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PubMed1983

Some letters on Jewish Medical Ethics.

Specializing in Jewish Medical Ethics--a term, I believe, first used as the title of my doctor's thesis (1955) subsequently condensed and revised in book form (1959)--I frequently receive inquiries from individuals and organizations seeking guidance on the Jewish attitude to moral issues in medicine. After a review of my voluminous correspondence on many phases of this subject, I have made a small selection on a variety of topics. The correspondence on the last of the four topics, 'Medical Experimentation on Animals', is the longest, because it contains an element of polemics. Since this might make it of special interest to the Journal's readers, and since this subject is infrequently discussed in the literature of Medical Ethics, I decided to include it in this brief selection.

Abortion, Induced↗
PubMed1986

Is there a reciprocal connection between the red nucleus and the interposed cerebellar nuclei? Conclusions based on observations of anterograde and retrograde transport of peroxidase-labelled lectin in the same animal.

The rubrointerposital projection was studied in cats where wheat germ agglutinin-horseradish peroxidase (WGA-HRP) was implanted in various parts of the interposed nuclei. No retrogradely labelled rubral cells were observed following implantations in the posterior interposed nucleus, and only very few such cells were identified in the contralateral red nucleus after implantations restricted to the anterior interposed nucleus with no contamination of cerebellar white matter or cortex. However, when WGA-HRP was delivered by a pressure injection, which in addition to the anterior interposed nucleus included the adjacent white cerebellar matter along the needle track and the overlying cortex, many retrogradely labelled cells were present contralaterally in the magnocellular red nucleus, with some also found in its rostral parvicellular part. The same observation was made when injection of free HRP exceeded the boundaries of the anterior interposed nucleus. These observations indicate that there is a negligible projection from the red nucleus to the contralateral interposed cerebellar nuclei. What has been considered to be rubrointerposital cerebellar fibres probably is the projection to the cerebellar cortex (Exp. Brain Res., 50 (1983) 353-358). Anterogradely labelled fibres could be followed from the implantations in the posterior interposed nucleus to a medial crescent of the entire contralateral red nucleus. Caudal as well as rostral parts of the posterior interposed nucleus project into the same area of the red nucleus. Implantations restricted to the anterior interposed nucleus label a projection to the contralateral magnocellular red nucleus which is topographically organized. The caudal part of the anterior interposed nucleus projects to the dorsomedial portion of the magnocellular red nucleus, the rostral part to its ventrolateral portion. In addition, a mediolateral organization in the anterior interposed nucleus coincides with a caudorostral arrangement in the red nucleus. This topical arrangement corresponds to what has previously been observed in cat and monkey, but due to the small implantation sites used in the present study a more precise mapping of the projection has been obtained. Furthermore, our implantations of WGA-HRP into the red nucleus show especially well the latter topical arrangement in the projection. The observations mentioned above are discussed and related to previous studies of the rubrocerebellar and cerebellorubral projections.

Animals↗
PubMed1979

Percutaneous absorption of clioquinol (Vioform).

The percutaneous absorption of clioquinol from three different preparations for skin treatment (Vioform cream, Locacorten-Vioform cream and Vioform-Hydrocortisone cream) was evaluated. After topical dosages corresponding to 30 mg clioquinol, concentrations in the blood were below the detection limit of the analytical procedure, i.e., smaller than 0.02 micrograms/ml; therefore the percutaneous absorption was evaluated by measuring cumulative urinary excretion of clioquinol and was compared to that found after an equivalent oral dose. The study was carried out in 4 healthy volunteers. The topical preparations were applied under occlusive dressings. Following epicutaneous application of the three topicals in quantities containing 30 mg clioquinol each, the urinary excretion of the drug was between 1.2 and 3.6% of the applied dose. When the same dose of clioquinol was administered orally to two volunteers, 52.4 and 92.9% of the dose was excreted in the urine. Taking the urinary elimination as the minimal amount of drug absorbed, the extent of percutaneous absorption from the three dermatological preparations amounted to 1.2-3.6% of the applied dose. There was no difference in the pattern of urinary excretion products among the three topicals and the oral formulation. The bulk of clioquinol was excreted as glucuronide (mean: 96 +/- 3%) and only a small fraction was excreted as sulfate (mean: 3.8 +/- 3%). A small amount of free clioquinol (1.1%) was measured in 1 subject only after the oral dose.

Administration, Oral↗
PubMed1987

Azelaic acid.

This review is an update on the literature accumulated over the past 10 years following the original observation that azelaic acid, a naturally occurring and nontoxic C9 dicarboxylic acid, possesses significant biologic properties and a potential as a therapeutic agent. These studies have shown that azelaic acid is a reversible inhibitor of tyrosinase and other oxidoreductases in vitro and that it inhibits mitochondrial respiration. It can also inhibit anaerobic glycolysis. Both in vitro and in vivo it has an antimicrobial effect on both aerobic and anaerobic (Propionibacterium acnes) microorganisms. In tissue culture it exerts a dose- and time-dependent cytotoxic effect on malignant melanocytes, associated with mitochondrial damage and inhibition of deoxyribonucleic acid (DNA) synthesis. Tumoral cell lines not containing tyrosinase are equally affected. Normal cells in culture exposed to the same concentrations of the diacid that are toxic for tumoral cells are in general not damaged. Radioactive azelaic acid has been shown to penetrate tumoral cells at a higher level than normal cells of the corresponding line. Topically applied (a 20% cream), it has been shown to be of therapeutic value in skin disorders of different etiologies. Its beneficial effect on various forms of acne (comedogenic, papulopustular, nodulocystic) has been clearly demonstrated. Particularly important is its action on abnormal melanocytes, which has led to the possibility of obtaining good results on melasma and highly durable therapeutic responses on lentigo maligna. It is also capable of causing regression of cutaneous malignant melanoma, but its role in melanoma therapy remains to be investigated.(ABSTRACT TRUNCATED AT 250 WORDS)

Acne Vulgaris↗
PubMedDate not supplied

Dose-dependent pharmacokinetics of MK-417, a potent carbonic anhydrase inhibitor, in rabbits following single and multiple doses.

MK-417, a potent carbonic anhydrase inhibitor capable of reducing intraocular pressure after topical application, is currently under investigation for the treatment of glaucoma. The purposes of this study were to characterize dose-dependent pharmacokinetics of MK-417 and to determine the accumulating effect of the drug during chronic topical administration in rabbits. Because the drug resided primarily in the erythrocytes, kinetic analyses were performed on whole blood concentration data. Following i.v. administration, both total blood clearance and apparent volume of distribution for MK-417 increased disproportionately between the low and high dose, while the half-life of the drug appeared to be independent of dose. Total blood clearance and apparent volume of distribution increased from 0.993 +/- 0.224 ml/hr/kg (mean +/- SD) and 88.6 +/- 9.4 ml/kg at a dose of 0.05 mg/kg to 2.73 +/- 0.17 ml/hr/kg and 272 +/- 5.5 ml/kg at a dose of 1 mg/kg. The dose-dependent kinetics of MK-417 are probably due to the saturable binding of carbonic anhydrase. Upon instillation of MK-417 into the eyes, the drug was rapidly and well absorbed. At the low dose of 0.05 mg/kg, the bioavailability varied from 58% to 98.5% with a mean value of 76.5 +/- 20.5%. Prediction of concentrations of MK-417 during chronic topical administration were performed based on the corresponding concentrations after a single topical dose using an overlay technique. Good agreement between the experimental data and the predicted blood concentrations of MK-417 during chronic dosing at 0.05 mg/kg, but not at 1 mg/kg, strongly suggests that linear kinetics apply in the case of the low dose but not in the case of the high dose.

Animals↗
PubMed1990

Two cell kinetic methods studied on the rat corneal epithelium.

A stathmokinetic method (using Colcemid) and the [3H]thymidine technique (pulse labelling with tritiated thymidine, [3H]TdR) have been evaluated in the rat corneal epithelium. The dose is not of critical importance for the Colcemid method, thus indicating an all or nothing effect within the dose range studied. A one point estimate is sufficient to calculate the mitotic rate (MR), and in the rat corneal epithelium a 4 h accumulation period is recommended. After administration of [3H]TdR there is an increasing response with increasing dose, followed by a levelling off at higher doses. It seems reasonable to use the lowest maximal effective dose. The labelling index (LI) can be reliably registered 1 h after administration of the drug. For each of the drugs we found corresponding results after topical application and intraperitoneal injection. Hence, topical application of small doses of both Colcemid and [3H]TdR makes interesting in vivo experiments on larger animals and even on human beings possible. Due to the extreme regularity of the corneal epithelium this part of the eye is an interesting organ for cell kinetic studies and provides an excellent tool for evaluating cell kinetic methods.

Administration, Topical↗
PubMed1977

A study of chemically induced acute inflammation in the skin of the rat.

Oedema due to application of benzene to the skin was reduced following prior sensory denervation and in animals systemically pre-treated with capsaicine (which is known to confer resistance to chemical irritants) or compound 48/80 (which depletes the body of mast cells). Increased degranulation of mast cells in the benzene-treated skin was unaffected by denervation but did not occur after treatment with capsaicine. Antidromic stimulation of a cutaneous nerve caused oedema and degranulation of mast cells, both of which were less severe than the corresponding effects of topically applied benzene. These effects were completely prevented by prior treatment with capsaicine and the oedema was less severe in 48/80-treated rats. Hence, the presence of mast cells was necessary for full development of the effects of antidromic stimulation. These observations indicate that axon reflexes in sensory fibres contribute to, but are not entirely responsible for, the development of oedema in chemically irritated skin. The prophylactic action of capsaicine may be due to the prevention of degranulation of mast cells rather than to a direct effect on cutaneous nerve endings. These conclusions are embodied in an hypothesis purporting to explain the involvement of axon reflexes, mast cells and various humoral mediators in chemically induced acute inflammation.

Animals↗
PubMed1986

Oral health of individuals aged 3-80 years in Jönköping, Sweden in 1973 and 1983. I. A review of findings on dental care habits and knowledge of oral health.

The aim of the present study was to present data from dental care habits and knowledge of oral health in two cross-sectional studies carried out in 1973 and 1983. A random sample of approximately 1000 individuals evenly distributed in the age groups 3, 5, 10, 15, 20, 30, 40, 50, 60 and 70 years was studied for each of these two years. In the 1983-year examination 80 individuals 80 years of age were also included. All subjects were inhabitants of the community of Jönköping, Sweden. A questionnaire about dental care habits and knowledge was used in combination with a clinical and radiographical examination. The participants answered 23-101 questions. The same questions were raised in 1973 and 1983. For most age groups more then 80 per cent visited a dentist yearly in 1983. This yearly attendance was higher than that for 1973. In the 20-year-old group 14 per cent of the individuals received dental care in the PDS in 1973 compared to 63 per cent in 1983. The main reason to visit a dentist in 1973 was by the patient's own initiative while in 1983 the appointments were based on the dentist's initiative. The number of subjects that felt discomfort in connection with a visit to the dentist had decreased between 1973 and 1983. Knowledge about the etiology of caries had increased between 1973 and 1983 was not the case for gingivitis and periodontitis. An increase had occurred in toothbrushing frequency and the use of toothpicks and disclosing tablets but this between 1973 and 1983. In 1983, 98 to 93 per cent of the subjects in the age groups 10-30 years had been exposed to topical fluorides. The corresponding figure for 30-year-olds in 1973 was 1 per cent. It is obvious that during the period 1973 to 1983 there has been an increase in dental attendance, knowledge of dental diseases, oral health and the use of preventive measures.

Adolescent↗
PubMed1987

Intraocular pressure effects of multiple doses of drugs applied to glaucomatous monkey eyes.

The effects of multiple dosing with 0.5% timolol maleate, 2% epinephrine hydrochloride, 4% pilocarpine hydrochloride, 1% vanadate, 1% forskolin (nonproprietary name, colforsin), or 0.5% prostaglandin F2 alpha on intraocular pressure (IOP) were each tested on eight cynomolgus monkey eyes in which glaucoma was induced by photocoagulating the trabecular meshwork with the argon laser. The week prior to drug therapy, baseline IOP measurements were carried out at hourly intervals from 9:30 am to 3:30 pm on three days. One to two days later, therapy was initiated. Each drug was applied topically to both eyes of each monkey twice daily for at least four days. The IOP was measured with a calibrated pneumatonometer at the same hourly intervals on treatment days as on the baseline days. The IOP at each time of day on treatment days was compared with the average baseline IOP measured at the corresponding time of day. Topical application of timolol, epinephrine, pilocarpine, vanadate, and prostaglandin F2 alpha significantly reduced IOP without evidence of tolerance or tachyphylaxis during the course of therapy. Forskolin did not significantly decrease IOP after the second day of treatment.

Animals↗
PubMedDate not supplied

Drug metabolism in skin. Comparative activity of the mixed-function oxidases, epoxide hydratase, and glutathione S-transferase in liver and skin of the neonatal rat.

Aryl hydrocarbon hydroxylase (AHH) activity in the skin of neonatal rats was compared to that in epidermis, dermis, and other body tissues. Following topical application of benzo[a]pyrene (BP) or the polychlorinated biphenyl mixture Aroclor 1254 there was induction of AHH in each tissue studied. There was a greater increase in the activity of skin enzyme as compared to other extrahepatic tissues. When whole-organ activity (pmol of 3-OH-BP per min per whole organ) was considered, skin represented 2%, 21%, and 27% or whole body activity in control, BP-treated, and Aroclor 1254-treated animals, respectively. Skin microsomes from control rats exhibited 2, 0.5, 24, and 6% of corresponding liver microsomal AHH, 7-ethoxycoumarin de-ethylase, NADPH-cytochrome c reductase, and epoxide hydratase activities, respectively. Glutathione S-transferase activity in skin cytosol was 15% of the corresponding hepatic activity. Following topical application of Aroclor 1254 there were increases in the activity of AHH and 7-ethoxycoumarin de-ethylase in the skin and the liver. Glutathione S-transferase (40-60%) and epoxide hydratase (83-94%) activities in neonatal rat liver were induced by skin application of Aroclor 1254.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1992

Communication between general practitioners and consultants: what should their letters contain?

OBJECTIVE: To canvass the views of all general practitioners and consultants working in Newcastle upon Tyne on the content of referral letters and replies, the feasibility of standardising certain aspects of referral letters, and the use of communications data for audit purposes. DESIGN: A postal questionnaire was sent to all general practitioners and consultants in Newcastle upon Tyne in May 1991. Questions were asked about the clinical and administrative content of letters, the utility of standard categories to state the reason for referral, the idea of using letters for feedback purposes, and communications as a potential topic for professionally led audit. SETTING: Area served by Newcastle upon Tyne Family Health Services Authority and District Health Authority. RESULTS: Replies were received from 274 (77%) doctors (115 general practitioners and 159 consultants). A majority (225; 82%) were in favour of items defined as "always important" forming a minimum requirement for referral letters and for consultants' replies. Using standardised categories to state the reason for referral was not endorsed: 102 (89%) general practitioners and 132 (83%) consultants preferred referrers to use their own words. Using referral communications to provide feedback was less popular with consultants (54; 34%) than general practitioners (72; 63%). Finally, a majority of doctors (179; 65%) were in favour of using written communications as a topic for professionally led audit. CONCLUSIONS: A high degree of consensus exists among clinicians about the content of referral communications. Although doctors may still reject the concept of standardised communications, they have unambiguously endorsed a standard for communication that they can aspire to, and they are prepared to use it as a yardstick for their actual performance.

Communication↗
PubMed1992

Suicide notes of the older adult.

Although not true in all countries, older adults are the developmental age group at highest risk for death by suicide in the United States. Our knowledge of suicide in the elderly is, however, limited. The psychological characteristics for suicide cannot be attributed primarily or even solely to being old. One avenue to understanding this complicated act in the elderly is suicide notes. Despite their limitations, suicide notes contain special revelations of the human mind and there is much one can learn from them about suicide in the older adult. This paper outlines the sparse literature on the topic of suicide notes of the older adult and then presents the author's own life-span research related to the elderly. The research indicated that long-term instability was critical in understanding suicide in the older adult. However, indirect expressions (e.g., ambivalence, unconscious implications) were much less frequently observed in the notes of the elderly than other adults. The research also found that older males often wrote about painful problems in their interpersonal relations in their final letters and this pain was significant in making their final decision. Future research, specifically regarding a protocol analysis based on a review of the research on suicide in the elderly, will be discussed.

Adult↗
PubMed1977

[Lipid-protein-interactions of human apolipoproteins-structural aspects and models of lipoproteins (author's transl)].

The plasma lipoproteins are complex macromolecular structures which play an essential role in fat transport and in energy and membrane metabolism of higher organized organisms. Much has been learned in the last decade about the structural and functional interrelationships of the different lipoprotein classes. Their protein moieties, the so-called apolipoproteins, have been purified and characterized, the primary structure of four of them is known. Initial recombination experiments showed a considerable potential of the (unfractionated) lipoprotein protein to bind to lipids and to form particles similar to native lipoproteins. Further binding experiments performed in several laboratories with the purified A- and C-apolipoproteins and different physico-chemically well defined lipids have lead to the identification of lipid binding sites within the protein molecules and the formation of amphipathic helices upon and during lipid binding. This possible common mechanism of lipid-protein fractions forms the basis of a recently proposed model of one lipoprotein class, namely the high density lipoproteins (HDL). The significance of protein-protein-interactions in the formation and maintenance of these lipoprotein particles is still unknown. Whether disturbed lipid protein interactions lead to structural and/or functional alterations of the corresponding lipoproteins is a topic of discussion. The pertinent literature is listed in this paper and the physiological relevance of these studies and their clinical aspects will be presented.

Apolipoproteins↗