Evaluation of the morphological effects of TDT 067 (terbinafine in Transfersome) and conventional terbinafine on dermatophyte hyphae in vitro and in vivo.

TDT 067 is a novel, carrier-based dosage form of terbinafine in Transfersome (1.5%) formulated for topical delivery of terbinafine to the nail, nail bed, and surrounding tissue. We examined the effects of TDT 067 and conventional terbinafine on the morphology of dermatophytes. Trichophyton rubrum hyphae were exposed to TDT 067 or terbinafine (15 mg/ml) and examined under white light, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Subungual debris from patients treated with TDT 067 in a clinical trial was also examined. Exposure of T. rubrum hyphae to TDT 067 led to rapid and extensive ultrastructural changes. Hyphal distortion was evident as early as 4 h after exposure to TDT 067. After 24 h, there was complete disruption of hyphal structure with few intact hyphae remaining. Exposure to terbinafine resulted in morphological alterations similar to those seen with TDT 067; however, the effects of TDT 067 were more extensive, whereas a portion of hyphae remained intact after 24 h of exposure to terbinafine. Lipid droplets were observed under TEM following 30 min of exposure to TDT 067, which after 24 h had filled the intracellular space. These effects were confirmed in vivo in subungual debris from patients with onychomycosis who received topical treatment with TDT 067. The Transfersome in TDT 067 may potentiate the action of terbinafine by delivering terbinafine more effectively to its site of action inside the fungus. Our in vivo data confirm that TDT 067 can enter fungus in the nail bed of patients with onychomycosis and exert its antifungal effects.

Frequent oral ulceration during early disease may predict a severe disease course in males with Behçet's syndrome.

OBJECTIVES: The numbers and recurrence rates of mucocutaneous manifestations can be highly variable among patients with Behçet's syndrome (BS) but it is not known whether these differences influence the disease course at the long-term. METHODS: We evaluated the outcome of 30 patients that made up the placebo arm of a 6 months controlled trial of thalidomide and looked at the relation between the frequencies of mucocutaneous manifestations during the trial and the development of major organ involvement necessitating immunosuppressives during the post-trial period. RESULTS: Fifteen (50%) patients had received immunosuppresives for major organ involvement during the post-trial period. Patients receiving immunosuppressive treatment were significantly younger at the onset of BS compared to those who did not (24.5±5 vs. 29.7±3.8 SD years; p=0.003). The mean number of oral ulcers recorded throughout the trial was significantly higher among patients using immunosuppressives compared to those who did not (2.09±0.96 vs. 1.43±0.8; p=0.029). This significance disappeared when adjusted for age of onset of BS (p=0.16). ROC curve analysis showed that having 10 or more ulcers during 6 months has a sensitivity of 86.7% and a specificity of 53% for the subsequent necessity of immunosuppressive use. The same association was not true for genital ulcers, follicular lesions and erythema nodosum. CONCLUSIONS: These findings on a limited number of patients suggest that frequent occurrence of oral ulceration during the initial years of the disease may predict the development of major organ involvement in men with BS.

Clinical implications of velocity vector imaging-based two dimensional strain imaging for the evaluation of left ventricular systolic functions.

Two-dimensional (2D) echocardiography is the most common imaging modality used to assess left ventricular (LV) myocardial function. Although the studies revealed useful conclusions, there are some limitations with the conventional measurement of ejection fraction. Two dimensional (2D) strain imaging is newer echocardiographic technique which is utilized for the evaluation of quantitative regional ventricular functions. Velocity vector imaging based- 2D strain imaging is the most recent technology with a few advantages sourced by its software. This review introduces a novel 2D strain imaging technology, explains its fundamental concepts and discusses clinical applications with all the major advantages and limitations.

Management of Behçet disease: a systematic literature review for the European League Against Rheumatism evidence-based recommendations for the management of Behçet disease.

OBJECTIVES: To present and analyse the literature sources regarding the management of Behçet disease (BD) identified during the systematic literature research, which formed the basis for the European League Against Rheumatism (EULAR) evidence-based recommendations for the management of BD. METHODS: Problem areas and related keywords regarding the management of BD were determined by the multidisciplinary expert committee commissioned by EULAR for developing the recommendations. A systematic literature research was performed using MedLine and Cochrane Library resources through to December 2006. Meta-analyses, systematic reviews, randomised controlled trials (RCTs), open studies, observational studies, case control studies and case series' involving > or = 5 patients were included. For each intervention the effect size and number needed to treat were calculated for efficacy. Odds ratios and numbers needed to harm were calculated for safety issues of different treatment modalities where possible. RESULTS: The literature research yielded 137 articles that met the inclusion criteria; 20 of these were RCTs. There was good evidence supporting the use of azathioprine and cyclosporin A in eye involvement and interferon (IFN)alpha in mucocutaneous involvement. There were no RCTs with IFNalpha or tumour necrosis factor (TNF)alpha antagonists in eye involvement. Similarly controlled data for the management of vascular, gastrointestinal and neurological involvement is lacking. CONCLUSION: Properly designed, controlled studies (new and confirmatory) are still needed to guide us in managing BD.

EULAR recommendations for the management of Behçet disease.

OBJECTIVES: To develop evidence-based European League Against Rheumatism (EULAR) recommendations for the management of Behçet disease (BD) supplemented where necessary by expert opinion. METHODS: The multidisciplinary expert committee, a task force of the EULAR Standing Committee for Clinical Affairs (ESCCA), consisted of nine rheumatologists (one who was also a clinical epidemiologist and one also a Rehabilitation Medicine doctor), three ophthalmologists, one internist, one dermatologist and one neurologist, representing six European countries plus Tunisia and Korea. A patient representative was also present. Problem areas and related keywords for systematic literature research were identified. Systematic literature research was performed using Medline and the Cochrane Library databases from 1966 through to December 2006. A total of 40 initial statements were generated based on the systematic literature research. These yielded the final recommendations developed from two blind Delphi rounds of voting. RESULTS: Nine recommendations were developed for the management of different aspects of BD. The strength of each recommendation was determined by the level of evidence and the experts' opinions. The level of agreement for each recommendation was determined using a visual analogue scale for the whole committee and for each individual aspect by the subgroups, who consider themselves experts in that field of BD. There was excellent concordance between the level of agreement of the whole group and the "experts in the field". CONCLUSION: Recommendations related to the eye, skin-mucosa disease and arthritis are mainly evidence based, but recommendations on vascular disease, neurological and gastrointestinal involvement are based largely on expert opinion and uncontrolled evidence from open trials and observational studies. The need for further properly designed controlled clinical trials is apparent.

Anti-Saccharomyces cerevisiae antibodies (ASCA) in Behçet's syndrome.

OBJECTIVES: Anti-Saccharomyces cerevisiae antibodies (ASCA) are found in 50-60% of patients with Crohn's disease. Increased as well as normal levels have been reported in Behçet's syndrome (BS). We reassessed the level of IgG and IgA ASCA antibodies in BS and in a group of diseased and healthy controls. METHODS: Eighty-five patients with BS were studied along with 20 patients with ankylosing spondylitis (AS), 24 with Crohn's disease (CD), 25 with ulcerative colitis (UC) and 21 healthy volunteers. A commercial ELISA kit was used (Inova Diagnostics). RESULTS: It was only the patients with CD who had significantly higher levels of antibodies compared with the rest of the group (ANOVA: ASCA IgG, p = 0.0001; ASCA IgA, p = 0.0001). 42% of CD, 4% of BS, 4% of UC and 15% of AS patients had a positive IgG+IgA ASCA. There was a significant trend for patients with gastrointestinal (GI) involvement with BS (n = 8) to be more positive for IgG and IgG+IgA ASCA compared to the rest of the patients with BS (n = 77) (Chi-square, IgG, p = 0.02, IgG+IgA, p = 0.001). CONCLUSION: The rate of positivity of ASCA in BS is comparable to that observed among patients with UC and AS. Patients with BS who have GI involvement may have higher levels of ASCA and this needs to be further studied.

Fibrinolytic activity and d-dimer levels in Behçet's syndrome.

OBJECTIVE: Thrombophlebitis occurs in a third of patients with Behçet's syndrome (BS). The thrombotic tendency in BS has been studied with inconclusive results perhaps due to the inadequate numbers of patients studied during the acute phase of the thrombosis as well as the lack of appropriate diseased controls. We have studied tissue-type plasminogen activator (t-PA) and its inhibitor (PAI-1), and d-dimer levels in BS patients with and without thrombosis both in the acute and chronic phases along with suitable diseased and healthy controls. METHODS: t-PA and PAI-1 were studied by ELISA and d-dimer by semiquantitative latex agglutination slide test in 30 BS patients without deep vein thrombosis (DVT), 10 BS with acute DVT (ADVT), 25 BS with chronic DVT, 27 with ankylosing spondylitis, 26 diffuse systemic sclerosis, 15 patients with ADVT due to other causes, 10 patients with sepsis, and 23 healthy controls. RESULTS: The t-PA levels in BS with ADVT were significantly lower than those in patients with ADVT due to other causes (7.4 +/- 6.2 vs. 13.4 +/- 6.3, P = 0.027) while PAI-1 levels did not show significant differences between the groups (P = 0.60). The numbers of patients with d-dimer levels of > or = 0.5 microg/ml in BS with ADVT were similar to those found in patients with ADVT due to other causes (9/10 vs. 14/14). CONCLUSION: The relatively low t-PA levels point to a defect in fibrinolysis in BS. d-dimer levels are increased in the acute phase of thrombosis in BS.

Neurologic involvement in Behçet's syndrome. A prospective study.

We investigated the prevalence and type of neurologic involvement in Behçet's syndrome in a prospective protocol. Of 323 consecutive patients with Behçet's syndrome seen during a 12-month period, 46 underwent neurologic evaluation because of headaches and/or neurologic symptoms and signs. Only 17 (5.3%) were found to have involvement of the nervous system. Hemispheric lesions were as common as brain-stem involvement. Headaches were of no clinical importance unless accompanied by other neurologic findings. Computed tomographic scans were of little diagnostic help. After 12 +/- 4 (SD) months of follow-up, only three patients showed worsening of their neurologic findings.

Seven-year follow-up of neurologic involvement in Behçet syndrome.

OBJECTIVE: To determine the long-term prognosis of neurologic involvement in Behçet syndrome. DESIGN: Forty-six patients with Behçet syndrome, who had been the subjects of a previous report with short-term follow-up, were reexamined 7 years later; 42 of them could be reexamined neurologically. Neuropsychological testing, magnetic resonance imaging, electromyography, and evoked potential studies were performed when available. RESULTS: Of the 27 patients who had had headaches without any neurologic symptoms or signs previously, 2 had developed an acute neurologic attack. In addition, 7 patients in this group showed minor abnormalities on neurologic examination and/or other laboratory investigations, without history of any attacks. Among the previous neuro-Behçet group (n = 15), as defined by the presence of neurologic signs or symptoms, other than headache, 7 had a stationary course, while 8 had been progressive. Three of the latter group had died. Patients with progressive course had had abnormal cerebrospinal fluid findings at the time of the previous report, whereas patients with a stationary course had not. CONCLUSIONS: Silent neurologic involvement may occur in Behçet syndrome. Patients should undergo periodic neurologic evaluation. The long-term prognosis in neuro-Behçet syndrome does not seem to be as favorable as we observed in short-term follow-up. Cerebrospinal fluid findings may predict prognosis.

Management of aneurysms in Behçet's syndrome: an analysis of 24 patients.

BACKGROUND: The surgical therapy of Behçet aneurysms is often unsuccessful, resulting in graft occlusions, anastomoses, and/or new aneurysms. METHODS: Twenty-nine aneurysms were documented in 24 Behçet's patients during a period of 19 years. All patients were male, ranging in age from 20 to 53 years (mean, 35 +/- 7.3 years). The mean duration of disease was 9 +/- 5 years. There were nine abdominal aorta, four iliac, three common femoral, five superficial femoral, four popliteal, one subclavian, one carotid, and one posterior tibial artery aneurysm. In addition, in one patient an aneurysm developed from the arterialized venous conduit that had been inserted for a common femoral artery aneurysm elsewhere. Five patients were already under immunosuppressive therapy for ocular problems at the time of diagnosis. Fifteen patients received immunosuppressive therapy after operation. We performed one abdominal aneurysmorrhaphy, two iliac artery PTFE graft interpositions, two aortobiliac bypasses (PTFE), six aortic tube graft (three PTFE, three Dacron) interpositions, one avrtofemoral bypass (PTFE), two iliofemoral bypasses (PTFE), two superficial femoral artery graft (PTFE) interpositions, and three popliteal graft interpositions (one PTFE, two vein graft). Also as an initial procedure one carotid, one subclavian, four superficial femoral, one popliteal, and one posterior tibial artery were ligated. RESULTS: Nineteen patients were followed up for a mean duration of 47.3 +/- 27 months (range, 1 to 108 months). The patient with a subclavian aneurysm died of massive bleeding on postoperative day 15. Four patients were lost to follow-up. In the abdominal aortic aneurysm group one patient died of gastrointestinal bleeding 4 years after the operation. Another patient from the same group died 5 years after operation without any vascular disease. In the common femoral artery group the patient with an occluded iliofemoral graft died of an exsanguinating pulmonary artery aneurysm in the first year after operation. Overall, there were five anastomotic aneurysms. In addition, after the initial operation two iliofemoral, one aortofemoral, and one popliteal interposition graft were occluded without disabling ischemia. CONCLUSIONS: Aneurysms limited to the extremities could be ligated without disabling ischemia. Abdominal aortic aneurysms could be treated with tube graft insertion, giving satisfactory results. Patients could tolerate graft occlusion without major ischemia.

Surgical therapy of pulmonary arterial aneurysms in Behçet's syndrome.

Two patients with Behçet's syndrome were operated for exsanguinating pulmonary artery aneurysm into a bronchus. Lower lobectomy was performed in the first patient. He died of hypoxia and sepsis on the 8th postoperative day. Pneumonectomy was undertaken in the second patient, who is well 30 months after the operation.

Short term cyclosporin A treatment of Behçet's disease.

Eleven separate three-month courses of cyclosporin A, an oral solution 10 mg/kg/day, were administered to eight patients with Behçet's disease with sight-threatening posterior uveitis. It was found to be effective in arresting the inflammatory activity in the eye as well as the mucocutaneous lesions of Behçet's disease. Improvement in visual acuity was observed within one week of starting therapy. Severe exacerbations in the ocular and mucocutaneous lesions occurred on withdrawal of the drug. At this dosage side effects included hirsutism in all women, and a slight rise of serum bilirubins in two patients and of blood urea in one patient. The latter two conditions responded rapidly to dose adjustment.

Low dose cyclosporin A versus pulsed cyclophosphamide in Behçet's syndrome: a single masked trial.

A single masked trial of cyclosporin A 5 mg/kg/day versus monthly 1 g intravenous boluses of cyclophosphamide was conducted among 23 patients with Behçet's syndrome and active, potentially reversible uveitis. The trial was unmasked after a mean of 12 (SD 2) months for the cyclosporin A group (n = 12) and a mean of 10 (SD 3) months for the cyclophosphamide group (n = 11). During the initial 6 months the visual acuity significantly improved (p < 0.001) in the cyclosporin A group whereas this was not observed in the cyclophosphamide group. The subsequent follow-up of patients up to 24 months suggested that the initial improvement in visual acuity with cyclosporin A was not sustained. More extensive and especially long-term studies of cyclosporin A in the uveitis of Behçet's syndrome are warranted.

Inefficacy of azapropazone in the acute arthritis of Behçet's syndrome: a randomized, double blind, placebo controlled study.

Sixty-three consecutive Behçet's syndrome patients with an acute arthritis of up to 10 days duration were treated either with azapropazone (APZ) 300 mg t.i.d. or placebo for three weeks. Twenty-eight patients (14 males, 14 females: mean age 36.2 +/- 8.1 SD years) from the APZ group and 29 patients (18 males, 11 females; mean age 34.2 +/- 8.4 SD years) from the placebo group completed the trial. At the end of the trial the arthritis persisted in 53.5% (15/28) of the APZ patients and in 41.3% (12/29) of the placebo patients (chi 2 = 0.85; NS). Six patients (6/28; 21%) from the APZ group and 9 patients (9/29; 31%) from the placebo group developed new joint involvement (chi 2 = 0.7; NS). There was no difference in the duration of arthritis between the two groups (19.9 +/- 8.3 SD days in the APZ groups vs. 19.7 +/- 8.2 SD days in the placebo group; NS). The degree of joint swelling, the tender joint score and the visual analogue score for pain significantly improved in both groups, but there was no difference in any of these parameters between the groups except for a significant difference in the visual analogue score for less pain at the first week in the azapropazone group (t = 2.23; p < 0.05). There were also no differences in the mean numbers of acetaminophen tablets used or in the CRP and ESR levels between the two groups. We conclude that azapropazone is not effective in controlling the arthritis of Behçet's syndrome.

Topical alpha interferon in the treatment of oral ulcers in Behçet's syndrome: a preliminary report.

The effect of topical recombinant interferon alfa 2c hydrogel (IFN alpha 2C) in the aphthous lesions of the mouth in Behcet's syndrome was assessed in twenty patients in a twelve-week open trial. IFN alpha 2C applied to the mouth for four weeks significantly reduced the number of aphthae in the post-treatment phase compared to the pretreatment and treatment phases. No side effects were recorded. Topical IFN alpha 2C seems to be effective in the treatment of the aphthae in Behcet's syndrome.

Male patients with Behçet's syndrome have stronger pathergy reactions.

The effects of patient's sex and age at onset on the pathergy reaction (cutaneous hypersensitivity to a needle prick) and its correlation with disease activity in Behcet's syndrome was investigated by two independent observers in a blind protocol. Among 92 male patients the pathergy reaction was more strongly positive (p less than 0.025) than among 67 female patients of similar age and disease duration. The age at onset did not affect the severity of the pathergy reaction, although, the early onset females (age at onset 24 years or less) had the lowest prevalence of pathergy positivity (52%), compared to early onset males and late onset (age at onset 25 years or more) males and females (73-75%). As previously reported the disease was more severe among males and among those with early onset of either gender. On the other hand, no correlation between the strength of the pathergy reaction and clinical severity could be discerned.

HLA antigens in recurrent oral ulceration: evidence against a common disease spectrum with Behçet's syndrome.

Among 50 patients with recurrent oral ulceration (ROU) the prevalence of HLA B5 was not increased as was the case among 50 patients with Behçet's Syndrome (BS) compared to 52 healthy controls. On the other hand, HLA DR4 was present in 16 of 30 (53%) patients with ROU whereas the same allele was present in 16% of BS patients and 22% of the healthy controls. These findings suggest that ROU and BS are not in the same disease spectrum.

Sebum production is increased in Behçet's syndrome and even more so in rheumatoid arthritis.

Sebum production is under hormonal control. We had shown that male sex is associated with more severe disease in Behçet's syndrome and the acneiform skin lesion of this disorder is not different from ordinary acne, an androgen-dependent lesion. Sebum excretion rate was higher in patients with Behçet's syndrome than in healthy controls, children and patients with ankylosing spondylitis. On the other hand, patients with rheumatoid arthritis had high levels of sebum excretion rate comparable to those found in patients with acne vulgaris. These suggest the presence of a sebotrophic hormone and/or other hormonal effects in Behçet's syndrome and rheumatoid arthritis.

Juvenile chronic arthritis in a Turkish population.

The clinical characteristics of 147 Turkish patients with juvenile chronic arthritis seen between 1980 and 1988 were analyzed retrospectively. There was a male predominance (1.3:1), and a relatively low occurrence of early onset pauciarticular disease (16%), chronic anterior uveitis (7%) and positive antinuclear antigens (6%), but a high incidence of secondary amyloidosis (10%) was seen.

Secondary amyloidosis in progressive systemic sclerosis.

Progressive systemic sclerosis (PSS) is a connective tissue disease that may affect many organs, including the kidneys. It is quite rare to see secondary amyloidosis due to PSS. We present a patient with a 9-year history of PSS who developed nephrotic syndrome, and whose renal biopsy was compatible with secondary amyloidosis. He died from massive upper gastrointestinal bleeding caused by oesophageal telangiectasia.