Thermoregulation in mice following acute administration of lead acetate

Several reports in the literature suggest a relationship between lead intoxication and thermoregulatory capacity. To investigate the effects of lead on the control of body temperature, mice of the BALB/c strain were injected intraperitoneally with lead acetate (0 to 100 mg/kg) while colonic temperature was measured 30, 60, and 90 min post-injection at ambient temperatures (Ta) of 20 and 30 degrees C. Lead acetate caused a transient hypothermia, an effect which was augmented at cooler Ta's. In a second experiment, mice were injected with 100 mg/kg lead acetate and placed in a longitudinal temperature gradient to measure their preferred Ta. Lead acetate significantly reduced the preferred Ta during the first 30 min post-injection which augmented the lead-induced hypothermia. In a third experiment it was found that lead acetate-induced lethality was potentiated with increasing Ta. Hence, the hypothermic response to acute lead acetate treatment may be beneficial to survival.     

The dexamethasone suppression index: enhancement of DST diagnostic utility for depression by expressing serum cortisol as a function of serum dexamethasone

The authors sought to determine whether the performance of the dexamethasone suppression test (DST) could be enhanced by expressing cortisol as a function of dexamethasone. Because cortisol concentration is a function of the reciprocal of dexamethasone concentration, this relationship was approximated by calculating the product of cortisol and dexamethasone as a dexamethasone suppression index. Preliminary assessment of test performance measures (sensitivity, specificity, and predictive power) showed that use of the dexamethasone suppression index was an improvement over the use of cortisol levels alone. Factoring dexamethasone levels into post-dexamethasone cortisol level measures may enhance the utility of neuroendocrine assessment in psychiatry.     

Preface to the ‘UKCCCR guidelines for the Welfare of animals in experimental neoplasia’

Preface to the UKCCCR guidelines for the Welfare of animals in experimental neoplasia     

CB 1954 revisited

Summary Although it has been the subject of considerable interest for 15 years, originally as a cytotoxic agent and more recently as a radiosensitizer, there is very little pharmacokinetic information on CB 1954 (2,4-dinitro-5-aziridinylbenzamide). We have developed a rapid high-performance liquid chromatography assay for the drug and its metabolites and applied it to detailed examination of the pharmacokinetics of CB 1954 in mice and dogs. With IV administration a dose of 50 mg/kg gave peak blood concentrations of 100 g/ml in mice, while 25 mg/kg gave peak palsma concentrations of 27 g/ml in dogs. Peak concentrations were 3 to 5-fold lower for the IP route in mice and the oral route in dogs, and the bioavailabilities were 85% and 40%, respectively. Elimination t_1/2 values were 1.4–2 h in mice and 2.5–4 h in dogs and were independent of route of administration. Plasma protein binding was 57% but tissue penetration in mice was generally good. Tumour: plasma ratios were 50%–90%, while brain: plasma ratios were lower, at 37%–50%. The parent drug and several metabolites were identified and quantified in mouse urine, the total recovery being 24%–29%, of which 16%–25% was parent drug. The metabolites were also found in the circulation and in tissues. No changes in pharmacokinetics were seen with repeated dosing in mice or with administration of the protective agent phenyl AIC. Phenobarbitone pretreatment produced a small reduction in elimination t_1/2, mainly by accelerating aziridine ring removal. Allopurinol increased the blood levels of the 5-amino nitroreduction product. These studies provide a pharmacokinetic basis for interpreting the antitumour activity and toxicity of CB 1954, as well as for the development of new mixed-function sensitizers.     

Calibration of a Microselectron HDR iridium 192 source

A method for the calibration of the output, in terms of an air kerma rate, of the high activity miniature iridium 192 sources used in the Microselectron HDR afterloading unit is described. An air kerma rate is measured using a calibrated thimble chamber in an "in-air" calibration jig. The results are compared with an air kerma rate derived from the manufacturer's test certificate. In some cases, the ionization chamber measurements have been followed by a further calibration check using thermoluminescent dosimetry. Other checks carried out when a new source is received are also briefly described.     

Neurological manifestations in chronic mountain sickness: the burning feet-burning hands syndrome

OBJECTIVE: To characterise the clinical features and nerve biopsy findings in patients with chronic mountain sickness (CMS) living in the Peruvian Andes, with particular attention to the occurrence of the "burning feet-burning hands" syndrome. METHODS: Symptoms and signs were documented clinically in 10 patients with CMS and compared with those in five healthy subjects all living at 4338 metres altitude. Sural nerve biopsies were obtained from three patients with CMS.The nerve fibre population and endoneurial microvessels were analyzed morphometrically. RESULTS: All patients with CMS experienced burning and tingling paraesthesiae in the distal parts of their limbs. Similar but milder symptoms confined to the feet occurred in four of five controls. Three patients with CMS had a mild sensory neuropathy on examination, controls were clinically normal. Nerve biopsies showed a mild demyelinating neuropathy in all three with a reduction in the unmyelinated axon population in one. The endoneurial blood vessels showed a reduced thickness in the basal laminal zone compared with control values but were otherwise normal. CONCLUSIONS: Apart from well recognised symptoms and signs of CMS, the study has shown that such patients may also exhibit a mild sensory neuropathy. Its relation to the burning feet-burning hands syndrome, which was not confined to the patients but was also found in controls at altitude, is uncertain. The time course and pattern of the centrifugal resolution of the burning paraesthesiae complex on low altitude sojourn of high altitude natives raises the possibility that a mechanism involving altered axonal transport may be involved. The reduced thickness of the basal laminal zone of microvessels implies that adaptive structural changes to hypobaric hypoxia may also occur in peripheral nerve and are similar to those reported in other tissues of high altitude natives.     

A phase I study of SR-4554 via intravenous administration for noninvasive investigation of tumor hypoxia by magnetic resonance spectroscopy in patients with malignancy.

PURPOSE: To perform a Phase I study of SR-4554, a fluorinated 2-nitroimidazole noninvasive probe of tumor hypoxia detected by (19)F magnetic resonance spectroscopy (MRS). EXPERIMENTAL DESIGN: SR-4554 administration, on days 1 and 8, was followed by plasma sampling for pharmacokinetic studies and by three MRS studies performed over 24 h on days 8 and 9. Unlocalized MR spectra were acquired from tumor (10- or 16-cm dual resonant 1H/19F surface coil; 1.5 T Siemens Vision MR system; 2048 transients acquired over 34 min; 1.28-ms adiabatic pulse; repetition time, 1 s). Plasma drug concentrations were measured with a validated high-performance liquid chromatography method. Noncompartmental pharmacokinetic analysis was performed. RESULTS: Eight patients underwent pharmacokinetic studies, receiving doses of SR-4554 of 400-1600 mg/m(2). Peak plasma concentrations increased linearly with the SR-4554 dose (r(2) = 0.80; P = 0.0002). The plasma elimination half-life was relatively short (mean +/- SD, 3.28 +/- 0.59 h), and plasma clearance was quite rapid (mean +/- SD, 12.8 +/- 3.3 liters/h). Urinary recovery was generally high. SR-4554 was well tolerated. A single patient experienced dose-limiting toxicity (nausea and vomiting) at 1600 mg/m(2). The maximum tolerated dose was 1400 mg/m(2). SR-4554 was detected spectroscopically in tumors immediately after infusion at doses of 400-1600 mg/m(2). At the highest dose (1600 mg/m(2)), SR-4554 was detectable in tumor at 8 h, but not at 27 h. CONCLUSIONS: SR-4554 has plasma pharmacokinetic and toxicity profiles suitable for use as a hypoxia probe. It can be detected in tumors by unlocalized MRS. Additional clinical studies are warranted.     

Hypertrophic perineurial dysplasia in multifocal and generalized peripheral neuropathies

Two cases are described, one with a multifocal cranial and limb neuropathy of adult onset associated with optic neuropathy, and the other with a diffuse demyelinating neuropathy characterized by congenital cataract, mental retardation and progressive lower limb paresis with an onset in childhood. Extensive investigation in both failed to establish the causation. No family history of similar disorder was obtained in either case. Nerve biopsy in both showed similar perineurial abnormalities, the endoneurium being compartmentalized by hypertrophic perineurial cells that exhibited dysplastic features. The appearances resemble those described in a previously reported case of multifocal neuropathy and probably represent an unusual but non-specific response to a peripheral neuropathy.     

Informed consent and neuroanatomic correlates of intentionality and voluntariness among psychiatric patients

The authors examine the less-studied components of patients' autonomous decision making, or decisional autonomy, in the light of current research in psychiatry and neuropsychology and developments in the construct of informed consent. The three components of decisional autonomy-understanding, intentionality, and noncontrol or voluntariness-are related to clinical constructs in psychiatry and neuropsychology, in particular to executive control functions. The authors review studies that examine deficits in prefrontal cerebral function in schizophrenia, depression, and some anxiety disorders that are related to intentionality and voluntariness. Assessment of decisional autonomy should encompass evaluation of impaired intentionality and voluntariness, not simply impaired understanding. The main response to finding such impairments should be to provide treatment to ameliorate them. New strategies for psychiatric care should be developed to address the clinical challenges of an increasingly complex view of decisional autonomy.