The collαgen III fibril has a "flexi-rod" structure of flexible sequences interspersed with rigid bioactive domains including two with hemostatic roles.

Collagen III is critical to the integrity of blood vessels and distensible organs, and in hemostasis. Examination of the human collagen III interactome reveals a nearly identical structural arrangement and charge distribution pattern as for collagen I, with cell interaction domains, fibrillogenesis and enzyme cleavage domains, several major ligand-binding regions, and intermolecular crosslink sites at the same sites. These similarities allow heterotypic fibril formation with, and substitution by, collagen I in embryonic development and wound healing. The collagen III fibril assumes a "flexi-rod" structure with flexible zones interspersed with rod-like domains, which is consistent with the molecule's prominence in young, pliable tissues and distensible organs. Collagen III has two major hemostasis domains, with binding motifs for von Willebrand factor, α2ß1 integrin, platelet binding octapeptide and glycoprotein VI, consistent with the bleeding tendency observed with COL3A1 disease-causing sequence variants.

Subcutaneous Administration of Otelixizumab is Limited by Injection Site Reactions: Results of an Exploratory Study in Type 1 Diabetes Mellitus Patients.

Targeting CD3 antigens on human T lymphocytes with monoclonal antibodies has been shown to reduce the rate of decline of C-peptides in recent-onset type 1 diabetes mellitus patients. However, effective doses are associated with infusion reactions typical of "cytokine release syndrome" and appear to be dose-limiting when administered as short-duration infusions. A possible alternative approach, which may reduce the rate of T cell activation and consequent systemic cytokine release, is to inject subcutaneously. We investigated single- and repeat-dose subcutaneous administration of the anti-CD3 monoclonal antibody otelixizumab in small cohorts of patients with type 1 diabetes. Transient reductions in free or unbound CD3 antigen on CD4+ and CD8+ cells and absolute lymphocyte count were observed in the blood of these patients during treatment, consistent with the known mechanism of action of otelixizumab and other anti-CD3 monoclonal antibodies. This was despite the very low systemic exposure of antibodies measured during the same time period. With the exception of sporadic headaches, other symptoms associated with cytokine release syndrome, such as fever, nausea, vomiting, myalgia, and arthralgia, were absent in treated patients. However, treatment-related injection site reactions were consistently observed. The reactions were erythematous and their sizes were dose-dependent; in some cases, reactions persisted for up to 2 weeks following the start of treatment. While patients responded well to topical corticosteroid treatment and prophylaxis reduced the intensity of injection site reactions, the reactions were considered dose-limiting and higher doses were not investigated.

Urinary C-peptide analysis in an intervention study: experience from the DEFEND-2 otelixizumab trial.

AIMS: To demonstrate that analysis of urinary C-peptide across multiple study sites in the context of an intervention trial (DEFEND-2) is a viable alternative to mixed meal testing and delivers results that correlate to mixed meal testing estimation of endogenous insulin production. METHODS: Second morning void urine was collected for analysis and was available from 161 subjects at baseline (55 placebo, 106 otelixizumab), and 146 subjects (47 placebo, 99 otelixizumab) at month 12. Urinary C-peptide concentration was corrected for urinary creatinine [urinary C-peptide/creatinine ratio (UCPCR)] and serum C-peptide from the mixed meal tolerance test was calculated using area under the plasma concentration-time curve (AUC) normalized over 120 min. The correlation between mixed meal stimulated C-peptide AUC (mmol/l/min) and UCPCR (nmol/mmol), as well as the correlation between insulin use (IU/kg), and HbA1c (%) with UCPCR, was determined. RESULTS: UCPCR and mixed meal testing C-peptide AUC were correlated, with a correlation coefficient of 0.4172. UCPCR was not correlated with exogenous insulin use (r = -0.089) or with HbA1c (r = -0.032). CONCLUSIONS: Urinary C-peptide estimation should be considered as a measure of endogenous insulin production in future Type 1 diabetes mellitus outcome trials. A change in the timing for urine collection (to 120 min post standard meal) may provide a tighter correlation to C-peptide measured via a traditional mixed meal test.

Efficacy and safety of low-dose otelixizumab anti-CD3 monoclonal antibody in preserving C-peptide secretion in adolescent type 1 diabetes: DEFEND-2, a randomized, placebo-controlled, double-blind, multi-centre study.

AIMS: Phase III DEFEND-2 investigated whether otelixizumab (3.1 mg over 8 days) preserved C-peptide secretion in patients with new-onset Type 1 diabetes, focusing on adolescents (12-17 years). METHODS: One hundred and seventy-nine patients (54 adolescents) were randomized to otelixizumab or placebo. The primary endpoint was change in 2-h mixed-meal-stimulated C-peptide area under the curve at month 12. Enrolment was suspended in April 2011 following negative efficacy results from DEFEND-1. DEFEND-2 terminated early after 12 months' efficacy and safety follow-up. RESULTS: Change from baseline C-peptide was not significantly different [∆ = -0.09 nmol/l (95% CI -0.17 to 0; P = 0.051)]. No differential C-peptide effect was seen for otelixizumab in adolescents and more adverse events were reported. CONCLUSIONS: Efficacy and tolerability of otelixizumab was similar to DEFEND-1. The 3.1-mg dose was non-efficacious in adults and adolescents. Further investigation of the mechanism of action seen at higher doses and therapeutic window is required. Clinical Trials Registry No: NCT 00763451.

Mapping structural landmarks, ligand binding sites, and missense mutations to the collagen IV heterotrimers predicts major functional domains, novel interactions, and variation in phenotypes in inherited diseases affecting basement membranes.

Collagen IV is the major protein found in basement membranes. It comprises three heterotrimers (α1α1α2, α3α4α5, and α5α5α6) that form distinct networks, and are responsible for membrane strength and integrity.We constructed linear maps of the collagen IV heterotrimers ("interactomes") that indicated major structural landmarks, known and predicted ligand-binding sites, and missense mutations, in order to identify functional and disease-associated domains, potential interactions between ligands, and genotype­phenotype relationships. The maps documented more than 30 known ligand-binding sites as well as motifs for integrins, heparin, von Willebrand factor (VWF), decorin, and bone morphogenetic protein (BMP). They predicted functional domains for angiogenesis and haemostasis, and disease domains for autoimmunity, tumor growth and inhibition, infection, and glycation. Cooperative ligand interactions were indicated by binding site proximity, for example, between integrins, matrix metalloproteinases, and heparin. The maps indicated that mutations affecting major ligand-binding sites, for example, for Von Hippel Lindau (VHL) protein in the α1 chain or integrins in the α5 chain, resulted in distinctive phenotypes (Hereditary Angiopathy, Nephropathy, Aneurysms, and muscle Cramps [HANAC] syndrome, and early-onset Alport syndrome, respectively). These maps further our understanding of basement membrane biology and disease, and suggest novel membrane interactions, functions, and therapeutic targets.

Hormonal correlates of human paternal interactions: a hospital-based investigation in urban Jamaica.

To expand our understanding of the neuroendocrine mechanisms underlying human fatherhood, including its cross-cultural expression, we investigated the hormonal correlates of fatherhood in the greater Kingston, Jamaica area. We recruited 43 men, aged 18-38, to participate: 15 single men; 16 "coresidential" fathers (men who live with their adult female partner and youngest child); and 12 "visiting" fathers (men who live apart from their adult female partner and youngest child). The research protocol entailed biological sampling before and after a 20-min behavioral session during which single men sat alone and fathers interacted with their partner and youngest child. Hormone measures relied upon minimally invasive techniques (salivary testosterone and cortisol, finger prick blood spot prolactin, urinary oxytocin and vasopressin). Results revealed significant group differences in average male testosterone levels (p=0.006), with post hoc contrasts indicating that visiting fathers had significantly (p<0.05) lower testosterone levels than single men. Prolactin profiles also differed significantly across groups (p=0.010) whereby post hoc contrasts showed that prolactin levels of single men declined significantly compared with the flat levels of visiting fathers (p<0.05). No group differences in cortisol, oxytocin or vasopressin levels were observed. However, among fathers, vasopressin levels were significantly and negatively (r=-.431, p=0.022) correlated with the age of a man's youngest child. These results thus implicate lower testosterone levels as well as prolactin and vasopressin in human fatherhood. These findings also highlight the importance of sociocultural context in human fatherhood while exhibiting parallels with existing data on the non-human vertebrate hormonal bases of paternal care.

Asthma control in a random sample of New Zealand adolescent asthmatics.

Asthma control, defined by asthma symptoms and lung function, and asthma medication use, was assessed in 123 adolescent asthmatics. Sputum eosinophilia (>or= 2.5% eosinophils) and bronchial hyperresponsiveness (BHR) to hypertonic saline were also measured to assess whether these additional objective parameters might aid in determining asthma control; 54.5% of subjects had adequately controlled asthma; 50.4% of all subjects reported inhaled corticosteroid use in the preceding 12 months; however, only 22.3% reported regular use. Although BHR and median eosinophil numbers were significantly higher in the inadequately controlled asthmatics, BHR and sputum eosinophilia had poor sensitivity for detecting inadequate asthma control.

Genotyping demonstrates that the strains of Proteus mirabilis from bladder stones and catheter encrustations of patients undergoing long-term bladder catheterization are identical.

PURPOSE: We established the incidence of bladder stones in patients who experienced recurrent encrustation and blockage of indwelling bladder catheters and examined the relationship between isolates of Proteus mirabilis from the stones and from the crystalline biofilms on the catheters. MATERIALS AND METHODS: The first 100 patients attending a clinic for patients experiencing problems with the management of long-term bladder catheters were studied. Flexible cystoscopy was used to detect bladder stones. Catheter encrustation was assessed visually and by electron microscopy. Bacteriological analysis was performed on the stones and catheter biofilms. P. mirabilis isolates were genotyped by pulsed field gel electrophoresis of restriction enzyme digests of bacterial DNA. RESULTS: Most patients (85%) had been referred because of catheter blockage and in 61 (72%) the catheters were encrusted. P. mirabilis was recovered from 37 of 47 encrusted catheters (79%) that were examined but not from any nonencrusted catheters. Of the 61 patients with encrusted catheters 38 (62%) had bladder stones. Pairs of isolates of P. mirabilis from the stones and the catheter biofilms from 6 patients were genotyped. The DNA profiles of each pair of isolates were identical. CONCLUSIONS: The majority of patients (62%) with recurrent catheter encrustation had bladder stones. The stones harbored the strains of P. mirabilis that rapidly colonize replacement catheters with crystalline biofilm. Flexible cystoscopy to detect and remove stones might help resolve the problem of recurrent catheter encrustation.

Developing alternative devices to the long-term urinary catheter for draining urine from the bladder.

The self-retaining urinary catheter is used for long-term drainage of urine from the bladder only as a last resort because of serious associated complications, yet it remains a routine method for managing older and disabled patients with loss of bladder control. Blockage of the catheter from calcified deposits within its lumen is a common occurrence, obstructing the passage of urine and causing an urgent, unpredictable problem for patients, carers and the nursing staff. The need for further research on the subject has been recognized for many years. The SuPort Project aimed to develop an alternative suprapubic urine collection system. This report outlines the approach adopted towards the design and selection of the novel device, the production problems that ensued and the small clinical trial of a modified prototype.

Endoluminal ultrasonography before retrograde endopyelotomy: can the results match laparoscopic pyeloplasty?

OBJECTIVE: To present the results of endopyelotomy using endoluminal ultrasonography (EUS) to identify crossing vessels, as the success rates of endopyelotomy are generally lower than pyeloplasty, especially in patients with crossing vessels. PATIENTS AND METHODS: Forty-one consecutive patients who underwent EUS before a planned retrograde endopyelotomy were analysed retrospectively. EUS was used to direct the endopyelotomy incision for patients with crossing vessels. Treatment was considered successful if the patient was asymptomatic and unobstructed or improved on renography. The results were compared to those from 18 patients treated by laparoscopic pyeloplasty, some of whom had undergone EUS. RESULTS: Crossing vessels were identified in 27 of the 41 patients (66%). Primary treatment consisted of endopyelotomy for 26 patients and laparoscopic pyeloplasty for 15. The overall success rate for 24 endopyelotomy patients with an adequate follow-up (mean 19 months) was 71%, with more success in patients with no crossing vessels (11 of 13 (85%) vs six of 11 (55%)). Of the 18 patients treated by laparoscopic pyeloplasty (mean follow-up 15.1 months) 17 were successful. CONCLUSION: The results for endopyelotomy were disappointing in patients with crossing vessels, despite using EUS. The results suggest that patients with crossing vessels should be treated by laparoscopic pyeloplasty. More data are needed to compare endopyelotomy with laparoscopic pyeloplasty in patients with no crossing vessels.

Flexible ureteroscopes: a user's guide.

OBJECTIVE: To compare, quantitatively and qualitatively, four small-diameter flexible ureteroscopes. MATERIALS AND METHODS: Four flexible ureteroscopes from different manufacturers, i.e. the DUR-8 (ACMI, Southborough, MA, USA), Olympus UPF-3 (Keymed, Southend-on-Sea, UK), Storz 11274AA (Karl Storz GmbH, Tuttlingen, Germany) and the Wolf 9 F (Henke Sass Wolf GmbH, Tuttlingen, Germany), were assessed quantitatively by measuring the active tip deflection and irrigation flow rate with laser fibres (200 micro m, 365 micro m), an electrohydraulic lithotripter (1.9 F) and grasping forceps (3 F) in position. They were then assessed subjectively by two endourologists who scored them, using a visual analogue scale (maximum 10), for insertion, deflection mechanism, manoeuvrability, rigidity, image quality and overall satisfaction. RESULTS: All the endoscopes are < 9 F at the tip, although the length of the smallest diameter (bevelled tip vs section of shaft) was variable. Tip deflection was 87-100% of the manufacturers' specifications and decreased by similar percentages with instruments in the working channel. The irrigation flow rate was comparable for instruments with a 3.6 F working channel (72-88 mL/min with an empty working channel), although much greater for the Wolf, which has a 4 F channel (116 mL/min). Direction and image size were nearly identical, as was the field of view, apart from the Wolf (60 degrees vs 90 degrees ). There was agreement in the user assessment for three instruments, with overall satisfaction scores being Storz (4), ACMI (7.5) and Olympus (8.6), but disagreement in scores for Wolf (1.9 vs 5.3). CONCLUSIONS: Whilst there were considerable similarities in the objective assessment among the instruments, the user assessment showed qualitative variability. Thus it is important to try the different instruments before selecting one. Additional variables to consider include durability, cost and service/warranty, which vary considerably among instruments.

Urinary catheter 'deflation cuff' formation: clinical audit and quantitative in vitro analysis.

OBJECTIVE: To investigate reports from district nursing staff of difficulty in removing long-term urinary catheters (LTCs) because of the formation of a 'cuff' on deflating the self-retaining balloon. PATIENTS AND METHODS: Problems experienced by district nurses when removing urethral and suprapubic LTCs were audited, noting the type of problem, the catheter and any action taken. Quantitative in vitro studies were conducted on the deflated self-retaining balloons after incubating a similar range of catheters in saline at 37 degrees C for 6 weeks, using suprapubic profilometry to assess the resistance to withdrawal (retention force). RESULTS: Questionnaires were returned on 154 patients with LTCs; 56% had urethral and 44% suprapubic catheters. The catheters were hydrogel-coated (83%), all-silicone (13%) and PTFE-coated (3%). Twenty-two (14%) of the sample reported problems with catheter removal in the previous year, including 15 (68%) with all-silicone catheters and 15 (68%) with suprapubic catheters; cuff formation was noted in 60%. In the laboratory, 10 of the balloons formed a 'cuff' on deflation, but there was great variability in the effect this had on the retention force, with values of 0.5-3 N for different catheters. CONCLUSIONS: Most problems with catheter removal involved all-silicone and suprapubic catheters. Suprapubic profilometry confirmed increased resistance to withdrawal by formation of a 'cuff' on deflation of the balloon of all-silicone catheters. These results suggest that the first choice of catheter material for long-term urethral and suprapubic use should be hydrogel-coated latex.

Plasmodium: assessment of the antimalarial potential of trifluralin and related compounds using a rat model of malaria, Rattus norvegicus.

A rodent model of malaria, Plasmodium berghei was used to assess the antimalarial potential of dinitroaniline herbicides. Trifluralin, pendimethalin, oryzalin, and benfluralin were all active against P. berghei in vitro at, or close to, submicromolar concentrations, with a rank order of potency similar to that against other protozoa. The dinitroanilines did not elicit a cytotoxic effect against a mammalian cell line at concentrations 100-fold higher than those for activity against P. berghei. Neither trifluralin nor oryzalin exhibited any antimalarial activity in vivo after oral administration at the maximum dose tolerated by the host. In a pharmacokinetic study, it was found that the lack of in vivo antimalarial activity was due to poor absorption. Other DNs which have better absorption characteristics than either trifluralin or oryzalin may offer more scope for antimalarial activity in vivo.

Changes in the cause of death among HIV positive subjects across Europe: results from the EuroSIDA study.

OBJECTIVES: The causes of death among HIV-positive patients may have changed since the introduction of highly active antiretroviral therapy (HAART). We investigated these changes, patients who died without an AIDS diagnosis and factors relating to pre-AIDS deaths. METHODS: Analyses of 1826 deaths among EuroSIDA patients, an observational study of 8556 patients. Incidence rates of pre-AIDS deaths were compared to overall rates. Factors relating to pre-AIDS deaths were identified using Cox regression. RESULTS: Death rates declined from 15.6 to 2.7 per 100 person-years of follow-up (PYFU) between 1994 and 2001. Pre-AIDS incidence declined from 2.4 to 1.1 per 100 PYFU. The ratio of overall to pre-AIDS deaths peaked in 1996 at 8.4 and dropped to < 3 after 1998. The adjusted odds of dying following one AIDS defining event (ADE) increased yearly (odds ratio, 1.53; P < 0.001), conversely the odds of dying following three or more ADE decreased yearly (odds ratio, 0.79; P < 0.001). The proportion of deaths that followed an HIV-related disease decreased by 23% annually; in contrast there was a 32% yearly increase in the proportion of deaths due to known causes other than HIV-related or suicides. Injecting drug users (IDU) were significantly more likely to die before an ADE than homosexuals (relative hazard, 2.97; P < 0.0001) and patients from northern/eastern Europe (relative hazard, 2.01; P < 0.0001) were more likely to die pre-AIDS than southern patients. CONCLUSIONS: The proportion of pre-AIDS deaths increased from 1994 to 2001; however, the incidence of pre-AIDS deaths and deaths overall declined. IDU and subjects from northern/eastern Europe had an increased risk of pre-AIDS death. HIV-positive patients live longer therefore it is essential to continue to monitor all causes of mortality to identify changes.

Re-auditing a regional lithotripsy service.

OBJECTIVE: To assess, in a repeat audit of a regional lithotripsy service, whether changes implemented after a regional audit in 1994 (which showed disappointing results from shock wave lithotripsy, attributable to both poor patient selection and an inadequate fixed-site lithotripter) have had any effect. PATIENTS AND METHODS: A data-collection sheet was devised to gather information on the site, size and number of stones treated, together with information on the lithotripsy treatment and outcome. Patients selected for the audit were the first 50 new patients treated with lithotripsy at each centre in 1999. As only one hospital has a fixed-site lithotripsy machine, the results of mobile lithotripsy were grouped by machine for analysis. RESULTS: There was an overall improvement in patient selection from the previous audits. Few stones of > 16 mm or < 4 mm were treated. Two units treated more ureteric stones, thought to reflect first the influence of a fixed-site lithotripter, and second a willingness to insert a ureteric stent and await the next mobile lithotripter visit. The stone free rates were all disappointingly low (16.7-26.7%) but the results improved when fragments of < 4 mm were included as "successful" giving an "overall success rate" of 45.9-66.7%. The unit with a fixed-site lithotripter appeared to perform better (two-thirds successful) than the mobile machines (Modulith SLX, 51%; Modulith SLK, 46%). One centre visited by both mobile machines had a success rate of 65% but a high rate of auxiliary procedures (35% vs 16-19% vs the fixed-site). CONCLUSION: Although these results show some improvement in patient selection for our regional lithotripsy service, stone-free and success rates are poorer than those reported elsewhere. This may reflect the modern lithotripsy machines that allow day-case treatment with minimal analgesia, and confirms reports by other authors who encourage a re-examination of success rates of shock wave lithotripsy.

Laparoscopic lymph node sampling in locally advanced prostate cancer.

OBJECTIVE: To assess the role of laparoscopic lymph node sampling in patients with locally advanced prostate cancer before radical radiotherapy, and to show that the procedure is safe when carried out by urologists with the appropriate training. PATIENTS AND METHODS: Patients were selected prospectively using a combination of prostate-specific antigen (PSA) level, clinical stage and Gleason grade, which predicted a > 20% risk of lymph node metastases. Between October 1998 and March 2001, 50 patients (mean age 65 years, range 54-78) underwent laparoscopic pelvic lymphadenectomy. Age, presenting PSA level, Gleason grade, clinical stage, operative time, length of stay, and any adverse events were recorded. The histology reports were reviewed for the presence of nodal metastases. The selection criteria were compared between the groups with and with no nodal metastases. RESULTS: The mean (range) PSA level of the men was 36.8 (4.4-184) ng/mL and the Gleason grade 6.8 (4-9); 58% had stage T3 disease and 12 patients (24%) had lymph node metastases. There were no statistically significant differences in PSA, Gleason grade or clinical stage between those with positive or negative nodes. The mean operative duration was 110 min, although this decreased from 133 min for the first 10 cases; one case was converted to an open procedure. The median (range) postoperative stay was 1 (1-12) days. There were two major (5%) and seven (17%) minor complications. CONCLUSIONS: This study confirms that laparoscopic lymph nodes can be sampled safely by urologists with experience in laparoscopic surgery. Patients with a significant risk of metastases can be selected preoperatively using a combination of PSA, clinical stage and Gleason grade. Lymph node sampling in this group is necessary, as there is no other method of reliably identifying the subgroup of patients with metastatic disease in which radical conformal radiotherapy cannot be justified.

Regional and temporal changes in AIDS in Europe before HAART.

In a prospective observational study 4,485 patients from 46 clinical centres in 17 European countries were followed between April 1994 and November 1996. Information on AIDS-defining events (ADEs) were collected together with basic demographic data, treatment history and laboratory results. The centres were divided into four geographical regions (north, central, south-west and south-east) so that it was possible to identify any existing regional differences in ADEs. The regional differences that we observed included a higher risk of all forms of Mycobacterium tuberculosis infections (Tb) and wasting disease in the south-west and an increased risk of infections with the Mycobacterium avium complex (MAC) in the north. In Cox multivariable analyses, where north was used as the reference group, we observed hazard ratios of 6.87, 7.77, 2.29 and 0.16 (P < 0.05 in all cases) for pulmonary Tb, extrapulmonary Tb, wasting disease and MAC respectively in the south-west. Pneumocystis carinii pneumonia (PCP) was less commonly diagnosed in the central region (RH = 0.51, 95% CI 0 32-0.79, P = 0.003) and most common in the south-east (RH = 1.04, 95% CI 0.71-1.51, P = 0.85). Comparisons with a similar 'AIDS in Europe' study that concentrated on the early phase of the epidemic reveal that most of the regional differences that were observed in the 1980s still persist in the mid-1990s.

A phase III study of recombinant human interferon gamma to prevent opportunistic infections in advanced HIV disease.

The efficacy and safety of recombinant human interferon gamma (rIFN-gamma) in the reduction of opportunistic disease in patients with advanced HIV-1 infection are assessed. A 12-month double-blind, placebo-controlled, multicenter, Phase III trial of rIFN-gamma in HIV-positive patients with CD4 < 100 x 10(9)/liter on stable antiretroviral therapy. Eighty-four patients were allocated treatment on a 1:1 basis to rIFN-gamma or placebo. Patients received rIFN-gamma 0.05 mg/m(2) or 0.9% saline subcutaneously three times weekly for 48 weeks (optional extension to 18 months). The primary end point was the incidence of opportunist infections (CDC categories B/C). Secondary end points included mortality, immunological, and virological parameters. Patients on placebo had a mean of 3.45 opportunist infections (OIs) in the first 48 weeks. Patients treated with rIFN-gamma had a mean of 1.71 OIs (p = 0.04). However, the model showed overdispersion and the inclusion of a dispersion factor raised the p value to 0.13. rIFN-gamma appeared to have a particular effect on the incidence of Candida, herpes simplex, and cytomegalovirus infections. Three-year survival in the rIFN-gamma arm was 28% compared to 18% in the placebo group (not significant). rIFN-gamma-associated side-effects of headache, fatigue, rigors, influenza-like symptoms, depression, myalgia, and granulocytopenia were reversible. There was no evidence for HIV activation. Although not significant, the trend towards decreased opportunistic infections and increased survival warrants consideration of further trials of rIFN-gamma. The study gives additional information on the safety profile of this cytokine.

Graded challenge in an aciclovir allergic patient.

An immunocompetent woman presented with a hypersensitivity skin reaction following suppressive therapy with aciclovir for recurrent culture proved genital herpes simplex virus infection. She developed a similar reaction when treatment was changed to famciclovir. Without antiviral suppression her recurrences were frequent and distressing. Graded challenge was performed and she became tolerant to aciclovir. She successfully continued suppressive therapy for 1 year with no further hypersensitivity reactions or recurrences.