha-MSH was approximately 3-, 5- and 6-fold greater than control levels at 24, 48 and 72 h, respectively. The 2 [Nle4,D-Phe7]-substituted fragment analogues were at least as active as the tridecapeptide analogue and therefore at least 100-fold more active than alpha-MSH in stimulating enzyme activity. These [Nle4,D-Phe7]-substituted analogues were more active in the melanoma tyrosinase assay than in the melanoma adenylate cyclase assay or other normal melanocyte (frog and lizard skin) bioassays.     

Long-term effects of acute and of chronic hypoxia on behavior and on hippocampal histology in the developing brain

Ten-day-old rat pups (P10) subjected to acute hypoxia (down to 4% O2) had as adults increased aggression (handling test), memory impairment (water maze test), and decreased CA1 cell counts. Pups subjected to chronic hypoxia (10% O2 from P0 to P21) had increased aggression, hyperactivity (open-field test), and decreased CA1 cell counts. Chronic hypoxia with superimposed acute hypoxia resulted in consequences that were not different from those of chronic hypoxia.     

Informed consent for elective and emergency surgery: questionnaire study

OBJECTIVES: To evaluate women's experience of giving consent to obstetric and gynaecological surgery and to examine differences between those undergoing elective and emergency procedures. DESIGN: A prospective questionnaire study. SETTING: A large teaching hospital. POPULATION: 1006 consecutive patients undergoing elective or emergency surgery in obstetrics and gynaecology. METHODS: Questionnaires were administered to women who had given consent to surgery following the introduction of national guidelines and consent form. Differences in responses between elective and emergency patients were assessed using frequencies, single and multivariable analyses. MAIN OUTCOME MEASURES: Patients' experience and recall of the consent process, their overall satisfaction and their views on what is important for adequate consent. RESULTS: There were significant differences between patients undergoing elective or emergency surgery. Patients undergoing emergency surgery were less likely to have read (OR 0.22) or understood (OR 0.40) the consent form, and were more likely to report feeling frightened by signing it (OR 2.52). They were more likely to report they felt they had no choice about signing the consent form (OR 2.11), and that they would have signed regardless of its content (OR 3.14). Overall, significantly more patients undergoing elective (80%) or emergency (63%) surgery reported satisfaction with the consent process. Patients were more likely to report satisfaction if they read (OR 1.80) and agreed with (OR 3.49) the consent form, and if someone checked that they understood (OR 3.09). CONCLUSION: Patients' needs may not be adequately addressed by current guidelines for consent to treatment, particularly in emergency circumstances. The introduction of more complex forms and procedures appears to conflict with patients' need for personal communication and advocacy. The implications on the ethical and legal standing of consent are considerable.     

Occlusion of dentinal tubules and selective block of pulp innervation prevent the nociceptive behaviour induced in rats by intradental application of irritants

Objectives: Application of irritants on the exposed dentine of the incisors has been shown to produce aversive behaviour in awake rats. This study aims to demonstrate that the observed aversion is due to the infiltration of irritants through the dentinal tubules and the activation of capsaicin sensitive fibres in the tooth pulp. Methods: Different groups of rats were subjected, under anaesthesia, to cutting of the distal 2 mm of their lower incisors and the fixation of an artificial crown that allows the application of 10-15 μl of solution. Several procedures were followed to prevent the action of the irritants including occlusion of the dentinal tubules, local application of lidocaine, selective ablation of the capsaicin sensitive primary afferents (CSPA) or incisor pulpectomy; the reactions to intradental application of either capsaicin (1%) or formalin (2.5%) were tested using a newly designed behavioural score. Results: Occlusion of dentinal tubules produced significant attenuation of the nociceptive behaviour induced by dentinal application of either capsaicin or formalin. Similar results were observed following either local block with lidocaine (2%), selective ablation of capsaicin sensitive afferents or total denervation by pulpectomy. Conclusions: The present results confirm the hypothesis of infiltration of irritants to the incisor pulp through the dentinal tubules and suggest that the reported inflammatory reaction and hyperalgesia are mediated, to a large extent, by capsaicin sensitive primary afferents.     

Probenecid interacts with the pharmacokinetics of morphine-6-glucuronide in humans

BACKGROUND: Evidence obtained from porcine cell cultures and experiments in laboratory animals indicates that transmembrane transporters may play a role in the distribution of the active morphine metabolite morphine-6-glucuronide (M6G). This was evaluated in a study in healthy volunteers. METHODS: Ten subjects received an intravenous M6G infusion for 30 min at a dosage of 0.5 mg/kg body weight, leading to M6G plasma concentrations approximately two to three times higher than those observed with analgesic morphine doses in subjects with normal kidney function. In a randomized, double-blind, three-way crossover fashion, subjects received 800 mg quinidine for inhibition of P-glycoprotein; 500 mg probenecid for inhibition of other transporters, including organic anion transporter peptide, multidrug resistance-related protein, and organic anion transporter families; or placebo 1 h before the start of M6G administration. Plasma concentrations of M6G and pupil size were measured for 7 h. RESULTS: Probenecid pretreatment resulted in a decrease in the clearance of M6G from 8.3 +/- 1 l/h to 6.7 +/- 1.3 l/h (factor of 0.8; P < 0.05 vs. placebo cotreatment). This was paralleled by an increase by a factor of 1.2 of the area under the miotic effect-versus-time curves (P < 0.05 vs. placebo). In contrast, quinidine pretreatment had no influence on the pharmacokinetics of M6G. CONCLUSIONS: The active morphine metabolite is subject to transmembrane transport by transporters inhibited by probenecid in humans.     

Dynamic effects of a 9 mm missile on cadaveric skull protected by aramid, polyethylene or aluminum plate: an experimental study

BACKGROUND: Most military helmets are designed to prevent penetration by small firearms using composite materials in their construction. However, the transient deformation of the composite helmet during a non penetrating impact may result in severe head injury. METHOD: Two experimental designs were undertaken to characterize the extend of injuries imparted by composite panels using in protective helmets. In the first series, 21 dry skulls were protected by polyethylene plates, with gaps between the protective plate and skull ranging from 12 to 15 mm. In another design, using 9 cadavers, heads were protected by aluminum, aramid, or polyethylene plates. Specimens were instrumented with pressure gauges to record the impact response. The ammunition used in these experiments was 9 mm caliber and had a velocity of 400 m/s. A macroscopic analysis of the specimens quantified fractures and injuries, which were then related to the measured pressures. RESULTS: Protective plates influenced both the levels of injury and the intracranial pressure. Injuries were accentuated as the plates was changed from aluminum to composite materials and ranged from skin laceration to extensive skull fractures and brain contusion. Fractures were associated with brain parenchymal pressures in excess of 560 kPa and cerebrospinal fluid pressure of 150 kPa. An air gap of a few millimeters between the plate and the head was sufficient to decrease these internal pressures by half, significantly reducing the level of injury. CONCLUSIONS: Ballistic helmets made of composite materials could be optimized to avoid extensive transient deformation and thus reduce the impact and blunt trauma to the head. However, this deformation cannot be completely removed, which is why the gap between the helmet and the head must be maintained at more than 12 mm.     

Conservative treatment for thoracic outlet syndrome

Conservative treatment of thoracic outlet syndrome consists initially of pain control and medicinal and physical measures. Therapy then addresses tight muscles, with strengthening of weakened neck and shoulder girdle muscles. Range of motion and nerve gliding exercises are instituted simultaneously, and the patient is educated in proper posture and ergonomics at home and in the work setting.