Initial experience of clinical pharmacology and clinical pharmacy interactions in a clinical pharmacokinetics consultation service

International statistics indicate that there is a close correlation between the consumption of saturated fats (dairy fats and meat fats) and the mortality from coronary heart disease (CHD), and this conception has been confirmed by many epidemiological studies. Such studies alone, however, cannot prove the existence of a cause-and-effect relationship between these two variables; dietary intervention trials are needed. The Finnish Mental Hospital Study was such a trial, conducted in two hospitals near Helsinki in 1959--1971. Practically total replacement of dairy fats by vegetable oils in the diets of these hospitals was followed by a substantial reduction in the mortality of men from CHD. Total mortality also appeared to be reduced. As to the causes of death other than CHD, none was significantly influenced by dietary change. This was also true for malignant neoplasms. To alleviate the burden of CHD on public health, many investigators have recommended important changes in the quantity and quality of dietary fats.     

Hearing and Sj?gren's syndrome

Immune sensorineural hearing loss is manifested in several systemic immune diseases. Although hearing loss has been previously documented in patients with Sj?gren's syndrome (SS), the effect of SS on hearing is unclear. This prospective study was designed to assess the presence of hearing loss in 14 patients with SS and, if sensorineural hearing loss was present, to determine if the hearing loss was immune-mediated. Patients were evaluated with basic audiologic tests as well as for cellular immune inner ear reactivity as measured by the lymphocyte transformation test (LTT). Three patients had evidence of sensorineural hearing loss. Two patients had a positive LTT without evidence of sensorineural hearing loss. This preliminary study suggests that SS may not directly cause sensorineural hearing loss, immuno-mediated or otherwise.     

On the many faces of Leber hereditary optic neuropathy

Leber hereditary optic neuropathy (LHON) is a maternally inherited disorder, associated with mutations in the mitochondrial DNA, which is notorious for its aspecific presentations. Two pedigrees are described with cases that are atypical for LHON with respect to sex, age of onset, interval between the eyes becoming affected, course of the disease, concomitant disorders, additional test results, final visual acuity, and/or results of mtDNA analysis. Moreover, the pedigrees themselves did not suggest maternal inheritance. We analysed the diagnostic and clinical genetic difficulties related to the atypical aspects of these pedigrees. We conclude that mtDNA analysis is justified in every case of optic nerve atrophy with no clear cause. Identification of one of the three LHON specifically associated mtDNA mutations is essential to confirm the diagnosis.     

Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice

The function of the central cannabinoid receptor (CB1) was investigated by invalidating its gene. Mutant mice did not respond to cannabinoid drugs, demonstrating the exclusive role of the CB1 receptor in mediating analgesia, reinforcement, hypothermia, hypolocomotion, and hypotension. The acute effects of opiates were unaffected, but the reinforcing properties of morphine and the severity of the withdrawal syndrome were strongly reduced. These observations suggest that the CB1 receptor is involved in the motivational properties of opiates and in the development of physical dependence and extend the concept of an interconnected role of CB1 and opiate receptors in the brain areas mediating addictive behavior.     

Cell surface regulators of complement, 5I2 antigen, and CD59, in the rat eye and adnexal tissues

PURPOSE: Cell surface complement regulatory proteins have been identified in high levels in ocular tissues, but no experimental model is available for examining their physiological roles. To develop such a model, the distribution of 5I2 antigen, a protein possessing the functions of the human decay-accelerating factor (DAF [CD55]) and membrane cofactor protein (MCP [CD46]), and rat inhibitory protein (CD59), the homologue of the human membrane inhibitor of reactive lysis (MIRL[CD59]) were characterized in the rat eye and ocular adnexal structures. METHODS: After euthanasia of female Wistar rats, followed by orbital exenteration, eyelids and orbital tissue including the lacrimal gland were separated from the globes and immediately snap-frozen in liquid nitrogen at -70 degrees C. Tissues then were sectioned at -20 degrees C and examined immunohistochemically for 5I2 antigen and rat CD59. RESULTS: Both molecules were found to be present in high levels in multiple sites. Corneal and conjunctival epithelia showed moderate to intense labeling for both regulators. Fibroblasts in the corneal stroma, conjunctiva, and sclera labeled similarly. Corneal endothelial cells showed intense labeling for rat CD59 but not for 5I2 antigen. The iris and ciliary body showed intense labeling for both proteins. The retina showed labeling at multiple levels, with that of rat CD59 being more intense than that of 5I2 antigen. The lacrimal gland labeled for both regulators. Vessels, muscle, and nerves in the orbit labeled intensely for both antigens. In the eyelid, conjunctiva, sebaceous glands, and muscle and nerve tissues labeled moderately to intensely for both molecules, whereas skin epithelium labeled less intensely. CONCLUSIONS: 5I2 antigen and rat CD59 are expressed in high levels and distributed similarly in the rat eye and lacrimal gland to DAF, MCP, and MIRL in the human eye and lacrimal gland. These findings establish the rat ocular surface as a model for studying the role of cell surface complement regulators in this site. This first identification of copious expression of these proteins in eyelid structures, which also participate in protection of the ocular surface, further suggests an important role for surface complement regulatory proteins in this location.     

Diffusion and transfer of antibody proteins from a sugar-based hydrogel

Diffusion of antibody protein from hydrogel films and hydrogel encapsulated in a microcapillary was studied. Thin hydrogel films were formed by crosslinking 6-acryloyl-B-O-methylgalactoside with N,N'-methylene-bis-acrylamide and the diffusive transport of monoclonal antimouse IgG-FITC into and out of the hydrate films was measured. Diffusion coefficients in 2 and 4% crosslinked hydrogel films were measured. The measured diffusion constants determined for IgG in both the 2 and 4% hydrogel films were comparable to the free diffusion of IgG in bulk water (Dmean approximately 10(-7) cm2/s). In addition, 2% crosslinked hydrogels were prepared in a capillary tube and the transport of antimouse IgG-FITC into and out of the hydrated hydrogel was measured. Kinetic analysis indicated that the protein transport through the capillary hydrogel was faster than would be expected for a simple diffusion process. Finally, by utilizing the diffusion of antibody from the capillary hydrogel, transfer of antibody to a silica surface was demonstrated. A capillary hydrogel loaded with antimouse IgG-FITC was used to transfer the protein to a silica surface forming a 30-micron spot of antibody, which was imaged using fluorescence microscopy. These results may lead to the development of a nonlithographic method of patterning antibodies on surfaces for use in integrated microimmunosensors.