Novel quinuclidine-based ligands for the muscarinic cholinergic receptor

Recent clinical studies on Alzheimer's patients have implied that only agents displaying high efficacy at the cortical muscarinic receptor have yielded encouraging results. This paper describes the design, synthesis, and biochemical characterization of novel quinuclidine-based muscarinic agonists which can readily penetrate into the central nervous system and which are capable of displaying high efficacy at cortical sites. With use of a biochemical assay capable of measuring receptor affinity and predicting cortical efficacy, it has been discovered that an oxadiazole ring and related heterocycles can function as bioisosteric replacements for the ester moiety found in several known muscarinic ligands. Within this series there exist compounds which span the efficacy range from high-efficacy agonist through partial agonists to antagonists with affinity comparable or superior to that of classical quaternary ammonium ligands. Consistent with recent molecular biology studies, structure-activity trends are interpreted in terms of separate binding sites for agonists and antagonists with H-bonding interactions characterizing agonist behavior and lipophilic binding characterizing antagonist behavior. Thus the aminooxadiazole moiety has structural features which are optimized for an agonist profile.     

Cardiovascular responses to heat stress and their adverse consequences in healthy and vulnerable human populations.

This paper reviews the basic thermoregulatory physiology of healthy people in relation to hazards from external heat stress and internal heat loads generated by physical exercise or radiofrequency (RF) radiation. In addition, members of the population are identified who may be particularly vulnerable to the effects of heat stress. These data are examined in relation to current international guidance on occupational and public exposure to RF radiation. When body temperature rises, heat balance of the body is normally restored by increased blood flow to the skin and by sweating. These responses increase the work of the heart and cause loss of salt and water from the body. They impair working efficiency and can overload the heart and cause haemoconcentration, which can lead to coronary and cerebral thrombosis, particularly in elderly people with atheromatous arteries. These adverse effects of thermoregulatory adjustments occur with even mild heat loads and account for the great majority of heat-related illness and death. They are, therefore, particularly relevant to determination of safe population exposures to additional sources of heat stress. It is concluded that exposure to RF levels currently recommended as safe for the general population, equivalent to heat loads of about one tenth basal metabolic rate, could continue to be regarded as trivial in this context, but that prolonged exposures of the general population to RF levels higher than that could not be regarded as safe in all circumstances.     

REPAIR AND RECOVERY FOLLOWING SPINAL CORD INJURY IN A NEONATAL MARSUPIAL (MONODELPHIS DOMESTICA)

1. Repair and recovery following spinal cord injury (complete spinal cord crush) has been studied in vitro in neonatal opossum (Monodelphis domestica), fetal rat and in vivo in neonatal opossum. 2. Crush injury of the cultured spinal cord of isolated entire central nervous system (CNS) of neonatal opossum (P4–10) or fetal rats (E15–E16) was followed by profuse growth of fibres and recovery of conduction of impulses through the crush. Previous studies of injured immature mammalian spinal cord have described fibre growth occurring only around the lesion, unless implanted with fetal CNS. 3. The period during which successful growth occurred in response to a crush is developmentally regulated. No such growth was obtained after P12 in spinal cords crushed in vitro at the level of C7–8. 4. In vivo, in the neonatal (P4–8) marsupial opossum, growth of fibres through, and restoration of, impulse conduction across the crush was apparent 1–2 weeks after injury. With longer periods of time after crushing a considerable degree of normal locomotor function developed. 5. By the time the operated animals reached adulthood, the morphological structure of the spinal cord, both in the region of the crush and on either side of the site of the lesion, appeared grossly normal. 6. The results are discussed in relation to the eventual longterm possibility of devising effective treatments for patients with spinal cord injuries.     

Case report: venous thromboembolism in AIDS.

Recently, the authors managed three patients with AIDS and venous thromboembolism. All three were active, ambulatory, and without known risk factors for pulmonary embolism or deep venous thrombosis. One patient had a low titer for IgG anticardiolipin antibody (1:13). Two had low normal values for free protein S, and the third patient had a very low value (5%). Clinicians caring for AIDS patients should be alert to the possibility that venous thromboembolism may complicate HIV infection.     

Bilateral malignant glaucoma.

Two cases of bilateral malignant glaucoma are presented. In one case the condition developed sequentially in the two eyes; pars plana vitrectomy was eventually needed in the operated eye, whereas the condition responded to medical treatment in the fellow eye. In the second case the two eyes were involved simultaneously nearly 1 year after surgery, and the glaucoma responded to medical treatment.     

Penetrating intracranial wood wounds: clinical limitations of computerized tomography

The case history of a patient with a periorbital penetrating wooden foreign body is presented. The computerized tomography (CT) densities of several different sources of wood were compared using an experimental model. The clinical usefulness and practical limitations of CT in the evaluation of intracranial foreign bodies is discussed, and the management of this type of injury is reviewed.