What are the costs and benefits of patient notification exercises following poor infection control practices in dentistry?

BACKGROUND: Allegations of serious failures in infection control practice were made against a dentist practicing in the South West of England. The dentist (who tested negative for Blood Borne Viruses (BBVs)) was immediately suspended. METHODS: Because inadequate infection control presents a potential risk of transmitting BBVs between patients, a notification exercise was undertaken. Of 7625 patients contacted, 2780 (37%) were tested. RESULTS: Nine cases of Hepatitis B (HBV) and four cases of Hepatitis C (HCV) were identified, of which seven were previously diagnosed. None of these were children. All of the six newly diagnosed cases had recognized risk factors for BBVs. The costs of the notification exercise were estimated at £311,500 of which £165,000 was staff costs, (£51,916 per newly diagnosed case). CONCLUSION: This study did not demonstrate any patient-to-patient transmission of blood-borne viruses but the response rate was relatively low. There are significant costs associated with undertaking notification exercises. These findings should inform future recommendations and practice in this area.

Stress urinary incontinence: issues and answers for women.

Women's healthcare issues have become increasingly important. Specific healthcare issues, including management of high blood pressure, obesity, and menopause have been on the forefront for years. Today, urinary incontinence in women of all ages is seen as a major healthcare concern. The impetus for this increased awareness began in 1988 at the National Institutes of Health Consensus Conference on Adult Urinary Incontinence, which was followed by the publication of the Guideline for Adult Urinary Incontinence by the Agency for Health Care Policy and Research in 1992. Since that time, there has been an increased focus on the problem of urinary incontinence. Many hope that more women will seek professional guidance for the evaluation and management of urinary incontinence as a result of this increased awareness. Healthcare professionals need to be current on the various options available for the management of urinary incontinence, particularly stress urinary incontinence, as it commonly affects women.

Lack of beneficial effects of growth hormone treatment in conscious dogs during development of heart failure.

The effects of chronic treatment with growth hormone (porcine GH, 0.56 mg.kg-1.day-1 s.c.) were examined in dogs with heart failure induced by rapid ventricular pacing (240 beats/min) for 4 wk. Fourteen conscious dogs were studied 2-3 wk after surgical instrumentation with catheters in the descending aorta and left atrium, a pressure gauge in the left ventricle (LV), a flow probe around the ascending aorta, pacing leads on the ventricular free wall and left atrium, and ultrasonic crystals on the opposing anterior and posterior endomyocardium of the LV. GH treatment for 4 wk significantly increased both body weight and plasma insulin-like growth factor 1 (IGF-1) compared with vehicle-treated dogs (P < 0.01, +2.0 +/- 0.5 vs. +0.3 +/- 1.1 kg; 1,043 +/- 218 vs. 241 +/- 64 ng/ml, respectively). However, the changes in resting LV systolic (i.e., both isovolumic and ejection phases) and diastolic function (i.e., isovolumic relaxation time constant tau) and the systemic vascular resistance were similar for the GH- and vehicle-treated groups during the development of heart failure. LV contractile reserve, assessed with step infusion of isoproterenol or dobutamine challenge, was markedly attenuated after heart failure, but there were no differences between the GH- and vehicle-treated groups. During the progression of heart failure, the increases in plasma atrial natriuretic peptide correlated (P < 0.01) directly with left atrial pressure and inversely with LV circumferential fiber shortening. However, GH treatment did not substantially modify these relationships. In addition, renal function and myocardial ultrastructure at the advanced stage of heart failure also showed similar changes for the GH- and vehicle-treated groups. We conclude that in conscious dogs during the development of congestive heart failure produced by rapid ventricular pacing, GH at a dose that increases body weight and plasma IGF-1 levels does not affect LV performance or systemic vascular dynamics.

Discovery and development of the novel potent orally active thrombin inhibitor N-(9-hydroxy-9-fluorenecarboxy)prolyl trans-4-aminocyclohexylmethyl amide (L-372,460): coapplication of structure-based design and rapid multiple analogue synthesis on solid support.

Early studies in these laboratories of peptidomimetic structures containing a basic P1 moiety led to the highly potent and selective thrombin inhibitors 2 (Ki = 5.0 nM) and 3 (Ki = 0.1 nM). However, neither attains significant blood levels upon oral administration to rats and dogs. With the aim of improving pharmacokinetic properties via a more diverse database, we devised a resin-based route for the synthesis of analogues of these structures in which the P3 residue is replaced with a range of lipophilic carboxylic amides. Assembly proceeds from the common P2-P1 template 7 linked via an acid-labile carbamate to a polystyrene support. Application of the methodology in a repetitive fashion afforded several interesting analogues out of a collection of some 200 compounds. Among the most potent of the group, N-(9-hydroxy-9-fluorenecarboxy)-prolyl trans-4-aminocyclohexylmethyl amide (L-372,460 8, Ki = 1.5 nM), in addition to being fully efficacious in a rat model of arterial thrombosis at an infusion rate of 10 micrograms/kg/min, exhibits oral bioavailability of 74% in dogs, and oral bioavailability of 39% in monkeys with a serum half-life of just under 4 h. On the basis of its favorable biological properties, inhibitor 8 has been subject to further evaluation as a possible treatment for thrombogenic disorders.

Synthesis of a series of potent and orally bioavailable thrombin inhibitors that utilize 3,3-disubstituted propionic acid derivatives in the P3 position.

As part of an effort to prepare efficacious and orally bioavailable analogs of the previously reported thrombin inhibitors 1a, b, we have synthesized a series of compounds that utilize 3,3-disubstituted propionic acid derivatives as P3 ligands. By removing the N-terminal amino group, the general oral bioavailability of this class of compounds was enhanced without excessively increasing the lipophilicity of the compounds. The overall properties of the molecules could be drastically altered depending on the nature of the groups substituted onto the 3-position of the P3 propionic acid moiety. A number of the compounds exhibited good oral bioavailability in rats and dogs, and numerous compounds were efficacious in a rat FeCl3-induced model of arterial thrombosis. Compound 7, the 3,3-diphenylpropionic acid derivative, showed the best overall profile of in vivo and in vitro activity. Molecular modeling studies suggest that these compounds bind in the thrombin active site in a manner essentially identical to that previously reported for compound 1a.

Potent noncovalent thrombin inhibitors that utilize the unique amino acid D-dicyclohexylalanine in the P3 position. Implications on oral bioavailability and antithrombotic efficacy.

In an effort to prepare orally bioavailable analogs of our previously reported thrombin inhibitor 1, we have synthesized a series of compounds that utilize the unique amino acid D-dicyclohexylalanine as a P3 ligand. The resulting compounds are extremely potent and selective thrombin inhibitors, and the N-terminal Boc derivative 8 exhibited excellent oral bioavailability and pharmacokinetics in both rats and dogs. The des-Boc analog 6 was not orally bioavailable in rats. The high level of oral bioavailability observed with 8 appears to be a direct function of its increased lipophilicity versus other close analogs. Although increased lipophilicity may serve to increase the oral absorption of tripeptide thrombin inhibitors, it also appears to have detrimental effects on the antithrombotic properties observed with the compounds. Compound 6 performed extremely well in our in vivo antithrombotic assay, while the much more lipophilic but essentially equipotent analog 8 performed poorly. We have found that in general with this series of thrombin inhibitors as well as with other unreported series, increased lipophilicity and the associated increases in plasma protein binding have detrimental effects on 2X APTT values and subsequent performance in in vivo antithrombotic models.

Headspace gas-liquid chromatographic determination of dithiocarbamate residues in fruits and vegetables with confirmation by conversion to ethylenethiourea.

Ethylene-bis-dithiocarbamate (EBDC) residues were determined as carbon disulfide (CS2) by an improved headspace gas-liquid chromatographic (GLC) procedure. Among 837 samples of 30 agricultural commodities tested, 43% contained residues above the detection limit for the method: 100% of broccoli samples; 80% of cabbage, kiwifruit, and grape samples; and 71% of cucumber samples. Most of the residues in kiwifruit were on or near the skin. Elimination of false-positive detections by the improved method was confirmed with kiwifruit in 2 independent procedures. Whole fruits were washed with 5% EDTA to remove surface residues of EBDC. Analysis of washes for CS2 by the headspace procedure after treatment with acidic stannous chloride and for ethylene thiourea by LC after prolonged treatment at 60 degrees C qualitatively identified the EDTA-soluble residues as EBDC. Although the improved method does not produce false-positive results, peak area responses of CS2 and the internal standard, thiophene, are influenced by chemical composition of the matrix. With matrixes high in sugar or lipids, the apparent CS2 content may be overestimated by 4-fold. Accurate determination of EBDC residues in these sample types requires appropriate adjustments to matrixes.

Passive diffusion through polymeric membranes: a novel cleanup procedure for analysis of azinphos-methyl and azinphos-ethyl residues in fruits and vegetables.

A novel procedure is described for simple removal of coextractives prior to analysis of fruits and vegetables for azinphos-methyl and azinphos-ethyl residues. The solvent extract is concentrated, placed in a polymeric membrane tube, and then dialyzed in cyclohexane. Both azinphos-methyl and azinphos-ethyl diffuse into the surrounding solvent while coextractants remain inside the membrane. The dialyzing solvent is exchanged during concentration with n-hexane and analyzed without further cleanup by gas-liquid chromatography with a specific thermionic detector. The detection limit for a 25 g grape sample with final volume of extract made to 15 mL was 0.01 mg/kg. Recoveries of both residues from grapes averaged 107% (spike levels of 0.3 to 2.0 mg/kg). From a 20 g spinach sample, recoveries averaged 82% for azinphos-methyl and 72% for azinphos-ethyl when final volume of extract was made to 5 mL (spike levels of 0.1 to 1.0 mg/kg). Recoveries from 20 types of fruits and vegetables (20 g sample spiked at 1 mg/kg for both azinphos-methyl and azinphos-ethyl) were consistently greater than 70%, except for strawberries (61-67%) and avocado (28-34%). The high lipid content of avocado may impede diffusion of azinphos-methyl and azinphos-ethyl through the polymeric membrane. A field evaluation of the procedure showed a strong correlation (r = 0.957) between azinphos-methyl residues on grapes and treatments with 2 spray formulations. The membrane cleanup procedure is a simple and cost-effective alternative to other column or liquid-liquid partitioning procedures for azinphos-methyl and azinphos-ethyl residue analysis.

Inhibition of thrombin by peptides containing Lysyl-alpha-keto carbonyl derivatives.

Several H-N-Me-D-Phe-Pro-Lysyl-alpha-keto carbonyl derivatives were shown to be potent thrombin inhibitors (Ki 0.2 to 27 nM). The inhibitory potencies of these compounds toward tissue plasminogen activator, plasmin and factor Xa were minimal; however, substantial cross-reactivity versus trypsin was observed (Ki values from 0.5 to 1500 nM). Inhibition of thrombin by alpha-keto carbonyl compounds appeared to occur via a one-step reversible reaction. The alpha-keto carbonyl inhibitors bound thrombin with a second order rate constant (k1 1-4 microM-1s-1) that was 10-100-fold slower than that expected for a diffusion-controlled reaction. Certain alpha-keto carbonyl inhibitors were as potent (on a weight basis) as hirudin when evaluated in a rat arterial thrombosis model. The modest oral bioavailability (10-19%) in rats demonstrated for three of the alpha-keto carbonyl thrombin inhibitors suggests the possibility that alpha-keto amide containing thrombin inhibitors may have utility as orally-active antithrombotic agents.

Coverage of routine neonatal metabolic screening in children born to women known to be infected with HIV-1.

Unlinked anonymous HIV-1 testing of neonatal samples routinely collected for metabolic screening is now carried out in many parts of the United Kingdom. The purpose of this study was to assess the completeness of screening coverage in infants born to women known to be infected with HIV-1. Research nurses at family HIV clinics in three London hospitals searched for Guthrie cards from all infants born to known infected residents of North East, North West, and South West Thames regions over a 32 month period. If no card was found initially, mothers were approached for more information. Overall coverage was estimated to be 96.4% (94.6% in infants of African origin and 100% in white infants). These figures are similar to recent general population coverage estimates in inner London. We conclude that the anonymous newborn HIV testing programme is providing sufficiently accurate information on both absolute levels and time trends in maternal seroprevalence.

A home health perspective on the management of urinary incontinence.

Urinary incontinence is now recognized as a major health care problem. Approximately 10 to 12 million persons are affected by urinary incontinence. The prevalence of urinary incontinence of noninstitutionalized (community-dwelling) persons older than 60 years ranges from 15% to 30%. Urinary incontinence is twice as common in women as in men. Two landmarks have promoted a greater awareness of urinary incontinence in our society: the National Institutes of Health Consensus Conference on Adult Urinary Incontinence, held in 1988, and the development of the Guideline for Adult Urinary Incontinence by the Agency for Health Care Policy and Research, in 1992. Urinary incontinence is no longer viewed as an impossible health care problem to manage, with many therapies available. Health care professionals in all arenas, including home health care, are interested in the causes and treatment of urinary incontinence.

Cardiac electrophysiologic and antiarrhythmic actions of tedisamil.

The Class III electrophysiologic and antiarrhythmic actions of the bradycardic agent tedisamil were assessed in vitro and in vivo. In ferret isolated right ventricular papillary muscles, tedisamil increased effective refractory period (ERP) in a concentration-dependent manner, with a 25% ERP increase achieved with 3.0 microM tedisamil, and a 133.4% +/- 28.8% increase in ERP achieved at the high 100 microM concentration tested. In anesthetized dogs, the cumulative i.v. administration of tedisamil significantly increased ventricular relative refractory period (VRRP) and ventricular effective refractory period (VERP) as well as electrocardiographic QTc intervals (100-1000 micrograms/kg i.v.). A 20msec increase in VRRP was achieved with 45.0 micrograms/kg i.v. tedisamil, and a 56.1 +/- 9.8 msec (40.1% +/- 8.1%) increase in VRRP was achieved at the highest dose tested (1000 micrograms/kg i.v.). In the same dosage range in anesthetized dogs, tedisamil produced significant hemodynamic effects, including reduction in HR (100-1000 micrograms/kg i.v.) and elevations in mean arterial pressure (1000 micrograms/kg i.v.), left ventricular developed pressure (1000 micrograms/kg i.v.) and the maximum rate of LV pressure development (100-1000 micrograms/kg i.v.). In anesthetized dogs studied chronically (8.2 +/- 0.6 days) after anterior myocardial infarction, tedisamil suppressed programmed stimulation-induced ventricular tachyarrhythmias (8/10, 80% suppression at 100-1000 micrograms/kg i.v.) and reduced the incidence of lethal ischemic arrhythmias developing in response to acute posterolateral myocardial ischemia (arrhythmic mortality 5/10, 50% tedisamil vs. 34/40, 85% vehicle control cohort; P = .027). The latter findings suggest that tedisamil might be useful in the prevention of malignant ventricular arrhythmias in the setting of myocardial ischemic injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Characterization of edg-2, a human homologue of the Xenopus maternal transcript G10 from endothelial cells.

We have isolated by polymerase chain reaction-amplified subtractive hybridization technique, several cDNA clones that are induced by phorbol myristic acetate in human umbilical vein endothelial cells (HUVEC). One such clone, termed edg-2, was sequenced and was found to encode a human homologue of a Xenopus maternal transcript G10. The deduced amino acid sequence of edg-2 contains a putative nuclear translocation sequence, an N-terminal acidic domain and a cysteine-rich C-terminal domain containing a putative Zinc-finger structure. The structure of edg-2 polypeptide suggests that it may be a nuclear regulator of transcription. The edg-2 mRNA was expressed ubiquitously in cell lines of epithelial and mesenchymal lineages. In addition, the edg-2 polypeptide sequence is highly conserved in evolution and is expressed by lower organisms such as yeast and C. elegans, suggesting that it may be an important regulator of general nuclear function.

Structure of the human cyclo-oxygenase-2 gene.

Cyclo-oxygenase (Cox), a rate-limiting enzyme in the synthesis of prostanoids, is encoded by two genes, Cox-1 and Cox-2, which are differentially expressed and regulated. Human Cox-1 and -2 polypeptides share 61% primary sequence identity. While the expression of Cox-1 is maximal in quiescent cells. Cox-2 expression is induced by growth factors and cytokines. We have screened a human genomic library with a probe from the 5'-untranslated region (UTR) of the human Cox-2 (hCox-2) cDNA and isolated two overlapping genomic clones. We have determined the DNA sequence of 0.8 kb upstream of the transcription start site, 6 kb of protein coding region, which includes 10 exons and 9 introns, as well as 2.5 kb of the 3'-UTR. The structures of the hCox-1 and hCox-2 and the murine TIS10 (Cox-2) genes are highly conserved, with a few exceptions. The 3'-UTRs of the Cox-1 and -2 genes are distinct; for example, the largest exon in the Cox-2 gene encodes the entire 3'-UTR, containing 22 copies of the 'AUUUA' RNA instability element. Sequence analysis of the 5'-flanking region has shown several potential transcription regulatory sequences, including a TATA box, a C/EBP motif, two AP-2 sites, three SP1 sites, two NF-kappa B sites, a CRE motif and an Ets-1 site. These efforts serve as a basis for future studies on transcriptional and post-transcriptional mechanisms of Cox-2 gene regulation.

Cardiac electrophysiologic and antiarrhythmic actions of two long-acting spirobenzopyran piperidine class III agents, L-702,958 and L-706,000 [MK-499].

The cardiac electrophysiologic and antiarrhythmic actions of two Class III ketone- and alcohol-containing spirobenzopyran piperidine analogs, L-702,958 and L-706,000 [MK-499], respectively, were assessed in vitro and in vivo. L-702,958 and L-706,000 [MK-499] selectively blocked the rapidly activating component of the delayed rectifier K+ current in guinea pig isolated ventricular myocytes (IC50 values, 14.6 and 43.9 nM, respectively), and prolonged effective refractory period in ferret isolated papillary muscles (EC25 values, 10.5 and 53.8 nM, respectively). In anesthetized dogs, L-702,958 and L-706,000 [MK-499] increased ventricular refractory periods (ED20 values, 3.3 and 9.2 micrograms/kg i.v., respectively) and concomitantly increased ECG QT interval and left ventricular+dP/dt. Cumulative i.v. administrations of up to 100 micrograms/kg of L-702,958 and 300 micrograms/kg L-706,000 [MK-499] in anesthetized dogs increased atrial and ventricular refractoriness and prolonged the ECG QT interval, but did not alter atrial, atrioventricular nodal, His-Purkinje or ventricular conduction indices. In anesthetized dogs studied chronically (9.2 +/- 1.1 days) after anterior myocardial infarction, the cumulative i.v. administrations of 100 micrograms/kg of L-702,958 and 300 of micrograms/kg L-706,000 [MK-499] suppressed the induction of ventricular tachyarrhythmia by programmed ventricular stimulation (suppression rates: 8 of 10, 80% and 9 of 11, 82%, respectively) and reduced the incidence of lethal ventricular arrhythmias (incidence of lethal ischemic arrhythmias: 4 of 10, 40% and 1 of 11 9%, respectively, compared to 34 of 40, 85%, in vehicle controls. L-702,958 and L-706,000 [MK-499] (cumulative 100 and 300 micrograms/kg i.v., respectively) did not facilitate the induction of arrhythmias by programmed ventricular stimulation in postinfarction dogs. After equivalently effective p.o. doses in conscious dogs, L-702,958 (10 micrograms/kg) and L-706,000 [MK-499] (30 micrograms/kg) increased ECG QT interval with long durations of action of approximately 9 and 14 hr, respectively. L-706,000 [MK-499] elicited a more consistent and sustained prolongation of the QT interval than L-702,958. These findings show that both L-702,958 and L-706,000 [MK-499] are potentially useful agents for the prevention of malignant ventricular arrhythmias in the setting of myocardial ischemic injury.

HIV/AIDS. Caring for families in the community.

Primary health care workers have a vital role in offering advice, support and comfort to families affected by Aids and HIV, write Sue Appleby and Corinne Moore. Here they describe the specialist health visiting service provided in Parkside, west London, for parents and children with HIV infection. But generic health visitors and school nurses must also be aware of the issues and alert to signs of undiagnosed infection as they are likely to be increasingly involved in providing a 'normal' service to families affected by Aids/HIV.

Cardiac electrophysiologic and antiarrhythmic actions of 3,4-dihydro-1'-[2-(benzofurazan-5-yl) ethyl]-6-methanesulfonamidospiro [(2H)-1-benzopyran-2,4'-piperidin]-4-one HCl (L-691,121), a novel class III agent.

The cardiac electrophysiologic and antiarrhythmic actions of 3,4-dihydro-1'-[2-(benzofurazan-5-yl)ethyl]-6-methyl-sulfonamid ospiro [(2H)-1-benzopyran-2,4'-piperidin]-4-one HCl (L-691,121), a novel spirobenzopyran piperidine class III agent, were assessed in vitro and in vivo. In ferret isolated papillary muscles, L-691,121 significantly prolonged effective refractory period (EC25 = 13 nM) and elicited a modest positive inotropic effect. In guinea pig isolated ventricular myocytes, L-691,121 prolonged action potential duration by selectively blocking (IC50 = 4.4 nM) a rapidly activating and rectifying component of the delayed rectifier K+ current, Ikr. The class III activity of L-691,121 in isolated papillary muscles was reverse frequency-dependent, and reversed by hypoxic perfusion. L-691,121 modestly depressed spontaneous beating rate (-14%) in guinea pig isolated right atria at concentrations up to 3 microM. In anesthetized dogs, the i.v. administration of 10 to 100 micrograms/kg of L-691,121 significantly increased atrial and ventricular refractoriness and prolonged the electrocardiographic Q-T interval, but did not alter atrioventricular nodal, His-Purkinje, atrial or ventricular conduction. In conscious dogs with spontaneous premature ventricular complexes at 48 hr after myocardial infarction, 10 to 1000 micrograms/kg i.v. of L-691, 121 failed to reduce premature ventricular complex frequency. However, in anesthetized dogs studied chronically (7.9 +/- 0.3 days) after infarction, 10 and 100 micrograms/kg i.v. of L-691,121 suppressed the induction of ventricular tachyarrhythmia by programmed stimulation in 8/14 (57%) and 11/14 (79%) dogs tested, respectively, and reduced the incidence of lethal ventricular arrhythmias triggered by a secondary myocardial ischemic event from 14/15 (93%) in vehicle controls to 5/14 (36%; P < .01) in L-691,121-treated (100 micrograms/kg i.v.) animals. The latter findings suggest the potential for L-691,121 to prevent the development of malignant ventricular arrhythmias in the setting of previous myocardial infarction.