Progressive symptoms and signs following institution of highly active antiretroviral therapy and subsequent antituberculosis therapy: immune reconstitution syndrome or infection?

A 36 year old man presented with weight loss, cough, fever, and exertional dyspnoea shortly after a diagnosis of HIV infection. Symptoms and initial radiological abnormalities worsened after highly active antiretroviral therapy was started. An eventual diagnosis was established but multiple problems occurred throughout the treatment period. Differentiation between immune reconstitution inflammatory syndrome and an infective cause was problematic.

The control of syphilis, a contemporary problem: a historical perspective.

The control of syphilis in the United Kingdom and United States has been managed in different ways in each country over the course of the last century. Older more established measures including contact tracing, serological surveillance, and health education strategies together with effective antibiotic therapy have had some success. However, changing social structures on both sides of the Atlantic Ocean have brought newer mathematical and epidemiological methods to the fore. This review looks at the past management of syphilis control in the United Kingdom and United States, and speculates on future prospects for disease management in these countries.

The design and synthesis of thrombin inhibitors: analogues of MD805 containing non-polar surrogates for arginine at the P1 position.

A series of monocyclic and bicyclic amino acids have been synthesised and incorporated into thrombin inhibitors based on CGH728, an analogue of the Mitsubishi compound MD805. Benzthiazolylalanine (Bta) was found to be a good non-polar substitute for arginine at the P1 position, yielding compounds with low nanomolar potency and good selectivity for thrombin.

Design and synthesis of thrombin inhibitors: analogues of MD-805 with reduced stereogenicity and improved potency.

Mitsubishi's MD-805, a potent and selective inhibitor of thrombin which contains four stereogenic centers, has been the starting point for an optimization program. A systematic synthetic study resulted in thrombin inhibitors achiral at P2 and P3 but with a 10-fold increase in potency over the original lead. A number of 4-substituted piperidines were synthesized and examined as replacements for 2-carboxy-4-methylpiperidine at P2; 4-fluoroethylpiperidine (FEP) among others provided inhibitors (e.g. 45g) of increased potency. An enantioselective route was developed to 3(R)-methyl-1,2,3,4-tetrahydroquinolinesulfonyl chloride. Inhibitors containing this enantiomerically pure P3 (42d) had similar potency to the racemic material and provided support, with modeling studies, for the preparation of the gem 3,3-disubstituted compounds. A series of inhibitors containing the novel 3, 3-dimethyl-1,2,3,4-tetrahydroquinolinesulfonyl (DMTHQS) P3 (Table 5) were synthesized and showed a similar activity profile as the monomethyl series. The combination of P3-DMTHQS, P2-FEP, and P1-arginine (45g) had a K(i) of 6 nM (MD-805 K(i) = 85 nM). In animal models of both venous and arterial thrombosis, one inhibitor (42e) was shown to produce a dose-dependent inhibition of thrombus formation that in some situations was superior to that of MD-805.

Factor VIII and DDAVP reverse the effect of recombinant desulphatohirudin (CGP 39393) on bleeding in the rat.

The infusion of a high dose of recombinant desulphatohirudin HVI (CGP 39393) for 40 min at 30 micrograms/kg/min, resulted in a prolongation of bleeding time in the rat when evaluated using transection of the tail. The prolonged bleeding was evident both immediately, and 30 min after cessation of the infusion of hirudin (CGP 39393). Bleeding time returned to normal after 60 min. The effect of several agents, reported to be successful in reducing bleeding tendencies in man, were evaluated in this rat model. The agents were administered immediately following cessation of the CGP 39393 infusion and their ability to normalize the prolonged bleeding-time, observed at 30 min after cessation of the CGP 39393 infusion, determined. Desmopressin (DDAVP), recombinant factor VIII and Vueffe reduced the bleeding time to the control range but did not exert any significant effects on the bleeding time in rats which did not receive CGP 39393. Epsilon-aminocaproic acid (EACA) and recombinant factor VII were ineffective, at the doses used. In conclusion, DDAVP, factor VIII and Vueffe are effective in reversing the effect of direct thrombin inhibition on bleeding in the rat.

A non-occlusive model of arterial thrombus formation in the rat and its modification by inhibitors of platelet function, or thrombin activity.

A technically simple model of arterial thrombosis in the rat, induced by a crush injury to the dorsal aorta is described. The mechanical injury to the artery caused deep medial injury and the formation of a platelet-rich thrombus with associated fibrin formation which was assessed both radiometrically and morphometrically. No significant inclusion of erythrocytes was noted in the thrombus. Administration of the platelet inhibitors aspirin, BM 13505 (a thromboxane receptor antagonist) or CGS 12970 (a thromboxane synthase inhibitor) reduced the extent of platelet deposition on the injured vessel, but no decrease in fibrin(ogen) was observed. In contrast, infusion of prostacyclin resulted in reductions in both these components of the thrombus. In studies involving inhibition of thrombin activity, the direct thrombin inhibitor CGP 39393 (recombinant desulphatohirudin) inhibited both the platelet and fibrin(ogen) deposition. The indirect thrombin inhibitors were less effective; unfractionated heparin and low-molecular-weight heparin inhibited both platelet and fibrin(ogen) deposition but only at doses which rendered the blood uncoagulable, as evaluated by the activated partial thromboplastin time. Dermatan sulphate only inhibited platelet deposition. The results suggest that thrombin plays a key role in the initiation of thrombus formation in this experimental model. The agonist prostaglandins (PGG2, PGH2, and TXA2) would appear to have a supporting role in the platelet deposition onto the thrombotic surface but do not have a role to play with respect to fibrin(ogen) deposition.

The characterisation of thrombus development in an improved model of arterio-venous shunt thrombosis in the rat and the effects of recombinant desulphatohirudin (CGP 39393), heparin, and iloprost.

An existing arterio-venous shunt thrombosis model in the rat has been modified to increase its usefulness for the testing of anti-thrombotic agents and characterised using morphological and radiometric techniques. The thrombus formed on the cotton thread held in the shunt was found to be composed of platelet aggregates surrounded by red thrombus. After 30 min of blood flow there was a 15-fold increase in the platelet content of the thrombus and a 4-fold increase in the fibrin(ogen) content compared with an equivalent weight of whole blood. Use of the anticoagulants recombinant desulphatohirudin (CGP 39393, 4 mg/kg, s.c.) and unfractionated heparin (800 IU/kg, s.c.) showed that approx. 90% inhibition of thrombus weight and approx. 80% inhibition of fibrin(ogen) content could be achieved without significant effect on the platelet content. Conversely, using the platelet inhibitor Iloprost (1 microgram kg-1 min-1), a reduction in thrombus weight of 50% was associated with 75% inhibition of platelet content and only 20% inhibition of fibrin(ogen). These observations suggest that the growth of this type of thrombus is largely the result of continued fibrin formation rather than continued platelet recruitment and activation.

Blood-taking practices and needle-stick injuries in house officers.

The blood-taking practices and prevalence of needle-stick injuries were recorded for 46 house officers working at the two largest teaching hospitals in Sheffield and 38 house officers working at three hospitals in London. Wearing gloves when performing venesection or inserting an intravenous cannula was generally perceived as making the procedure more difficult and no house officer in either centre wore gloves when performing routine venesection. Twenty-five (54.3%) of the house officers from Sheffield resheathed needles by hand, while a further 14 (28.3%) placed the sheath onto a work surface before attempting to manoeuvre the needle back into its sheath. Only 7 (17.4%) house officers denied resheathing needles after performing venesection. Twenty-seven (58.7%) admitted to having had a needle-stick injury within 3 months of commencing their first house officer post. Twenty-seven (71.1%) of the house officers from London resheathed needles, the remainder disposing of the needle by placing it straight into an appropriate container. Twenty-five (66%) admitted to having had a needle-stick injury the first 6 months of being a house officer. Training in the correct techniques of venesection with emphasis on either avoiding resheathing needles or resheathing safely is essential early in the medical student curriculum and needs regular repetition.

The effects of recombinant desulphatohirudin on arterial thrombosis in rats.

The role of thrombin in the formation of arterial thrombi is poorly understood. With the new availability of the specific thrombin inhibitor, recombinant desulphatohirudin, in large quantities this is now under investigation. A new model of arterial thrombosis in rats is described where a thrombus is formed on a mechanically injured vessel in vivo. Both platelet and fibrin deposition is inhibited by a recombinant hirudin (CGP 39393) at doses which prolong the activated partial thromboplastin time (APTT) to no more than 3-4 times the control level. In contrast, both unfractionated heparin and Fragmin only inhibit thrombosis when the APTT is excessively prolonged (i.e. to greater than 15 times the control value). It is concluded that CGP 39393 is an effective antithrombotic in arterial thrombosis at lower levels of anticoagulation than either heparin or Fragmin.

Microbiological flora in men with non-gonococcal urethritis with particular reference to anaerobic bacteria.

In a microbiological study of the urethral flora in men with non-gonococcal urethritis (NGU), Chlamydia trachomatis (isolated from 30% of men) was the only organism isolated significantly more often from men with NGU than controls (P less than 0.01). Bacteroids species, especially of the melaninogenicus-oralis group, were the predominant anaerobic bacterial isolate from both men with NGU (isolated from 24%) and controls (isolated from 30%). There was no evidence that aerobic bacteria, anaerobic bacteria or herpes simplex virus made a significant contribution as primary pathogens in non-chlamydial NGU. Gram-positive cocci were the only anaerobic organism isolated more often from chlamydia-positive men (29%) than chlamydia-negative men (16%) with NGU (P less than 0.01). The significance of this remains unclear.

Experience in Sheffield: follow-up of abnormal cervical cytology.

Failure to re-attend for follow-up is a significant problem in patients attending genitourinary clinics. In this study, despite the efforts made to trac patients with cervical cytological abnormalities, adequate follow-up or further investigation was achieved in only 15.3% of women with inflammatory changes on initial cytology, 38.5% with herpes simplex virus changes, 34.5% with human papillomavirus changes, 60.8% with mild dyskaryosis, 79.9% with moderate dyskaryosis and 97% with severe dyskaryosis. Until the natural history of the minimal atypias is more fully understood, it may be that more vigorous surveillance in such women should be considered.

Efficacy of combined metronidazole and triple tetracycline therapy in the treatment of non-gonococcal urethritis.

In a double-blind placebo-controlled trial using triple tetracycline (Deteclo, Lederle) 300 mg twice daily for two weeks in conjunction with metronidazole (Flagyl, May & Baker) 400 mg or matching placebo twice daily for seven days, it was shown that the addition of anti-anaerobic therapy did not significantly affect the number of cases of persistent urethritis or the relapse of patients with non-gonococcal urethritis (NGU).

Recombinant desulphatohirudin (CGP 39393) anticoagulant and antithrombotic properties in vivo.

The effects of the newly available biotechnology product, recombinant desulphatohirudin (CGP 39393) have been investigated in rats. This highly potent and selective thrombin inhibitor exhibited marked anticoagulant properties with controllable titration of anticoagulant effect, as measured by activated partial thromboplastin time (APTT), up to nearly four times control values. Furthermore, CGP 39393 exhibited impressive antithrombotic activity in vivo. In an arteriovenous shunt model of thrombus formation on a cotton-thread, the compound was capable of complete inhibition of thrombus development (ED50 = 0.3 mg/kg i.v. and 1.0 mg/kg s.c.). Venous stasis thrombosis was also highly susceptible to inhibition by CGP 39393 (ED50 = 0.01 mg/kg i.v. and 0.45 mg/kg s.c.). Comparison of the anticoagulant and antithrombotic activities of the compound shows that potent antithrombotic effects (83-97% inhibition in the rat shunt model) are achieved within the generally acceptable range of anticoagulation. These results suggest a clear potential for this new agent in the clinical treatment of thrombotic disease.

Relation between incidence of gonorrhoea in Sheffield and efficiency of contact tracing: a paradox?

An attempt has been made to correlate the yearly incidence of gonorrhoea in Sheffield (1979-85) with two variables to show contact tracing efficiency: infectious patient days (days from the start of contact tracing to the attendance of contacts) and the percentage of source contacts brought to investigation within 30 days. No such correlation has been found. The possible reasons for this, which include the unreliability of incidence figures as a sole criterion of control and the organisation of contact tracing activities, are discussed.