Urethritis due to Neisseria meningitidis in a London genitourinary medicine clinic population.

A retrospective study was performed in a department of genitourinary medicine to determine the prevalence and clinical features of urethral and cervical infection with Neisseria meningitidis among patients being screened for sexually transmitted diseases. During the 28 month period of the study 11 isolates (from 10 patients) of N. meningitidis were identified from 5571 urethral cultures from homosexual men (0.2%). This compares with an isolation rate of 4.7% for N. gonorrhoeae; 1.2% samples screened for chlamydial antigen were positive. There were no isolates from 8992 urethral cultures from heterosexual men or 15,976 cervical cultures. Eight of the cases identified had features of urethritis at diagnosis; 6 were diagnosed initially as non-specific urethritis (NSU) and 2 as gonorrhoea on the basis of microscopy of a urethral smear. Eight of the 10 patients were treated with amoxycillin and/or a tetracycline, and all but one had a clinical and microbiological cure. In the study population the prevalence of N. meningitidis infection was low and restricted to homosexual men; however, it may be associated with symptoms.


The impact of HIV disease on an Irish prison population.

Between January 1987 and January 1991, 168 known HIV-infected prisoners have been incarcerated in Dublin's Mountjoy prison. This figure constitutes 16.6% of the total HIV-infected population in the Republic of Ireland over the same period. One hundred and forty-one (84%) of these prisoners have attended the Department of Genitourinary Medicine, St James's Hospital, Dublin. This group displayed considerable morbidity from HIV-related disease. Respiratory tract infection was the most frequent complication seen. Much additional morbidity was directly attributable to intravenous drug use. A survey of a representative group of inmates revealed that 64.7% were diagnosed HIV-positive in prison. The mean length of time spent incarcerated since the diagnosis of HIV infection was 38.9 months. Twenty-nine of 34 individuals who answered a questionnaire were imprisoned for drug-related crimes and 32 of 34 prisoners admitted to parenteral drug use within the prison. As the HIV epidemic unfolds in Dublin, increasing numbers of prisoners with symptomatic HIV disease will spend time incarcerated in Mountjoy prison. This will pose a considerable burden on prison and hospital medical services alike.


Gonorrhoea: signs, symptoms and serogroups.

Over 19 weeks, 104 male patients attending a genitourinary medicine clinic with gonococcal urethritis were asked to complete a questionnaire detailing symptoms. Sixty-seven questionnaires were duly completed. The examining nurse documented signs. Ninety-one isolates of Neisseria gonorrhoeae were serogrouped and auxotyped, 55 of these were from patients who had completed a questionnaire. Patients presented earlier if they had a past history of gonorrhoea (p = 0.02). The serogroup of N. gonorrhoeae did not influence the amount of discharge, the presence of meatal inflammation, dysuria or penile tip irritation or the delay in presentation after appearance of discharge. Auxotype AHU was not associated with asymptomatic gonorrhoea.


Prevalence of urogenital Chlamydia trachomatis infection in El Salvador. II. Gynaecology outpatients.

The prevalence of urogenital infection caused by Chlamydia trachomatis was examined in 100 non-pregnant women with cervicitis, and 100 healthy women, in San Salvador City, El Salvador. Pharmacia Chlamydia EIA test was used for the detection of chlamydial antigen in urethral and cervical specimens from all the women. Direct immunofluorescence was used for confirmative tests on the EIA positive and the negative gray zone samples. C. trachomatis antigen was detected in 28% of the women with cervicitis compared with 5% in the group of healthy women (P < 0.001). The cervicitis group were also screened for Neisseria gonorrhoeae which was isolated from 12% of them. One strain out of 12 was beta-lactamase producing (PPNG). Five per cent of the women with cervicitis had simultaneous C. trachomatis and N. gonorrhoeae infections.


Sexual behaviour amongst travellers: a study of genitourinary medicine clinic attenders.

Two hundred and fifty attendees at two London genitourinary medicine clinics were asked to complete an anonymous self-administered questionnaire, enquiring about sexual behaviour whilst abroad. Two hundred and forty-three questionnaires were evaluable. In the study group there were 116 women, and 127 men (62 heterosexuals and 65 homosexuals). Ninety women, 53 heterosexual men and 53 homosexual men had travelled abroad over the preceding 6 months. Of these 18 (20%) of women, 26 (51%) of heterosexual men and 19 (36%) of homosexual men had sex with a local foreign contact on holiday. Although both heterosexual and homosexual men were statistically more likely to have sex abroad with a local inhabitant, women were more likely to have unprotected sexual intercourse with a local partner. This has important implications for the spread of sexually transmitted disease including hepatitis B and HIV.


Treatment of anogenital warts in genitourinary clinics in England and Wales.

A questionnaire on the treatment of anogenital warts was sent to 150 consultants in genitourinary medicine, 78 (52%) were returned completed. A wide range of treatments were used; podophyllin was the commonest first line treatment of multiple penile (60.3%), perianal (57.7%) and vulval (61.5%) warts. Cryotherapy was a popular choice for intrameatal warts (65.3%), small numbers of vulval warts (33.3%) and as second line therapy for penile (35.9%) and perianal (33.3%) warts. Vaginal warts were treated with podophyllin (39.7%) or cryotherapy (29.5%). Various combinations of podophyllin, trichloroacetic acid and cryotherapy were used (2.6%-24.3%) although there is no evidence this offers benefit over single therapy. Podophyllin is frequently used despite side effects, a poor clearance rate and in vaginal warts, difficult access. Initial therapy with more time-consuming procedures such as cryotherapy or electrocautery may be of benefit to selected patients.


Characterization of sulphoalkyl ether derivatives of beta-cyclodextrin by capillary electrophoresis with indirect UV detection.

A capillary electrophoresis method which characterizes the degrees of substitution of heterogeneous sulphoalkyl ether beta-cyclodextrin derivatives is described. The separation is based on the different electrophoretic mobilities observed from changes in the overall charge of the molecule as a result of substitution. Individual peaks of the electropherogram then provide a measure of each degree of substitution of the present beta-cyclodextrin. Detection of these beta-cyclodextrin derivatives is performed by indirect UV detection.


Pharmacokinetics of 2-(alpha-thenoylthio)-propionylglycine (TTPG) in healthy volunteers--an oral dose-proportionality investigation.

The dose linearity of 2-(alpha-thenoylthio)-propionylglycine (TTPG) pharmacokinetics after a single oral administration at three different TTPG doses (180, 540 and 1080 mg) was evaluated in 12 healthy volunteers according to an open, randomized, cross-over study with a 1-week wash-out period between each administration. The duration of the study, for each subject, was 4 weeks. Plasma concentration and urinary excretion of TTPG and its two systemic metabolites, namely propionylglycine (tiopronin) and thiophenecarboxylic acid (TCA) were assayed by a previously well validated HPLC method. Due to differences in the physical and chemical properties of these compounds, two assays were needed, one to measure TTPG and TCA as such, and one to measure derivatized tiopronin. Both used UV detection. TTPG, tiopronin and TCA were quickly detected in plasma, suggesting that the drug administered is rapidly absorbed and biotransformed, in part, in the systemic circulation into the two metabolites noted above. Time-to-peak for all three analytes showed a trend to increase with increasing doses of TTPG, being: 0.42, 0.40 and 0.67 h (P < 0.01) with TTPG; 0.53, 0.47 and 0.73 h (P < 0.05) with TCA; and 1.33, 2.13 and 2.58 h (P < 0.01) with tiopronin. Cmax showed the opposite behaviour with values (ng ml-1) normalized to the dose of 540 mg: 1235, 905 and 513 (P < 0.001) with TTPG; 888, 547 and 383 (P < 0.001) with TCA; and 7290, 6950 and 5170 (P < 0.01) with tiopronin.(ABSTRACT TRUNCATED AT 250 WORDS)


Gold concentrations in blood fractions of patients with rheumatoid arthritis treated with Myocrisin.

Gold levels in the plasma and blood cells of patients treated with the gold drug Myocrisin (sodium aurothiomalate) were determined by atomic absorption spectrometry. There is a correlation between whole blood gold and plasma gold concentrations which is different for smokers and non-smokers. Most cellular gold is associated with the membrane and is present in concentrations approximately equivalent to the number of reactive sulphydryl groups on the exofacial surface of the cell. Since gold would be expected to react with SH groups and since these groups are vital for cellular function, a possible role for gold in modifying cellular metabolism is indicated.


Photodegradation kinetics under UV light of aztreonam solutions.

A photodegradation study of aztreonam solutions exposed to UV irradiation showed that the major product of degradation was the anti-isomer together with some unidentified products. This result was similar to that obtained with cefotaxime and it is postulated that this would be generally true of compounds containing an alkoxyimino group.


Supercritical fluid chromatography of selected oestrogens.

The separation of selected oestrogens (oestrone, equilin, alpha-oestradiol, beta-oestradiol and d-equilenin) using capillary supercritical fluid chromatography (SFC) was studied. Three different stationary phases (SB-methyl-100, SB-biphenyl-30 and SB-cyanopropyl-50) were studied for the separation of the compounds. A baseline separation of the oestrogens was achieved on a SB-cyanopropyl-50 column using a carbon dioxide density gradient at an oven temperature of 73 degrees C. Typical analysis time on a 7 m column was 21 min. Retention times of each oestrogen decreased with an increase in either mobile phase density or oven temperature. Accuracy and precision of the SFC method were in the 1-5.5% range. The SFC method was applied to three different dosage forms containing oestrogens.


Degradation of dacarbazine in aqueous solution.

The effects of initial concentration (0.05-5.0 mg ml-1, 2.5 x 10(-4)-0.025 M) (pH 1-13), buffer concentration (0.01-0.075 M), light, antioxidants and co-solvents on the degradation of dacarbazine in aqueous solution were investigated at 37 degrees C. Liquid chromatography was used to monitor the degradation of dacarbazine as well as the appearance of degradation products. The kinetics of hydrolysis of dacarbazine in the dark were pseudo first-order and independent of the initial concentration of the drug. The degradation of dacarbazine was accelerated by light and at low concentration proceeded by pseudo zero-order kinetics. The pH-rate profiles showed that both the photolytic and the hydrolytic reactions were dependent on the ionization state of the molecule. The main degradation product of both hydrolysis and photolysis was detected by liquid chromatography and confirmed by mass spectrometry to be 2-azahypoxanthine.


The identification of related substances in triamcinolone acetonide by means of high-performance liquid chromatography with diode array detector and mass spectrometry.

A study of an HPLC method for the analysis of related substances in triamcinolone acetonide is described. Several systems of solvents and samples of different lots and preparative origins were examined and a rapid-scanning diode array UV detector (DAD) was particularly useful. With the proposed technique it was possible to identify 9 alpha-bromo desonide as a principal impurity, which was present in all examined samples of triamcinolone acetonide. This identification was rendered possible by the investigation of the second derivative of the UV spectra and by means of study of the mass spectrum. Furthermore, it was possible, primarily on the basis of the spectrophotometric data, to formulate reliable hypotheses on the possible identification of 9 beta, 11 beta-epoxide of the desonide which was present at very low levels and to exclude the presence of 11-deoxy-9(11)-unsaturated desonide. The presence of the above-mentioned related substances was explained considering the scheme of synthesis described in the literature. The spectrophotometric characteristics of the studied compounds and the limits of applicability of the present procedure are discussed.


Simultaneous determination of simvastatin and its hydroxy acid form in human plasma by high-performance liquid chromatography with UV detection.

Simvastatin (SV), an analogue of lovastatin, is the lactone form of 1',2',6',7',8',8a'-hexahydro-3,5-dihydroxy-2',6'-dimethyl-8'(2'',2''-di met hyl-1''-oxobutoxy)-1'-naphthalene-heptanoic acid (SVA) which lowers plasma cholesterol by inhibiting 3-hydroxy-3-methylglutaryl-CoA reductase. A fast, simple and accurate method for determining SV and SVA concentrations in human plasma has been developed and validated for use in the analysis of plasma samples from patients and healthy volunteers. This method involves an extraction procedure using a mixture of acetonitrile-water and reversed-phase high-performance liquid chromatography with UV detection. The procedure was linear from 20 to 1000 ng ml-1 for SV and from 25 to 1000 ng ml-1 for SVA, respectively. The method was accurate with relative errors of 5.0, 2.1 and 3.2% for human plasma controls containing 50, 250 and 500 ng ml-1 of SV, respectively. The corresponding precision was 2.3, 1.8 and 1.0% (RSD%). Similarly, relative standard deviations less than 2.3% and relative errors of less than 5.2% were obtained from human plasma controls containing SVA at identical concentrations. The method is suitable for pharmacology and pharmacokinetic studies of simvastatin.


The diminution of liver glutathione content and changes in activities of antioxidant enzymes in long-term acetaldehyde poisoning.

The effect of acetaldehyde administration for 4 weeks on antioxidant protection systems was investigated in liver of rats. Liver SOD activity was decreased from control value 542.4 U/g of tissue to 411.2 U/g of tissue in experimental group (24% decrease). GSH-Px activity was practically unchanged and liver CAT activity was significantly decreased (35%). Sulfhydryl compounds in liver non-proteins following ACH treatment were decreased from 4.22 mumol/g of tissue in control group to 2.86 mumol/g of tissue (23%). Furthermore acetaldehyde treatment caused significant increase in MDA level in liver (78% increase).


Fibrin stabilizing factor activity of the skin carcinoma.

Activity of fibrin stabilizing factor and contents of sulphydryl group in the homogenate of malignant skin carcinomas (melanoma, spinocellular carcinoma, basal cell carcinoma, fibromyoma, liposarcoma) is higher than in the homogenate of benign neoplasm (lipoma, papilloma) and in the homogenate of the normal skin. Fibrin stabilizing factor activity and contents of sulphydryl group in the blood serum of subjects with malignant skin carcinomas is slightly lower than in the blood serum of subjects benign neoplasm and in healthy subjects.


Triglyceride, high density lipoprotein, and coronary heart disease.

The National Institutes of Health Consensus Development Conference on Triglyceride, High Density Lipoprotein, and Coronary Heart Disease brought together experts in lipid metabolism, epidemiologists, and clinicians as well as other health care professionals and the public to address the following questions: (1) is the relationship of high triglyceride and/or low HDL cholesterol with coronary heart disease causal? (2) Will reduction of high triglyceride and/or elevation of HDL cholesterol help prevent coronary heart disease? (3) Under what circumstances should triglycerides and HDL cholesterol be measured? (4) Under what circumstances should active intervention to lower triglyceride and/or raise HDL cholesterol be considered in high risk individuals and the general population? (5) What can be accomplished by dietary, other hygienic, and drug treatments? (6) What are the significant questions for future research? Following two days of presentations by experts and discussion by the audience, a consensus panel weighed the evidence and prepared their consensus statement. Among their findings, the panel concluded that (1) existing data provide considerable support for a causal relationship between low HDL and CHD; however, with respect to TG data are mixed and the evidence on a causal relationship is incomplete; (2) initial TG and/or HDL levels modify benefit achieved by lowering low density lipoprotein cholesterol (LDL-C); however, evidence from clinical trials is insufficient to draw conclusions about specific benefits of TG and/or HDL altering therapy; (3) HDL-C measurement should be added to total cholesterol measurement when evaluating CHD risk in healthy individuals provided accuracy of measurement, appropriate counseling, and followup can be assured; (4) there is general agreement with the Adult Treatment Panel (ATP) guidelines that LDL-C is essential in cardiovascular risk assessment, as well as that persons with elevations of LDL-C greater than 150 mg/dl refractory to nondrug therapies may require drug treatment; (5) there is a strong consensus that hygienic approaches (diet, exercise, smoking cessation, weight loss) should be employed to lower TG and/or raise HDL; there is no consensus for the use of drug treatment in patients with borderline hypertriglyceridemia and low HDL-C levels in the presence of a desirable LDL-C level.


The effect of quercetin and lithium ions on platelet aggregation.

Quercetin inhibited aggregation of porcine blood platelets induced by collagen (IC50 = 0.2 mM), ADP (IC50 = 0.5 mM), thrombin (IC50 = 0.02 mM) and ionophore A23187 (IC50 = 1.5 mM). Preincubation of platelets with 10 mM LiCl abolished the inhibitory effect of quercetin on the aggregation of these cells induced by thrombin. Lithium ions per se caused potentiation of the aggregation of platelets induced by thrombin. Neither potentiation of aggregation by Li+, nor the abolishing of the inhibitory effect of quercetin by Li+ was observed when platelets were activated by ionophore A23187. Since lithium ions inhibit activity of enzymes degradating inositol phosphate, the obtained results can be interpreted to mean that quercetin affect platelet aggregation by the inhibition of inositol phosphates production.


AMP deaminase from porcine blood platelets, regulation by adenine nucleotides, phosphate and by Na+ and K+ ions.

Porcine blood platelets contain a relatively high amount of AMP deaminase (14.4 U per 10 11 cells). The enzyme showed sigmoidal behaviour as a function of AMP concentration with a S0.5 value (substrate concentration required for half-maximum velocity) of 3.6 and 4.0 mM in the presence of Na+ and K+ respectively. MgATP and MgADP at micromolar concentration activated the enzyme. Activation by saturating MgATP and MgADP in the presence of Na+ or K+ converted the rate versus substrate plots to hyperbolic with a dramatic decrease of S0.5. Phosphate at milimolar concentrations inhibited the enzyme and this inhibitory effect was totally reversed as the concentrations of MgATP and MgADP rised to physiologically high levels. Na+ and K+ activated the enzyme in the absence of MgATP and MgADP. Both cations largely enhanced the Vmax with Na+ being more potent. A comparison of the kinetic behaviour of the enzyme in vitro with the metabolite concentrations in vivo suggest that a substantial regulation can occur through changes in AMP and Na+ concentrations.


Direct muscular neurotization as a method of treatment of irreparable nerve injuries.

Authors have presented of 12 patients with irreparable nerve injuries treated by direct motor nerve implantation into muscle belly (direct muscular neurotization). Results were evaluated in Sunderland scale. Motor function of the neurotized muscles following 12 months from operation was in range of between M3 and M4.


The serum immunoglobulins level in maxillofacial bacterial infections.

The IgG, IgA and IgM levels in the serum of 23 patients with maxillofacial bacterial infections were determined. The high IgG level noted on admission further increased in the serum of 14 patients with acute inflammation and decreased in the serum of 10 patients with a chronic course. The level of IgM in the serum of patients with acute inflammation was higher than in the patients with chronic inflammation and decreased in both groups on the 7th day of treatment. The IgA level was high on admission in both groups and fell on the 7th day of treatment. Our results suggest that analysis of the serum level of IgG, IgA and IgM may be of diagnostic and prognostic value in the treatment of maxillofacial bacterial inflammation.


The results of laminectomy and laminoplasty in cervical myeloradiculopathy.

The authors present the results of laminectomy and laminoplasty in 20 patients with cervical myeloradiculopathy according to the JOA score. Improvement was noted in 74% of the patients after laminoplasty and in 70% of the patients after laminectomy. On the whole decompression is a good method of treatment in this kind of disease.


[Mechanical characteristics of biological soft tissue].

In a detailed study mechanical properties of tendons, muscles, nerves, blood-vessels and skin of just slaughtered pigs have been investigated in nearly stationary stress tests. Tensile tests have produced tensile strength, ultimate stress and their appropriate strains, Young's modulus and the work up to fatigue of samples. In hysteresis tests the deformation work has been determined as a function of numbers of stress cycles. The hysteresis decrease with the number of stress cycles and approaches asymptotically to cero. By preconditioning of tendons, nerves and blood-vessels to steady state significant differences of strain at tensile strength and of Young's modulus have been established. Moreover for nerves the tests have revealed significant deviations of tensile strength. Bruise tests have been carried out with muscle tissue. For the described setup the limit force can be specified, at which pathological changes appear. Subsequently conducted histological investigations have demonstrated this. In dynamical bruise tests there appeared no pathological changes in muscle tissue in spite of higher transmitted energy.


[Tensile strength studies of self-cutting titanium osteosynthesis screws].

The tapping screws of the Medicon Osteosynthese System applied in the jaw and facial area were checked for their mechanical sturdiness. Screwing tests with bones and aluminium were carried out. The minimum fracture moment, the moment transferrable by the screw slot and the required moment for a tight seat of the Osteosynthese plate on the bone surface were calculated. The screws and plates are of titanium alloy TiA16V4 (US standard) for implantats. In a sample taken at random of test screws the fracture moments were measured and examined. All the screws support considerable loads and the fracture moments are almost 20% higher that the minimum fracture moment for TiA16V4 screws specified in DIN 267, part 18.


[Exposure of surgical/orthopedic operating room personnel to monomer vapors during the use of bone cements--review of the literature and report of experiences].

PMMA bone cements are used for the fixation of artificial joint replacements. During their application in the operating theater, a small amount of the monomer evaporates. Operating room staff and surgeons are often not adequately informed about the negative properties and the effects on health of these vapours. Basic information about monomers and their toxicity, and safety regulations have been compiled. On the basis of present knowledge, the authors do not regard the repeated use of bone cement throughout the course of a day to represent a hazard to health.


EEG classification by learning vector quantization.

EEG classification using Learning Vector Quantization (LVQ) is introduced on the basis of a Brain-Computer Interface (BCI) built in Graz, where a subject controlled a cursor in one dimension on a monitor using potentials recorded from the intact scalp. The method of classification with LVQ is described in detail along with first results on a subject who participated in four on-line cursor control sessions. Using this data, extensive off-line experiments were performed to show the influence of the various parameters of the classifier and the extracted features of the EEG on the classification results.


Distance distribution in a dye-linked oligonucleotide determined by time-resolved fluorescence energy transfer.

Fluorescence energy transfer is potentially a useful technique for obtaining structural and dynamic information on duplex and branched DNA molecules suitably labeled with donor and acceptor dyes. We have assessed the accuracy and limitations of FET measurements in nucleic acids with respect to the localization of the dyes and the flexibility of the dye-DNA linkages. A nine base-pair duplex oligonucleotide was synthesized with donor and acceptor dyes linked at the opposing 5' termini by alkyl chains. A careful analysis of the fluorescence decay of the donor revealed that the donor-acceptor distance in this molecule was not well defined, but was described by a rather broad distribution. The mean donor-acceptor distance and the distribution of distances have been recovered from the donor decay. Orientational effects on energy transfer have been included in the analysis. The implications of these findings for FET measurements in nucleic acids are considered.


A computational and experimental study of the bending induced at a double-triple helix junction.

We have studied the conformation of a 17 base-pair homopyrimidine.homopurine triple helix formed on a fragment of duplex DNA derived from Simian Virus SV40. Gel retardation assays indicate that an 80 base-pair fragment has an altered conformation when the triple helix is formed, which is most likely to result from an induced bend in the DNA. Investigation of the detailed conformation of the double helix-triple helix junctions has been performed by means of molecular modelling. Bending on the 5' and 3' sides of the third strand oligonucleotide are not located at equivalent positions with respect to the junctions, which is explained in terms of base stacking. The junction effects on DNA structure, induced by the requirement for cytosine protonation in the Hoogsteen-bonded strand to form CGC+ base triplets, are also discussed.


Unique and independent parameters (UIP) formulation for thermodynamic models of complex protein-ligand systems.

A method for reformulating the thermodynamic (delta G) description of complex equilibria is presented. The purpose of this reformulation is to take a system of N complexes which is completely defined by N delta Gs, and recast it in terms of a new set of N delta Gs. This reformulation is an extension of the concept of interaction energy (J. Wyman, Adv. Protein Chem. 19 (1964) 223-286). The new delta Gs obtained by this reformulation reflect the intrinsic properties of the binding sites and the hierarchical nature of potential interactions between them. A simple set of rules are developed which allow for the description of complex protein-ligand binding schemes and these rules are used to derive schemes for hemoglobin O2 binding. This reformulation represents the foundation for the theoretical description of the coupling of energy in protein-ligand systems as illustrated by the theoretical analysis of allosterism in a dimeric protein presented in the following paper. This reformulation also provides the foundation for the analysis of data pertaining to complex equilibria.


Thermodynamic model of cooperativity in a dimeric protein: unique and independent parameters formulation.

A model of the cooperative interaction of ligand binding to a dimeric protein is presented based upon the unique and independent parameters (UIP) thermodynamic formulation (Gutheil and McKenna, Biophys. Chem. 45 (1992) 171-179). The analysis is developed from an initial model which includes coupled conformational and ligand binding equilibria. This completely general model is then restricted to focus on conformationally mediated cooperative interactions between the ligands and the expressions for the apparent ligand binding constant and the apparent ligand-ligand interaction constant are derived. The conditions under which there is no cooperative interaction between the ligands are found as roots to a polynomial equation. Consideration of the distribution of species among the various conformational states in this general model leads to a set of inequalities which can be represented as a two dimensional plot of boundaries. By superimposing a contour plot of the value of the apparent ligand-ligand interaction constant over the plot of boundaries a complete graphical representation of this system is achieved similar to a phase diagram. It is found that the parameter space homologous to Koshland-Nemethy-Filmer type of model is most consistent with both positive and negative cooperativity in this model. The maximal amount of positive and negative cooperativity are found to be simple functions of Kc, the equilibrium constant associated with the change of a subunit and ligand from the unligated to ligated conformation. It is shown that under certain limiting conditions the apparent allosteric interaction between ligands is equal to the conformational interaction between subunits. The methods presented are generally applicable to the theoretical analysis of thermodynamic interactions in complex systems.


Potential therapeutic targets in multistep oncogenesis.

There are three important considerations in the development of novel drug therapies: firstly, whether a suitable target can be accurately defined; secondly, does the target allow discrimination between normal cells and tumour cells; and thirdly, how easily could the tumour cells acquire resistance? This article will concentrate on two of the genetic alterations most commonly associated with multistep tumourigenesis, and discuss their potential as therapeutic targets with respect to the considerations above.


Drugs active against growth factor and oncogene phosphatidylinositol signalling pathways.

Increased knowledge of growth factor and oncogene intracellular signalling presents us with unique opportunities to develop new classes of antiproliferative drugs. The degeneracy of intracellular signalling may allow normal cells to be relatively unaffected by drugs that inhibit just one signalling pathway. Oncoproteins themselves have proved difficult to target and the drugs lack selectivity. More success has come with drugs targeted against other components of signalling pathways. Two examples of such classes of drugs are given. The ether lipid anticancer drugs inhibit intracellular signalling at multiple points; phosphatidylinositol phospholipase C, protein kinase C, intracellular Ca2+ release and phosphatidylinositol-3'-kinase. D-3-deoxy-3-substituted myo-inositols and phosphatidylinositols are a new class of growth inhibitory compounds that appear to act as antagonists of myo-inositol signalling.


Protein kinase C modulation.

PKC-modulators represent valuable additions to the arsenal of anti-tumor agents. They act as antiproliferative agents and are useful in overcoming drug-resistance by inhibiting mdr-mediated drug efflux. They increase the cytotoxicity to platinum complexes (and other DNA-damaging agents), probably by interfering with drug-induced detoxification and repair mechanisms. PKC-modulators are potentially active in overcoming ras-induced cis-platinum-resistance by antagonizing p21ras functions.


Modulation of adenylate cyclase signalling.

Adenylate cyclase via production of cyclic AMP (cAMP) can transduce dual signals, positive and negative, on cell growth and differentiation. Such dual signals are transmitted by RI and RII cAMP-binding receptor proteins respectively, the regulatory subunits of cAMP dependent protein kinases. The growth stimulatory RI and inhibitory RII are in a strict balance to maintain normal cells, and departure from such balance can cause a great variety of human diseases, including cancer. Experimental approaches using site-selective cAMP analogues, antisense oligodeoxynucleotides, and gene transfer have shown that restoration of the normal balance of RI/RII provides a biological means to the suppression of malignancy.


Tyrosine kinase inhibitors.

Tyrosine kinases are associated with the cytoplasmic domains of growth factor receptors as well as oncoproteins and many have the potential to cause transformation if mutated or hyperexpressed. Tyrosine kinases therefore represent an excellent target for the development of cancer drugs. A large number of inhibitors have now been identified and many show promising cytostatic activity, particularly using in vitro models. Some in vivo activity has been reported. Progress with various structural classes is reviewed. It is not clear whether specific or broad spectrum tyrosine kinase inhibitors should be developed as potential anticancer drugs. It does seem likely, however, that tyrosine inhibitors will enter clinical trial in cancer patients.


Pharmacological probes of Ras function.

Numerous approaches toward anti-ras drugs are being explored. Efforts range from cell-based assays which screen fermentation products to more structural or mechanism-based in vitro screening and design. For the mechanism-based approaches, extensive research efforts on the function and regulation of the ras oncogene protein have identified potential points of intervention, including protein expression, membrane localization, guanine nucleotide activation, and interaction with effector systems.


Antisense oligonucleotides.

Growing evidence indicates that antisense oligodeoxynucleotides can specifically inhibit gene expression thereby providing an essential tool for understanding gene function and the potential to affect abnormal cell proliferation. Because oncogene activation is intimately involved in tumour initiation and progression, down-regulation of oncogene expression is associated with a selective or a preferential inhibition of tumour as compared to normal cell proliferation. Even though numerous studies attest the short-term in vitro efficacy of antisense oligodeoxynucleotides as inhibitors of tumour growth, the use of these compounds as therapeutic agents awaits a more rigorous demonstration of their long term effects and favourable pharmacological properties.


A fundamental role for cell cycle regulation in the chemosensitivity of cancer cells?

The majority of clinically effective anticancer drugs inhibit some aspect of the machinery responsible for DNA replication and chromosome segregation. Drug action also arrests cells at defined points in the cell cycle called checkpoints. These checkpoints ensure that subsequent cell cycle events are inhibited until the inflicted damage is repaired. The fidelity of checkpoint control and susceptibility of cells to apoptosis while repair is underway may be important factors in the success of chemotherapy. We discuss these concepts and focus particularly on possible applications to improved antitumor therapy with DNA damaging agents.


Induction of apoptosis--new targets for cancer chemotherapy.

Many anticancer agents induce an active cell death process, apoptosis, in sensitive tumour cells. Elucidation of molecular mechanisms underlying apoptosis may shed light on why some tumour cells survive chemotherapy, and may identify new targets for anticancer agents whose effects are not tightly linked to proliferative status. The signal transduction events which initiate apoptosis are unclear. A change in cytosolic calcium is generally assumed to be a key signal for apoptosis although the evidence for this is not conclusive. Other putative signal transducers which may modulate apoptosis are protein kinase C and cAMP. Genes which induce apoptosis in response to such signals are largely unidentified, but certain oncogenes, notably bcl-2, act to delay or suppress apoptosis in several cell types.


Glucocorticoid-induced apoptosis in the thymus.

Destruction of thymus cells was one of the earliest observed properties of adrenal glucocorticoids. The cells affected are primarily immature, CD4/CD8 double-positive lymphocytes. This process has been clearly shown in vivo and in vitro to be apoptosis, as characterized by cell shrinkage, membrane alterations, nuclear collapse and chromatin fragmentation into oligonucleosomes. Glucocorticoid-induced thymocyte death requires new mRNA and protein synthesis. A beginning has been made in identifying the genes involved in thymocyte apoptosis. A case is made for the death of unselected thymocytes in vivo being regulated by endogenous glucocorticoids.


Activation-induced apoptosis in lymphoid systems.

Lymphocytes become activated when antigen receptors on the cell surface are cross-linked, or when they are exposed to agents that mimic this signal. Although such activation is usually associated with the production of immune mediators (e.g. antibodies, cytokines) and entry into the cell cycle, it can alternatively lead to death via apoptosis. This activation-induced apoptosis was first observed in developing lymphocytes and has been proposed as a mechanism for negative selection, by which immature cells with potential for autoreactivity are eliminated from the maturation pathway. Activation-induced apoptosis has also been observed in normal, mature lymphocytes under some conditions, and this may account for the phenomena of peripheral deletion, in which mature T cells are eliminated upon exposure to high doses of antigen. It may also be an important mechanism whereby CD4+ T cells are depleted in HIV+ individuals. Although the phenomenon of activation-induced apoptosis is not understood, recent studies have begun to implicate specific signal transduction pathways and gene products in the process. Among the latter is the c-myc proto-oncogene, which paradoxically can play an essential role in several forms of apoptosis, including that induced by activation of lymphocytes.


Induction of apoptosis in cells of the immune system by cytotoxic stimuli.

Apoptosis is a physiological mode of death where the dying cell plays an active part in its own demise, which contrasts sharply with what is seen in necrosis. In the present paper I have shown that when cells of the immune system are exposed to a range of cytotoxic agents, such as the RNA synthesis inhibitor actinomycin D, the DNA polymerase inhibitor aphidicolin or the topoisomerase I inhibitor campthothecin, they rapidly undergo cell death via apoptosis. This is characterized by DNA fragmentation to yield the now hallmark ladder pattern of death by this mechanism. All of these agents are capable of inducing apoptosis irrespective of what phase of the cell cycle a cell is in. These studies also indicate that apoptosis can occur in immune cells without recourse to macromolecular synthesis.


Apoptosis in cytotoxic T lymphocytes and their targets.

Cytotoxic T lymphocytes have been useful not only in understanding immune responses but also in providing valuable insights into the biology and mechanism of apoptosis. In this article two examples of apoptosis directly related to cytotoxic T lymphocyte biology are discussed. These are apoptosis of activated cytotoxic T cells as a result of antigen clearance and subsequent growth factor deprivation and apoptosis of target cells following interaction with cytotoxic T lymphocytes.


The bcl-2 oncogene and apoptosis.

The bcl-2 oncogene is activated as a consequence of the t(14;18) chromosomal translocation in human follicular lymphomas. Bcl-2 functions to inhibit apoptosis in a variety of in vitro and in vivo experiments, suggesting interference with a central mechanism of apoptosis. The bcl-2 protein is associated with the inner mitochondrial membrane, however, the biochemical function of bcl-2 is unknown. Transgenic mice which overexpress bcl-2 provide evidence for bcl-2's role in memory B cells and thymic education as an intracellular survival factor. Additional regulators of apoptosis, such as the p53 tumor suppressor gene, may be altered in human cancers as one step in tumorigenesis.


A pin-assisted retention technique for resin-bonded restorations.

The value of pins for auxiliary retention has been demonstrated many times. The use of pins with resin-bonded restorations allows for improved aesthetics and less tooth reduction while increasing resistance to dislodging forces. Clinical and technical procedures for resin-bonded bridges with pin-assisted retention are presented.


Implant positioning for periodontal, functional, and aesthetic results.

Implant positioning requires the adherence to a very precise protocol in order to achieve the best periodontal, functional, and aesthetic results. In this article, the authors discuss the step-by-step procedure, including pre-implant study, transfer techniques, implant positioning, gingiva grafts, and post-implant hygiene.


Chairside computer-generated ceramic restorations: the Cerec third generation improvements.

Cerec chairside computer-generated ceramic restorations have well passed a five-year clinical observation period with convincing clinical success. The new system COS 2.1 allows an essentially automatic design of inlays, the construction of 3/4 and 4/5 cusp protection onlays, and individually-shaped aesthetic laminate veneers. The new E-drive grinding increases the machining capacity by factor 3 to 4, reduces edge roughness by 50%, and doubles machining precision. Cementation gap width at the cervical margin is 37-48 microns in normal-depth preparations and 54-76 microns in deep cavities. It is the purpose of this article to review the third generation improvements of this method.


Implant team: problems and solutions with osseointegrated implants.

The concept of an implant team, in which the implants are placed by the periodontist or oral surgeon and the prosthetic procedures are performed by a restorative dentist, provides a system of checks and balances. A team concept may minimize the potential for failure and provide an environment of cooperation that can lead to even better success, with a minimum of difficulty and fewer complications. In this author's experience, a wide variety of avoidable problems may become evident in the implant restorative area. This article examines some of the more common problems and provides suggestions for solutions.


Root coverage: a comparison of techniques: the free gingival graft versus the subepithelial connective tissue graft.

This past decade has seen the goals of periodontal surgery undergo much refinement. Gingival recession is a frequent concern to both the clinician and patient. Regeneration of the lost gingival tissues is now an achievable goal. This article reviews and compares two techniques currently employed for predictable root coverage.


Aesthetic all-porcelain anterior restorations.

The translucence of all-porcelain restorative materials very closely resembles that of natural teeth, thereby enabling the nearest possible emulation of natural teeth. Because of this quality and the suitability for bonding, all-porcelain has become the choice material for anterior jackets, three quarters, and veneers. In this article, the author uses actual cases to substantiate and illustrate her evaluation.


Interim report of Sino-Monica-Beijing for the years 1985-1989.

Interim results of Sino-Monica-Beijing for the 5 year period 1985-1989 are reported. The cardiovascular disease (CVD) risk factors increased between the surveys carried out in 1984-1985 and 1988-1989, especially blood cholesterol and body mass index.


Outcome among untreated hypertensives in the general population in Taiwan.

The outcome of untreated hypertension was investigated in a population of 17,713 persons in southern Taiwan who were aged 15 or over when they had taken part in a blood pressure survey in 1963. In the 27-year follow-up period, 55.8% of the overall mortality was comprised of those who were found to be hypertensive (as defined by WHO) in 1963, 31.3% by borderline hypertensives, and 22.6% by normotensives. The 27-year mortality rate due to stroke was much higher in hypertensives than in normotensives (11.4% vs 1.8%, respectively). The 5-year survival rates for mild, moderate and severe hypertensives were 89.9%, 82.7% and 72.3%, respectively, and the 20-year rates were 60.2%, 37.2% and 25.2%, respectively. The causes of death were also recorded: among hypertensives, stroke accounted for 23.2% of all deaths of known cause, cancer 20.5%, cardiovascular disease 21.7%, respiratory disease 11.8%, and other causes 22.9%. From the results, it is concluded that obvious differences in mortality and cause of death exist between untreated hypertensives and normotensives.


Therapeutic effect of andriol on serum lipids and apolipoproteins in elderly male coronary heart disease patients.

The elevated estradiol/testosterone (E2/T) ratio had been proved to be a risk factor for coronary heart disease (CHD) in elderly males and to exert an adverse effect on lipid metabolism. We conducted a randomized cross-over study to determine the effect of Andriol, a new androgenic preparation, on plasma lipids and apolipoproteins. The results showed a significant difference in most parameters between patients receiving Andriol and the control group: in the former, serum T level was elevated significantly (P < 0.001), E2 level was unchanged (P > 0.05) and the E2/T ratio was reduced (P > 0.05). Blood levels of total cholesterol (TC) and triglyceride (TG) were lowered dramatically (P < 0.001) and high density lipoprotein cholesterol (HDL-ch) was raised (P < 0.05), but apolipoprotein-AI (APO-AI) and B (APO-B) levels remained unchanged. No obvious side effect was observed in those who took Andriol.


The effect of IH764-3 on fibroblast proliferation and function.

The effect of IH764-3, a potent component isolated from Salvia miltiorrhiza, on the proliferation and function of cultured fibroblasts was studied. It was found that the fibroblast growth curve had a dose-dependent relationship with IH764-3 concentration. The incorporation of 3H-TdR and 3H-proline into fibroblasts was significantly inhibited by IH764-3, and calmodulin, fibronectin and thrombospondin contents in the test group were obviously lower than those in the control group. Flow cytometry showed that in the IH764-3-treated group, the percentage of cells in G0/G1 phase was higher than that in the control. Electron microscopic observation (TEM and SEM) showed that in the treated group, collagen secretion was decreased. All of these results indicate that IH764-3 exerts a direct inhibitory effect on fibroblast proliferation and affects their ability to synthesize collagen.


[14C]-glucose metabolism of Oncomelania snails.

To elucidate the importance of glucose metabolism in Oncomelania snails, uniformly labelled D (14C)-glucose [(U-14C)-glucose] has been used as a tracer for observing glucose uptake, incorporation into macromolecules and the activity of enzymes involved in its metabolic pathway. Radioactivity of Oncomelania increased with time of exposure (3, 6, 12 and 24 h) to [(U-14C)-glucose] solution. In snails treated with 2 ppm bromoacetamide for 24 h, the radioactivity of soft tissues was markedly less than that of normal snails. Oncomelania can synthesize glycogen from absorbed glucose, and the absorbed (U-14C)-glucose may be incorporated into nucleic acid, protein and lipid, with 14CO2 excreted as an end metabolic product. 6-phosphoglucose dehydrogenase and 6-phosphogluconate dehydrogenase activities were demonstrated by the reduction of NADP and determination of 14CO2 from (1-14C)-glucose, respectively. The results indicate that there exists a phosphopentose pathway in Oncomelania.


The role of endotoxin in the pathogenesis of experimental multiple system organ failure: a preliminary report.

In this study, an animal model of multiple system organ failure (MSOF) in rabbits, engendered by feeding E. coli prior to severe hemorrhagic shock, was used for the purpose of investigating 1) the relationship between lipopolysaccharide (LPS) and MSOF, and 2) the effectiveness of Re-LPS antiserum in preventing MSOF. The results showed that endotoxemia occurred very early, and its degree correlated well with that of organ dysfunction. Re-LPS antiserum administration abated the toxic effects and lowered the incidence of MSOF. These results suggest that sequential analysis of circulating LPS levels may be useful for the early diagnosis of MSOF, and that gut-derived endotoxin might play an important role in the pathogenesis of experimental MSOF.


The stress distribution of the lumbar spine and disc degeneration.

A three-dimensional finite element model of the lumbar motion segment was developed to study the effect of disc degeneration upon stress distribution in the lumbar spine. The results showed that after degeneration of the intervertebral disc, the stress distribution and load transmission of the lumbar spine are significantly changed. It is concluded that these changes provide a biomechanical basis for understanding the etiology of spinal canal stenosis and nerve root entrapment.


How the degenerate signal is recognized and delivered in the course of protein translocation across biological membranes.

Protein translocation across a membrane is generally directed by a degenerate signal peptide encoded in the nascent polypeptide chains. Effective signal recognition and the subsequent traversal of the polypeptide chain through the membrane are ensured by the mechanism of cotranslational translocation and/or by chaperone molecules which universally bind to nascent polypeptides and keep them under-structured and translocation-competent. In order to decipher the degenerate signal with a high degree of fidelity, the cells seem to have evolved a multistep signal recognition and relay mechanism, by which a weak, less-specific interaction between individual signal peptides and a defined signal recognition factor can take place, while the highly specific signal delivery can be achieved by only allowing the correct, effective signals to pass through all check-points along the relay cascade. In addition, a "double recognition" and energy-dependent "proof-reading" mechanism may be involved in single steps of such weak-bond interactions.


Hemophilic blood cyst--a case report.

We report a case of hemophilic blood cyst in a patient with human immunodeficiency virus (HIV) infection. The pathogenesis, diagnosis and treatment are discussed, and neither inflammatory changes nor pathological cells were seen in the numerous histological sections obtained surgically.


Influence of storage on signal transduction pathways and platelet function.

The use of platelet concentrates in prophylactic and therapeutic transfusions has increased considerably. The design of suitable storage bags and improvements in procurement, processing, and storage practices have contributed significantly to the quality of stored platelets and their increased shelf life. There continues to be activation of platelets during procurement of blood, shipment, processing, and storage. By using appropriate preventive measures, inhibitors of platelet activation and protectants, platelet activation can be minimized. Although platelets seem to recover from initial activation and function normally, their in vitro response varies depending on the degree of activation occurring during preparative procedures. By and large, response to weak agonists diminishes rapidly during aging in storage. Further studies are essential to determine the reason for the development of this acquired defect. The normal response of stored platelets to a potent agonist such as thrombin suggests that signal generation and transduction mechanisms are not significantly compromised during storage. Epinephrine-mediated membrane modulation may contribute significantly to their improved in vivo performance during transfusions.


Contribution of perfusion techniques to the evaluation of the hemostatic effectiveness of platelet concentrates.

Perfusion systems allowing the morphometric analysis of platelet interactions with vessel subendothelium under flow conditions have been applied to evaluate the quality and function of stored platelets. Studies performed in vitro indicate that despite the existence of storage lesions, platelets in concentrates stored for up to 5 days retain their ability to interact with the subendothelium. Perfusion studies ex vivo with nonanticoagulated blood from anemic-thrombocytopenic patients have shown the critical hemorrheological role of red blood cells facilitating platelet interactions with subendothelium. Similar studies performed on severely thrombocytopenic patients who received transfusions of platelets stored at 4 degrees C indicate that incompletely viable platelets can contribute to primary hemostasis through procoagulant mechanisms. The latter results suggest that storage lesions which contribute to impairment of platelet function may result in enhancement of platelet procoagulant activities. Perfusion techniques have contributed to the evaluation of the hemostatic effectiveness of platelet concentrates. These techniques will provide a useful model to test the impact of new storage technologies on platelet hemostatic function.


Effect of additive solutions on platelet biochemistry.

Use of a synthetic medium for resuspension and storage of platelets has several advantages. In addition to the opportunity to save plasma, the use of a synthetic medium offers better possibilities for obtaining platelet products by automatic component processing in a more cost-effective and convenient manner. A synthetic medium also has the potential to avoid transfusion reactions caused by noncompatible plasma proteins and to improve platelet quality, which will lessen the number of units needed in transfusion. Platelets produce a substantial amount of lactic acid by metabolism of glucose. Thus, risk of pH fall is a major problem which platelet additive solutions must address. Two approaches have been used: (1) use of a glucose-free medium, and (2) use of a glucose-containing medium with a buffer system to neutralize the production of lactic acid. Using various synthetic media described in the literature, studies described in this paper suggest that some glucose is needed in the final suspending medium in order to obtain satisfactory maintenance of platelet quality during 5 days of storage. With the presence of acetate in the additive solution, platelet respiration is increased and glycolysis substantially decreased; therefore, with 10-20% of CPD-plasma carryover, sufficient glucose may be present in the final suspending medium to last for 5 days of storage. In addition, phosphate in the additive solution markedly enhances platelet glycolysis, and inhibitors of platelet activation reduce platelet metabolic activity and improve platelet viability and function.


Ultrastructural changes in stored platelets.

A wide variety of lesions develop in blood platelets stored in vitro for long periods of time. Most of them reflect activation and damage caused by lack of gas exchange across the wall of the container and a fall in pH below 6. Newer bags facilitate O2/CO2 exchange and maintain a neutral pH. As a result, most of the lesions reflecting acidic damage or destruction have disappeared. Some storage lesions persist, however. Formation of platelets resembling doughnuts occurs in the first 24 or 48 hours after collection and concentration. They are infrequent in currently used bags. Giant alpha granules resulting from fusion of normal-sized organelles, however, are not rare. They appear as early as 4 to 5 days, even under the best conditions, and increase in frequency up to 14 days. The basis for their development remains obscure.


The role of membrane lipid in the platelet storage lesion.

Because of their hemostatic and structural importance and their chemical and physical lability, membrane lipids are likely to be involved in the development of the platelet storage lesion. Chemical analysis using the new method of high-performance liquid chromatography with laser light scattering detection (HPLC-LLS) reveals platelet lipid to be composed of more than 22 individual components, the most abundant of which are phosphatidylcholine (PC), phosphatidylethanolamine (PE), cholesterol (C), sphingomyelin (SM), phosphatidylserine (PS), and phosphatidylinositol (PI). Surprisingly, an asymmetric distribution of these lipids is maintained in the resting platelet with PS concentrated in the inner leaflet of the plasma membrane. The exposure of PS may be important in platelet activation because of its powerful procoagulant effect. Studies of the effect of blood bank storage on platelet lipid composition have repeatedly shown a steady loss of all components, which may be temperature dependent. Studies of platelet factor 3 activity and flow cytometry of stored platelets have revealed the lipid is lost through the process of microvesiculation. Coupled to this storage induced depletion of platelet lipid is a loss of more than half of the potential capacity of lipid-dependent platelet functions by day 5. The most likely underlying mechanism for this loss of lipid mass and functional capacity is lipid peroxidation, a process that could be blocked with antioxidants. Lipid peroxidation may also interfere with other membrane constituents such as glycoprotein IIb/IIIa and the aminophospholipid-specific translocase. Thus, lipid peroxidation should be a major focus in studies aimed at preventing or reversing the platelet storage lesion.


Identification of yolk platelet-associated hydrolases in the oocytes of Rhodnius prolixus.

The yolk platelets from Rhodnius prolixus, a blood-sucking bug, are composed mostly of vitellin and here are shown to contain at least two hydrolytic enzymes, a phosphatase and a cathepsin D-like proteinase. Both the proteinase and the phosphatase have an acid pH optimum. No hydrolytic activity was observed under alkaline or neutral conditions. Among several proteinase inhibitors tested, only pepstatin could abolish vitellin breakdown in vitro. The proteinase appears to be bound to the yolk platelet membranes. The phosphatase activity, using p-nitrophenyl phosphate as substrate, was enhanced after disruption of the platelet membrane by Triton X-100. This activity could be inhibited by tartrate but not by p-cloromercuribenzoate.


The effect of pinealectomy on circadian plasma melatonin levels in house sparrows and European starlings.

We determined 24-hr plasma melatonin profiles in intact, sham-pinealectomized, and pinealectomized European starlings (Sturnus vulgaris) and house sparrows (Passer domesticus) in a light-dark (LD) cycle and in constant darkness (DD). In the intact and sham-pinealectomized birds of both species, a melatonin rhythm was found, with low levels during the day and high levels during the night. Pinealectomy abolished the nighttime peak of melatonin in both species; hence, levels were low at all times sampled. This uniform response of plasma melatonin to pinealectomy contrasts with the differential response of circadian activity rhythms to pinealectomy for these two species. In DD, locomotor activity in pinealectomized house sparrows is usually arrhythmic, whereas in starlings a rhythm usually persists. This suggests that in the latter species free-running circadian rhythms are not necessarily dependent on a rhythm in plasma melatonin. The same is true for the synchronized activity rhythm observed in pinealectomized birds of both species in LD, as well as for the damped rhythm that persists in pinealectomized house sparrows following an LD-to-DD transfer. The results are consistent with the hypothesis that the pineal and its periodic output of melatonin constitute only one component in a system of at least two coupled pacemakers. They also suggest that there are species differences in the relative role played by the pineal and other pacemakers in controlling circadian rhythms in behavior.


Circadian feeding and locomotor rhythms in pigeons and house sparrows.

Feeding and locomotor activities were measured simultaneously in homing pigeons (Columba livia) and house sparrows (Passer domesticus). Feeding, as well as locomotor activity, was found to be regulated by a circadian clock in both of these species. Implantation of melatonin-filled capsules or exposure to constant light abolished feeding and locomotor rhythms in both species. Removal of the pineal gland from pigeons did not abolish either rhythm, whereas pinealectomy abolished both feeding and locomotor rhythms in house sparrows. Although feeding rhythms were generally more robust than locomotor rhythms in both of these species, different feeding and locomotor free-running periods were not observed within any individual pigeon or house sparrow. These results are consistent with the hypothesis that each of these species has a single pacemaker that regulates the timing of feeding and locomotor activity, but they do not rule out the possibility that separate clocks regulate these behaviors.


Light pulses induce "singular" behavior and shorten the period of the circadian phototaxis rhythm in the CW15 strain of Chlamydomonas.

While measuring action spectra for phase-shifting the circadian clock of Chlamydomonas, we observed that light pulses started near the phase response curve (PRC) "breakpoint" caused a reduction of the amplitude of the phototactic rhythm and two unexpected effects: (1) nonmonotonic fluence response curves (FRCs), and (2) shortening of the period of the subsequent free-running rhythm. The reduction of the rhythm's amplitude is dependent upon both the fluence and wavelength of the light pulse. The results are consistent with the amplitude being dependent upon the perceived "strength" of the stimulus, and with the nonmonotonic FRCs and reduced amplitude reflecting a light-induced change of the pacemaker's state variables to a region of the phase plane close to the "singularity." The period change that is evoked by single stimuli exhibits novel characteristics: large changes in period and a phase specificity that correlates with "singular" behavior. These period changes also appear to be a function of the stimulus strength, but indirectly; the magnitude of the period change is most strongly correlated with the magnitude of the light-induced phase shift. These results are interpreted in the context of limit cycle models of circadian clocks, and are used to suggest new tactics for measuring action spectra of light-induced clock resetting.


Photoperiod modulates pubertal shifts in behavioral responsiveness to testosterone.

This study examined the effect of photoperiod on pubertal maturation of steroid-dependent reproductive behaviors in male European ferrets (Mustela putorius furo). In the first experiment, levels of neck gripping, mounting, and pelvic thrusting in gonadally intact prepubertal (PRE) ferrets were compared with those of adults that had undergone puberty either while housed in short days (8 hr light/16 hr darkness per day; SD), or after transfer from SD to long days (18 hr light/6 hr darkness per day; LD) at 12 weeks of age. Both LD and SD adults demonstrated significantly greater amounts of neck gripping and mounting than PRE males. In addition, a significantly greater proportion of adults in both SD and LD displayed at least one incidence of the three behaviors compared to PRE ferrets. There were no statistically significant differences in behavior of the gonadally intact LD and SD adults. In the second experiment, dose-response curves for behavioral responses to subcutaneous injections of 0, 0.5, 1.25, 2.5, 5, and 10 mg/kg testosterone propionate (TP) in oil were generated in castrated PRE, SD, and LD males. The lowest dose of TP elicited significantly greater amounts of all three behaviors in LD adults than in PRE ferrets. In addition, levels of mounting and thrusting elicited by the lowest dose of TP were significantly greater in LD adults than in SD adults. These data indicate that pubertal activation of male sexual behavior in male ferrets is accompanied by a pubertal increase in responsiveness to the behavioral effects of testosterone. Furthermore, the degree of behavioral responsiveness of adult ferrets to testosterone is modulated by environmental photoperiod experienced during reproductive maturation.


Sleep and waking have a major effect on the 24-hr rhythm of cortical temperature in the rat.

The relationship between the time course of cortical temperature (TCRT) and sleep-wake alternation was investigated by correlation analyses and a computer simulation. The data for these analyses were collected in 10 rats in a 4-day experiment (LD 12:12), during which vigilance states and TCRT were determined for consecutive 8-sec epochs. On day 1 baseline recordings were obtained; on day 2 the animals were sleep-deprived; and days 3 and 4 served as recovery days. The correlation analyses revealed that the alternation of sleep and waking accounted for 84% of the variance of TCRT when analyzed for hourly intervals. The residual variance displayed a 24-hr periodicity with an amplitude of 0.15 degrees C. Similar results were obtained in a separate data set of a 2-day experiment, which consisted of a baseline day (LD 12:12) and a day with constant darkness. The periodicity of the residual variance of TCRT can therefore be considered to represent the circadian temperature rhythm not masked by the vigilance states. In the computer simulation, the time course of TCRT was simulated on the basis of the sequence of the vigilance states with an 8-sec time resolution. It was assumed that TCRT increases during waking and rapid-eye-movement (REM) sleep according to an exponential saturating function, and decreases exponentially during non-REM sleep. The simulations could account for 88-93% of the variance of TCRT. We conclude that in the rat, the major part of the variation of TCRT is accounted for by vigilance states, whereas a minor part can be attributed to a direct effect of the circadian pacemaker.


Behavioral inhibition of circadian responses to light.

Circadian locomotor rhythms in rodents may be synchronized by either photic or nonphotic events that produce phase shifts of the rhythm. Little is known, however, about how these two types of stimuli interact to produce entrainment. The well-characterized circadian photic response of the golden hamster was examined in situations where a short light pulse and locomotor activity, a nonphotic event, occurred simultaneously. Light-induced phase advances were attenuated when animals were active during light exposure. The results show that circadian responses to light depend upon the environmental situation in which the light is given, and call into question the implicit assumption in circadian rhythm research that phase shifting and entrainment to light-dark cycles depend simply on photic activation of well-known retinofugal pathways. Moreover, since light therapy is becoming an important component in the treatment of circadian-based disorders in humans, the results emphasize the need for evaluation of the behavioral aspects of light therapy protocols.


Electrospray mass spectrometry of Malayan pit viper (Calloselasma rhodostoma) venom.

A high-performance liquid chromatography protocol has been developed for the analysis of snake venoms. This system has been used to isolate eight fractions from Malayan pit viper (Calloselasma rhodostoma) venom. The fractions have been analysed using electrospray mass spectrometry. A number of major components were found with masses ranging from 13,670 to 22,750 Da.


A novel derivatization method for peptides to increase sensitivity and backbone fragmentation in liquid secondary-ion mass spectra.

Derivatization is used to increase both negative-ion sensitivity and positive-ion sequence information in the liquid secondary-ion mass spectra (LSIMS) of a series of peptides. The derivatization method involves acylation with pentafluorobenzoyl fluoride in a single-step reaction, and the reaction mixture is applied directly to the probe tip for analysis. Acylation takes place at the unprotected N-terminus, tyrosine, and lysine. The derivatives exhibit increased signal-to-noise ratio for [M-H]- ions, especially where there is not already an acidic amino acid residue in the peptide. In positive-ion LSIMS, the N-terminal group acts to retain the charge at the N-terminus, simplifying the fragmentation by producing N-terminal fragment ions. It also increases positive-ion fragmentation, sometimes very dramatically, making sequence determination more straightforward. The simplicity of the process, together with the enhancements it provides, make this a generally useful method for obtaining peptide structural information.


Application of fast-atom bombardment mass spectrometry for sequencing of a hemoglobin fragment, naturally occurring in human cerebrospinal fluid.

Recent studies have revealed the presence of a new group of opioid peptides, the hemorphins, in the human pituitary as well as in human cerebrospinal fluid. The hemorphins are structurally related to sequence segments residing in the beta, delta, gamma or epsilon-chains of hemoglobin. In this study we have applied fast-atom bombardment mass spectrometry (FAB-MS) to elucidate the sequence of a hemorphin fragment isolated from the cerebrospinal fluid of patients with cerebrovascular bleedings. The FAB-MS was used in conjunction with carboxypeptidase Y digestion and results indicated that this procedure proved to be a powerful tool for rapid sequence determination. The recovered peptide was thus found to be identical with the sequence 32-41 of the above mentioned hemoglobin chains.


Determination on the microscale of plasmatic lactic acid as its t-butyldimethylsilyl derivative by stable-isotope dilution using capillary gas chromatography/mass spectrometry.

A new sensitive and precise method for the determination of lactic acid in plasmatic microsamples (50 microL) has been developed. Lactic acid was directly extracted from plasma by ethyl acetate in acidic conditions, and analysed as its di-t-butyldimethylsilyl derivative by capillary gas chromatography/electron-impact mass spectrometry (GC/MS). The internal standard was a previously synthesized deuterated compound, 3-[2H]-(2R)-lactic acid. The method gives good reproductibility and precision, the overall standard deviation being better than 3%. The GC/MS assay was in good agreement with the enzymatic determination.


N-cadherin transcripts in Xenopus laevis from early tailbud to tadpole.

Cadherins are Ca(++)-dependent cell adhesion molecules which play a key role in morphogenesis and histogenesis. Two mRNAs clones (8 and 9) corresponding to two N-cadherin pseudo-allelic genes are present in Xenopus laevis. We report here that these transcripts share a highly homologous coding region but diverge in the non-coding region. We have determined the pattern of N-cadherin expression at the mRNA level by in situ hybridization with a riboprobe complementary to the EC5 domain of Xenopus N-cadherin clone 8. This part of the sequence is the least conserved in the cadherin gene family, minimizing the risk of cross-hybridization to other cadherins. N-cadherin transcripts are not detectable in the first stages of development. Expression first appears in the neural plate and reaches its maximum level in the CNS at tailbud stage. From early tadpole, it diminishes, so that a very weak signal is detected in the premetamorphic frog brain. N-cadherin expression is not uniform within the CNS, with some areas such as the roof of the rhombencephalon and the olfactory bulbs expressing higher levels of the transcripts. N-cadherin is present in several mesodermal derivatives such as the notochord, the pronephros, and the heart. It is, however, virtually absent from the myotomes and appears in skeletal muscles at later stages of differentiation. All placodes express high levels of N-cadherin. The non-neural ectoderm and the endoderm are always negative. In the brain and the heart, high levels of hybridization are observed with probes corresponding to both copies of the N-cadherin pseudo-allelic genes in their 5' non-coding region, indicating that both alleles are transcribed.


Diffusion or autocatalysis of retinoic acid cannot explain pattern formation in the chick wing bud.

We have collected several experimental data of pattern duplications due to the ZPA transplantation or application of retinoic acid on the developing chick limb bud. We have compared these data with the predictions of models based on diffusion or autocatalysis of retinoids. It turns out that these models cannot comprehensively explain the data. More specifically, retinoic acid cannot be either diffusing from a ZPA source or participate in an autocatalytic gradient formation.


EMA: a developmentally regulated cell-surface glycoprotein of CNS neurons that is concentrated at the leading edge of growth cones.

To identify cell-surface molecules that mediate interactions between neurons and their environment during neural development, we used monoclonal antibody techniques to define a developmentally regulated antigen in the central nervous system of the mouse. The antibody we produced (2A1) immunolabels cells throughout the central nervous system; we analyzed its distribution in the developing cerebral cortex, where it is expressed on cells very soon after they complete mitosis and leave the periventricular proliferative zone. Expression continues into adult life. The antibody also labels the epithelium of the choroid plexus and the renal proximal tubules, but does not label neurons of the peripheral nervous system in the dorsal root ganglia. In dissociated cell culture of embryonic cerebral cortex, 2A1 labels the surface of neurons but not glia. Immunolabeling of neurons in tissue culture is particularly prominent on the edge of growth cones, including filopodia and the leading edge of lamellipodia, when observed with either immunofluorescence or freeze-etch immunoelectron microscopy. Immunopurification with 2A1 of a CHAPS-extracted membrane preparation from brains of neonatal mice produces a broad (32-36 kD) electrophoretic band and a less prominent 70 kD band that are sensitive to N-glycosidase but not endoglycosidase H. Thus the 2A1 antibody recognizes a developmentally regulated, neuronal cell surface glycoprotein (or glycoproteins) with complex N-linked oligosaccharide side chains. We have termed the glycoprotein antigen EMA because of its prominence on the edge membrane of growth cones. EMA is similar to the M6 antigen (Lagenaur et al: J. Neurobiol. 23:71-88, 1992) in apparent molecular weight, distribution in tissue sections, and immunoreactivity on Western blots, suggesting that the two antigens are similar or identical. Expression of EMA is a very early manifestation of neuronal differentiation; its distribution on growth cones suggests a role in mediating the interactions between growth cones and the external cues that guide them.


Questionnaire surveys of cases of tick bite and Lyme borreliosis in hunters in Hokkaido with reference to detection of anti-Borrelia burgdorferi antibody.

An epidemic of Lyme borreliosis on Hokkaido island, Japan, was surveyed by questionnaire in 587 hunters. The 308 returns (52.4%) revealed episodes of tick bite (usually 2 or more) in 210 cases. Skin rashes appeared in 164 cases. Associated itching, pain, etc., but not skin rash, were more frequent after 2 or more tick bite. Previous determinations of anti-Borrelia burgdorferi antibody titers in these subjects and in controls suggested an association with outdoor activities other than hunting, and among 33 cases of dermatological symptoms and 23 of articular symptoms, 4 and 2, respectively, were antibody-positive. Most of these antibody-positive subjects had suffered tick bite at least twice, but had had no antibiotic treatment. Three subjects with joint disorders were antibody-positive. These findings suggested that the many hunters exposed to Borrelia burgdorferi frequently carried latent infections, and that some had latent form of arthritis, dermatitis and other disorders.


Higher cortical dysfunction, antiphospholipid antibodies and neuroradiological examinations in systemic lupus erythematosus.

We performed neuropsychological tests to investigate higher cortical dysfunction in 21 patients with systemic lupus erythematosus (SLE). We also measured antiphospholipid antibodies (APA), performed brain computed tomography (CT), and obtained a single photon emission CT (SPECT) to measure regional cerebral blood flow (rCBF) in order to elucidate a possible relationship between APA and higher cortical dysfunction. Higher cortical dysfunction was noted in as many as 16 (76%) out of 21 cases. APA were positive in 8 (38%) out of 21 cases. Although the relationship between APA and higher cortical dysfunction was not significant, patients positive for lupus anticoagulant (LA) were found to have higher cortical dysfunction. Brain CT revealed at least one abnormality in 6 cases (29%) but none had a localized lesion, SPECT disclosed a reduced rCBF in 9 cases (43%). The findings on brain CT and SPECT were unrelated to higher cortical dysfunction.


Cardiovascular and sympathetic nervous responses to mental stress in hyperthyroid patients.

We measured the cardiovascular and sympathetic nervous responses to mental stress in subjects with hyperthyroidism. Ten hyperthyroid subjects and 10 age- and sex-matched normal subjects performed mental arithmetic. At rest, the heart rate was higher in hyperthyroid subjects than in normal subjects, but systolic blood pressure, plasma norepinephrine, and epinephrine concentrations did not differ between the two groups. Systolic blood pressure and heart rate during stress, and the changes in blood pressure and in plasma epinephrine concentration from rest to stress, were higher in hyperthyroid subjects than in normal subjects. Therefore, cardiovascular and adrenal responses to mental stress were abnormally high in subjects with hyperthyroidism.


Response to oral corticosteroid in patients with chronic obstructive pulmonary disease.

We studied the effect of 30 mg of prednisolone on 29 Japanese patients with chronic obstructive pulmonary disease (COPD). The mean value of the baseline forced expiratory volume in one second (FEV1; mean +/- SEM) was 1.14 +/- 0.12 l (46.9 +/- 3.9% pred) and the FEV1 following the steroid trial was 1.30 +/- 0.12 l (53.7 +/- 4.3% pred). Post-trial FEV1--baseline FEV1/predicted FEV1 was 6.8 +/- 1.9%. Five patients (17%) had more than a 15% increase in FEV1 as a percentage of predicted FEV1. Post-trial FEV1/baseline FEV1 was 117.3 +/- 4.3%, and 12 patients (41%) had more than a 20% increase in FEV1 after the trial. Acute bronchodilator response to beta-agonist correlated positively with the response to corticosteroid. Baseline spirometries, blood eosinophil counts, serum IgE levels, sputum eosinophil counts, family history of asthma, and history of paroxysmal dyspnea did not vary across responders and non-responders. Patients with severe COPD should be treated to achieve the best possible pulmonary functions indicated by a steroid trial within the limit of acceptable levels of adverse effects.


Malignant lymphoma in the mesentery with immune thrombocytopenia.

A 69-year-old man was referred to our hospital for further evaluation of an abdominal mass. After admission, he was suspected of having a malignant mesenteric tumor. Laboratory data disclosed thrombocytopenia with increased levels of platelet-associated immunoglobulin G. On surgery, the tumor involved the ileal mesentery, invading the urinary bladder and mucosal surface of the terminal ileum. The diagnosis of mesenteric lymphoma with immune thrombocytopenia was made. Complete remission was obtained after surgery and the subsequent three courses of combination chemotherapy. However, thrombocytopenia still persisted. This rare presentation is discussed with a review of the available literature.


Inherited heterozygous protein C deficiency and dysfunctional protein S with recurrent venous thrombotic diseases: a study of three generations of a Japanese family.

We describe a rare occurrence of a family affected with venous thrombosis, exhibiting a protein C (PC) deficiency and dysfunctional protein S (PS). The propositus and his father developed recurrent venous-thrombosis. Their PC deficiency was characterized by low levels of both antigen and activity, and their dysfunctional PS was suggested by low PS activities despite the presence of normal free PS antigen. Over three generations, six family members had a PC deficiency, and three had both a PC deficiency and a dysfunctional PS. The mode of inheritance of PC deficiency appears to be autosomal dominant.


Isolated IgA deficiency accompanied by autoimmune thyroid disease.

Selective immunoglobulin (Ig) A deficiency is reported to occur in 1 in 16,000 in Japan and has been reported to be complicated with various autoimmune diseases. A 49-year-old woman was diagnosed as having autoimmune thyroid disease. Her serum IgA, IgM and IgG were revealed to be 4.1, 154 and 1930 mg/dl, respectively. Severe skin eruption which occurred with 30 mg/day of methimazole (MMI) or 300 mg/day of propylthiouracil (PTU), was relieved by reducing MMI to 15 mg/day and administering anti-allergic drugs. Although the influence of IgA deficiency on autoimmunity and allergy still remains unclear, this is a report of IgA deficiency associated with autoimmune thyroid disease.


Hypersensitivity pneumonitis induced by Shiitake mushroom spores.

Hypersensitivity pneumonitis due to the inhalation of Shiitake mushroom spores was demonstrated in a 38-year-old woman. Symptoms of cough, nausea and malaise, and clinical findings of cyanosis, bibasilar crackles, reduced lung volumes, hypoxemia, leukocytosis, elevated ESR, positive C-reactive protein, and bilateral diffuse reticulonodular shadows on chest roentgenogram improved after the patient was removed from exposure. Alveolitis was demonstrated by transbronchial lung biopsy, as well as an increase in lymphocytes in bronchoalveolar lavage. Serum precipitins and specific IgG antibodies to an extract of Shiitake mushroom spores, but not to other common molds or mushroom body, were detected in serum. Provocative inhalation test with the extract of mushroom spores caused the same clinical symptoms and signs as experienced in the workroom. This is the first report of typical hypersensitivity pneumonitis induced by Shiitake mushroom spores. Mushroom spores as well as thermophilic actinomycetes must be considered a causative agents for mushroom worker's lung.


Increased interleukin-6 activity in cardiac myxoma with mediastinal lymphadenopathy.

We report a case of cardiac myxoma with mediastinal lymphadenopathy which seems to be a very rare feature. Laboratory examination revealed high level of interleukin-6 (IL-6) activity in serum. Interestingly, after removal of cardiac myxoma, mediastinal lymphadenopathy disappeared on the chest CT and the level of serum IL-6 was decreased. These findings suggest that IL-6 which was probably derived from myxoma, may have played an important role in the development of lymphadenopathy.


Brain tumor in a pedigree of cancer family syndrome.

Brain tumors have not been previously described as a cancer found in cancer family syndrome (Lynch Syndrome II). Astrocytoma found in the 24-year-old son of a proband of cancer family syndrome with an unusual aggregation of transitional cell cancer is reported. The possibility of brain tumors as a rare spectrum of neoplasms in cancer family syndrome is discussed.


Hashimoto's thyroiditis in HTLV-I carriers.

We describe two HTLV-I virus carriers who have biopsy-proven Hashimoto's thyroiditis. The first patient, a 64-year-old female, has had goiter and hypothyroidism since the age of 56. The second patient, a 66-year-old male, developed hyperthyroidism and goiter at the age of 44, but at present he is hypothyroid. Both patients are positive for anti-thyroid antibodies and anti-HTLV-I virus antibody. Findings of the thyroid biopsy specimens were consistent with Hashimoto's thyroiditis. These data suggest that Hashimoto's thyroiditis develops in HTLV-I carriers who have no clinical evidence of HAM/TSP.


Renal artery aneurysm: the significance of abdominal bruit and use of color Doppler.

A case of renal artery aneurysm is presented. The patient had no hypertension and no signs of arteriosclerosis obliterans or aortitis syndrome, except for abdominal bruit. A saccular aneurysm, 1 cm in diameter, was demonstrated by two-dimensional and color Doppler ultrasound and documented by angiography. The aneurysm was embolized by a steel coil. The abdominal bruit, though uncommon, is a very important bed-side sign of renal artery aneurysm, if the patient exhibits no arteriosclerosis obliterans or aortitis syndrome. Ultrasound Doppler is very useful in screening for aneurysm.


Fatal abdominal thorotrast granuloma.

We report a case of fatal abdominal thorotrast granuloma seen in a 65-year-old man who had undergone a femoral angiography of thorotrast with some accidental extravasation 49 years previously. As the thorotrast granuloma gradually increased in size, it caused ureteral obstruction, venous thrombosis, and perforation of the urinary bladder and rectum. Symptomatic abdominal thorotrast granuloma is quite rare and this is the first reported case of the granuloma associated with perforation through the urinary bladder and rectum.


Essential thrombocythemia developing into refractory anemia and complicated by acute myeloid leukemia.

We report a case of essential thrombocythemia (ET) that climaxed in acute myeloid leukemia after developing into refractory anemia. The male patient had ET that was stable for 8 years on carboquone therapy. However, at the age of 72 years he developed an acute terminal illness that was characterized by severe pancytopenia, circulating myeloblasts, extensive bone marrow infiltration by myeloblasts, and an abnormal karyotype [46, XY, t(8q-; 20q+)]. He subsequently died of severe bilateral pneumonia and heart failure. This case suggests that ET may be similar to polycythemia vera; progression to leukemia is unusual except after chemotherapy. Therefore, treatment of patients with asymptomatic ET may not be advisable.


Rhabdomyolysis accompanying thyroid crisis: an autopsy case report.

Rhabdomyolysis is occasionally associated with metabolic disorders such as diabetic coma, severe electrolyte disturbances and myxedema coma. We describe rhabdomyolysis accompanying thyroid crisis. A 50-year-old man with Graves' disease developed rhabdomyolysis, congestive heart failure and hepatic failure during the course of thyroid crisis and then died of acute renal failure. Postmortem examination revealed rhabdomyolysis in the cardiac and psoas muscles, old myocardial infarction, hepatic centrilobular necrosis, renal cortical necrosis, and follicular hyperplasia in the thyroid. Circulatory collapse and dehydration under excessive hypermetabolic state presumably suppressed the source of energy and oxygen for muscle cells, leading to cellular damage.


Paraganglioma associated with hypoglycemia.

A 63-year-old female had frequent attacks of palpitations with sweating and occasional loss of consciousness for 7 years before admission. These symptoms and documented hypoglycemia (blood glucose: 46 mg/dl) suggested insulinoma, but computed tomography demonstrated a retroperitoneal tumor which was diagnosed as a paraganglioma by histological examination of the resected specimen.


Ocular vitamin therapy. A review and assessment.

Vitamin therapy for diseased conditions of the eye has regained momentum in the United States, especially for the treatment of age-related macular degeneration. This review looks at the potential effects of vitamin therapy as it relates to everyday primary eye care practice. The discussion covers the generalities of vitamins, their actions, and potential toxicities. In addition, specific attention is paid to the ocular conditions that have been proposed as benefiting from oral and topical vitamin therapies. The analysis is made on a clinicopathological basis rather than being drawn from anecdotal accounts and unsubstantiated claims.


Liability and ophthalmic drug use.

Ophthalmic drug use has been an aspect of optometry for more than two decades. Although utilization of these drugs has produced significant changes in the clinical and legal responsibilities of optometrists, the liability posture of the profession has remained unaltered. Studies of malpractice claims against optometrists and ophthalmologists have demonstrated that ophthalmologists are much more likely to be charged with negligence for adverse drug reactions and that drug-related malpractice claims are not a liability issue for optometrists. Based on the experiences of both professions, this paper describes the adverse effects of common ophthalmic drugs, with emphasis on those drug reactions that have resulted in litigation.


Chemical treatment of verrucae.

Viral warts such as verrucae vulgaris, verrucae plana, and cutaneous horns, when located in close proximity to the eye, can be the cause of chronic, mild conjunctivitis. Removal by chemical cautery using bichloroacetic acid, or by simple excision for pedunculated verrucae, can produce a welcome reduction in symptoms. Chemical cautery may also be employed for the cosmetic treatment of xanthelasma. The proper techniques for cautery and for excision, as well as the evaluation of patients for complications, are discussed.


A review of common ophthalmic antibacterial and corticosteroid-antibacterial combination drugs.

The use of antibacterial agents and corticosteroid-antibacterial combinations are essential to the practice of primary care optometry. In this paper we review common antibacterial drugs available for the treatment of ocular infection or prophylaxis, and offer some clinical guidelines for their use. Corticosteroid-antibacterial combination drugs, used primarily to suppress ocular inflammation, are also discussed, and the distinctions between common drugs are described.


New antibacterial drugs for topical ophthalmic use.

Three new antibacterial drugs have recently been approved for topical ophthalmic use. Ciprofloxacin (Ciloxan) and norfloxacin (Chibroxin) are fluoroquinolones with very broad activity spectra; both have been found to be safe and effective for the treatment of conjunctivitis. Ciprofloxacin, in the commercially available concentration (0.3%), has also been found to be a safe and effective treatment for corneal ulcers. Trimethoprim-polymyxin B (Polytrim) is a new combination product that has been used successfully for the treatment of conjunctivitis. Use of these three new drugs will significantly enhance the ability of the primary care clinician to treat bacterial infections of the cornea and conjunctiva.


Topical carbonic anhydrase inhibitors: a new perspective in glaucoma therapy.

Oral carbonic anhydrase inhibitors have been used extensively in the treatment of all types of glaucoma. These agents reduce intraocular pressure by suppressing the rate of aqueous humor formation. Despite their efficacy as ocular hypotensive agents, these agents are not always used for protracted therapy because of significant systemic side effects. Consequently, topically active carbonic anhydrase inhibitors have been a goal of glaucoma researchers for many years. Recently, a new class of carbonic anhydrase inhibitors has entered clinical trials as ocular hypotensive agents. The thienothiopyran-2-sulfonamides, consisting of compounds MK-927, MK-417, and MK-507, are being actively investigated. These agents possess both lipid and aqueous solubility, thereby allowing intraocular penetration through both the cornea and the sclera. They are all potent inhibitors of the human carbonic anhydrase II isoenzyme found in the nonpigmented epithelium of the ciliary body. Preliminary results indicate the order of potency is 2% MK-507 > 1.8% MK-417 > 2% MK-927. Maximum diurnal intraocular pressure reduction generally requires administration of these agents three times daily. Up to a 26.2% reduction in intraocular pressure occurs following multiple-dose therapy with 2% MK-507 given three times a day. These new topical carbonic anhydrase inhibitors appear to be tolerated extremely well; relatively minor ocular side effects, including transient stinging, burning, and tearing, have been frequently reported. In contrast to oral carbonic anhydrase inhibitors, no significant systemic side effects have been documented during clinical testing. Topical carbonic anhydrase inhibitors will probably be marketed in the near future, thus culminating many years of research effort. These agents may provide a safe, effective means of reducing aqueous humor production and intraocular pressure without producing significant systemic side effects.


[Competence sharing between health insurance and medical service].

The borderlines between the areas of competence of the German compulsory health insurance authorities and their Medical Service can be drawn as follows: 1. The German compulsory health insurance body is legally obliged to clarify the facts concerning a patient and his illness. It is therefore imperative for the health insurance body to prepare the ground in each individual case in such a manner that the case in question can be entrusted to a doctor called upon to write an expertise, but the final decision in respect of the insurance coverage rests exclusively with the health insurance body. 2. The Medical Service system is component for helping to find the fact that must be known before the administrative procedure to arrive at a decision is initiated. The expertise given by the Medical Service is a decision help invaluably important on the grounds of specialist knowledge, knowledge of facts and experience gathered from medical practice. Wherever the borderlines of such competencies are overstepped, there is a risk of errors occurring in the expertise and in the administrative decisions based thereon. Such sources of error can be eliminated only if both parties know and accept their limitations and also do not expect the other side to cross these boundaries.


[Psychology in the context of medical expert assessment].

One of the tasks of the Medical Service of the compulsory health insurance system in Germany is to conduct follow-up examinations if an employee has been unfit for work for a prolonged period. This involves problems of expertise that are discussed in the present article from the viewpoints of definition, problems and psychological skill in the handling of each individual case. Good interaction between all the parties concerned proves to be an important factor to ensure sociomedical effectivity and to relieve tensions.


[Health and urban renewal: experiences with the "Healthy Kreuzgassen Quarter--with reference to Vienna--healthy city].

In the context of the WHO-project "Vienna-Healthy City" problems concerning health promotion in an urban renewal district were examined. On that occasion planners and physicians practised intersectoral collaboration. Some of the results, especially the answers of the occupants of two blocks concerning health, environment and health promotion are presented and discussed.


[Hepatitis A, hepatitis B--incidence of inpatient cases].

The incidence of hepatitis A, treated at hospitals in Austria in the year 1990, was 4,3/10(5) (n = 326), of hepatitis B 3,47/10(5). In hepatitis A the highest incidence was observed in children (5-9 years: 14.3/10(5)). Two peaks were observed in hepatitis B; 20-24 years: 5.93/10(5) and 60-64 years: 3.84/10(5). Both disease had the highest incidence in the district of Vorarlberg (hepatitis A 12.4/10(5), hepatitis B 6.86/10(5)), the lowest in the district of Burgenland (0.37/10(5) and no case of hepatitis B).


[Fatality in diabetic coma during foreign travel].

The case history and the autopsy findings of a 44-year-old women who died shortly after her flight to Khartoum (Sudan) in a hospital is presented. The clinical diagnosis in Africa was "shock caused by gastroenteritis". The body was embalmed thoroughly and brought back to Germany. The autopsy was performed just prior to the cremation (according to "section 3 Abs. 2 Nr. 2 Feuerbestattungsgesetz"). Morphological findings (nodular glomerulosclerosis and glycogen nephrosis with Armanni-Ebstein-cells) and postmortem biochemical analyses of vitreous humour led to the diagnosis of a hyperglycaemic coma. The fatal course might have been prevented by sufficient health information to the patient (who suffered from type 1 diabetes); the diagnostic errors in the hospital could have easily been avoided by careful anamnesis and diagnostic procedures.


[The federal communicable disease law and refuse disposal from hospitals and medical practices].

Several laws and guidelines on the disposal of waste from hospitals and practice differentiate between diverse types of waste. The LAGA instruction sheet lists five types: type A = hospital waste, type B = medical waste, type C = infectious waste, type D = chemical waste, and type E = human pathological material. Especially the basis of differentiation between medical and infectious waste is the list of notifiable infectious diseases according to section 3 of the Federal Law on Epidemic diseases. Section 10a confines the list to contagious infectious diseases. However, some tropical epidemics and endemic infectious diseases are not taken into account. On the other hand, the list includes a few harmless childhood and other diseases. There is not scientific evidence that wastes of this kind have led to infections in the community. Therefore, the Federal Law on Epidemic Diseases does not seem to be a suitable basis for the differentiation between medical and regulated medical wastes.