Long-term effectiveness and safety of secukinumab for treatment of refractory mucosal and articular Behçet's phenotype: a multicentre study.

OBJECTIVE: To evaluate the effectiveness and safety of secukinumab in patients with a mucosal and articular Behçet's phenotype resistant to conventional and biologic treatment. METHODS: A multicentre retrospective study was performed on 15 patients with a mucosal and articular phenotype of Behçet's syndrome fulfilling the International Criteria for Behçet's Disease and refractory to treatment with colchicine, disease-modifying antirheumatic drugs and at least one antitumour necrosis factor-α agent. Minimum follow-up was set at 6 months. Six patients with a polyarticular involvement were treated with secukinumab 300 mg/month, while all other cases received secukinumab 150 mg/month. Dose increase from 150 to 300 mg per month and shortening of administration frequency were allowed for poor disease control. Response evaluation was based on the number of oral ulcers in the previous 28 days and Disease Activity Score-28 for articular manifestations. RESULTS: At 3 months of follow-up, nine (66.7%) patients achieved a response (complete or partial), and this proportion further increased to 86.7% at 6 months, 76.9% at 12 months, 90.0% at 18 months and 100.0% after 24 months. Notably, all patients who started with secukinumab 300 mg/month achieved complete response by month 6. Seven (46.7%) patients could achieve a response only after switching to a higher dosage. CONCLUSIONS: Our study suggests that secukinumab at a dose of 150 and 300 mg per month is safe and effective for the long-term treatment of patients with Behçet's syndrome with a mucosal and articular phenotype refractory to previous treatments. Notably, secukinumab 300 mg/month resulted in superior complete mucosal and articular responses with no serious or dose-related adverse effects.

Systemic sclerosis, birth order and parity.

AIM: A recent study identified increasing birth order to be a risk factor for the development of systemic sclerosis (SSc). This finding supports the theory that transplacental microchimerism may be a key pathological event in the initiation of SSc. We investigated the relationship between birth order and parity and the age of onset of SSc in South Australia. METHOD: A retrospective analysis of patient data in the South Australian Scleroderma Register was performed. Data were obtained from a mailed questionnaire. Control data was collected prospectively using a similar questionnaire. The relationship between birth order, family size or parity and risk of subsequent development of SSc was analyzed by mixed effects logistic regression analysis. RESULTS: Three hundred and eighty-seven index probands were identified and compared with 457 controls. Controls were well matched for gender, but not for age. No statistically significant relationship was identified between SSc and birth order, parity in females, family size, age at first pregnancy in females or gender of first child in parous females. CONCLUSION: Our data suggests that parity, age at first pregnancy and the gender of the first child are not relevant factors in our understanding of the epidemiology and pathogenesis of SSc. Birth order and family size in both genders also appears irrelevant. These results argue against microchimerism as being relevant in the pathogenesis of SSc and add further support to the theory that stochastic events may be important in the etiopathogenesis of SSc.

Antimicrobial peptide coating of dental implants: biocompatibility assessment of recombinant human beta defensin-2 for human cells.

PURPOSE: Artificial materials such as dental implants are at risk of bacterial contamination in the oral cavity. Human beta defensins (HBDs), small cationic antimicrobial peptides that exert a broad-spectrum antibacterial function at epithelial surfaces and within some mesenchymal tissues, could probably help to reduce such contamination. HBDs also have protective immunomodulatory effects and have been reported to promote bone remodeling. The aim of this study, therefore, was to investigate the influence of recombinant HBD-2 on the proliferation and survival of cells in culture. MATERIALS AND METHODS: Human mesenchymal stem cells (hMSCs), human osteoblasts, human keratinocytes (control), and the HeLa cancer cell line (control) were incubated with recombinant HBD-2 (1, 5, 10, or 20 µg/mL). Cell proliferation and cytotoxicity were evaluated via a water-soluble tetrazolium salt (WST-1) and lactate dehydrogenase assays, respectively. RESULTS: HBD-2 was not toxic in any tested concentration to hMSCs, osteoblasts, keratinocytes, or HeLa cells. Furthermore, proliferation of hMSCs and osteoblasts increased after treatment with HBD-2 at all tested concentrations, and keratinocyte proliferation increased when treated at 20 µg/mL. In contrast, HeLa cancer cells were not affected by HBD-2 as tested. CONCLUSIONS: HBD-2 is not only biocompatible but also promotes proliferation of hMSCs, osteoblasts, and keratinocytes in culture. Further investigation of HBD-2 functional surface coating of artificial materials is recommended.

Leflunomide for inflammatory arthritis in end-stage renal disease on peritoneal dialysis: a pharmacokinetic and pharmacogenetic study.

OBJECTIVE: To study the pharmacokinetics and pharmacogenetics of leflunomide and document its efficacy and safety in the treatment of inflammatory arthritis in a patient with end-stage renal disease (ESRD) who was on peritoneal dialysis. CASE SUMMARY: Therapy for a 78-year-old man with ESRD who required peritoneal dialysis was started with leflunomide 10 mg/day for psoriatic arthritis. The dosage was increased to 20 mg/day after 3 months. Monitoring was continued until the patient's unexpected death from myocardial infarction at 8 months. Total and unbound teriflunomide (the active metabolite of leflunomide) concentrations were measured by liquid-chromatography-tandem mass spectrometry. Genotyping for CYP2C19 and ABCG2 polymorphisms, both known to influence teriflunomide pharmacokinetics, was also performed. DISCUSSION: Total concentrations of teriflunomide varied between 5.2 and 23.2 mg/L, while unbound concentrations varied between 0.0306 and 0.1468 mg/L. The unbound fraction varied between 0.367% and 0.71%. Teriflunomide was found in the dialysate at a concentration of 0.0981 mg/L. A single CYP2C19 loss of function allele was present, as was wild-type ABCG2. Leflunomide appeared to be therapeutically effective, as evidenced by a reduction in daily prednisolone dosage from 20 mg to 6mg; the Disease Activity Score in 28 joints (DAS28) was 5.46 at enrollment and 4.03 after 7 months. Health Assessment Questionnaire-Disability Index improved from 0.5 to 0.125 at 7 months. Numerous significant adverse events that were considered unrelated to leflunomide occurred. CONCLUSIONS: Dose adjustment for leflunomide does not appear to be required in the context of ESRD requiring peritoneal dialysis. We present novel evidence that a small amount of teriflunomide is removed by peritoneal dialysis. This case suggests that leflunomide is safe to use as therapy for inflammatory arthritis despite the presence of ESRD requiring peritoneal dialysis.

Facial self-perception, well-being, and aesthetic surgery.

BACKGROUND: It is controversial whether impaired well-being is associated with (a) an increased likelihood of having a negative body/facial image; or (b) dissatisfaction with the postoperative result following aesthetic surgery. We set out to improve current knowledge in this matter. METHODS: A total of 324 subjects (n = 162 females, n = 162 males, 18-30 years) were photographed, asked to complete the adjective mood scale and to rate 46 statements regarding their own appearance, and its impact on social functioning as well as their willingness to undergo aesthetic surgery on a visual analog scale. The photographs of these subjects were also assessed by 50 independent judges. RESULTS: Average self-awarded ratings of appearance were significantly more positive in subjects with normal as compared to those with impaired well-being (P = 0.014). Items regarding the impact of appearance on social functioning were answered significantly more negatively by subjects with impaired well-being as compared with those with the normal well-being (P = 0.001). Subjects with impaired well-being did not declare an increased willingness to undergo aesthetic surgery (P > 0.197). Assessment by the independent judges did not reveal differences in the average level of attractiveness of subjects with impaired well-being and those with normal well-being (P = 0.666). CONCLUSIONS: Impaired well-being is associated with impaired facial selfperception, independent of attractiveness. Willingness to undergo aesthetic surgery seems not to be affected by one's sense of well-being. In the subjects with impaired well-being who undergo aesthetic surgery, facial self-perception seems unlikely to be improved.

Antimicrobial Peptide immunity protects human nasal and auricular cartilage against infection.

BACKGROUND: Despite being impervious to surveillance by the adaptive immune system because of its lack of vascularity, infection of the nasal and auricular cartilage after surgery such as rhinoplasty or otoplasty is rare. Why is this so? Our goal was to determine whether the expression of antimicrobial peptides provides a previously unrecognized nonepithelial layer of innate immune defense within the nasal and auricular cartilage. MATERIALS AND METHODS: Seven samples of nasal septum cartilage and 2 biopsies from auricular cartilage grafts were harvested during rhinoplasty and otoplasty procedures. Ten cadaveric samples of auricular and 9 samples of nasal cartilage were also obtained. Immunohistochemical staining was directed against the human beta-defensin antimicrobial peptides (hBD) 1, 2, and 3. A semiquantitative analysis was performed to measure immunoreactivity. RESULTS: All 3 human beta-defensins were detected along the perichondral line and within the cartilage matrix in the nasal and auricular samples. Areas with positive immunohistochemical staining were also detected within chondrocyte cytoplasm. CONCLUSIONS: We provide the first evidence of antimicrobial peptide expression (hBD-1, -2 and -3) within the perichondrium and cartilage matrix layers of the nasal and auricular cartilage. This previously unrecognized innate immune function of perichondrocytes and chondrocytes may explain the resistance of the nasal and auricular cartilage to infection after surgical procedures despite the absence of a vascular system.

The battle against multi-resistant strains: Renaissance of antimicrobial essential oils as a promising force to fight hospital-acquired infections.

Hospital-acquired infections and antibiotic-resistant bacteria continue to be major health concerns worldwide. Particularly problematic is methicillin-resistant Staphylococcus aureus (MRSA) and its ability to cause severe soft tissue, bone or implant infections. First used by the Australian Aborigines, Tea tree oil and Eucalyptus oil (and several other essential oils) have each demonstrated promising efficacy against several bacteria and have been used clinically against multi-resistant strains. Several common and hospital-acquired bacterial and yeast isolates (6 Staphylococcus strains including MRSA, 4 Streptococcus strains and 3 Candida strains including Candida krusei) were tested for their susceptibility for Eucalyptus, Tea tree, Thyme white, Lavender, Lemon, Lemongrass, Cinnamon, Grapefruit, Clove Bud, Sandalwood, Peppermint, Kunzea and Sage oil with the agar diffusion test. Olive oil, Paraffin oil, Ethanol (70%), Povidone iodine, Chlorhexidine and hydrogen peroxide (H(2)O(2)) served as controls. Large prevailing effective zones of inhibition were observed for Thyme white, Lemon, Lemongrass and Cinnamon oil. The other oils also showed considerable efficacy. Remarkably, almost all tested oils demonstrated efficacy against hospital-acquired isolates and reference strains, whereas Olive and Paraffin oil from the control group produced no inhibition. As proven in vitro, essential oils represent a cheap and effective antiseptic topical treatment option even for antibiotic-resistant strains as MRSA and antimycotic-resistant Candida species.

Nasal shape and gender of the observer: implications for rhinoplasty.

BACKGROUND: In a previous study we focused on gender specific nasal shapes. The aim of this study was to evaluate if preferences in nasal shape are also dependent on the gender of the observer. METHODS: Stratified on the basis of each photographed subject's (n=311) own evaluation, female and male composite pictures of "average" (n=128, each), "optimal" (n=16, each) and "most unpleasant" (n=8, each) noses were created in a previous study. These composites were assessed by 308 independent female and male judges using a visual analogue scale. RESULTS: On average, female judges were found to accord significantly higher ratings of attractiveness as compared to male judges for the composite images independent of the gender of the person shown (p=0.020). The difference was greatest when assessing most unpleasant male composites (p<0.003) but was not apparent when assessing "optimal" female and "optimal" male noses. Despite this, women displayed the same preferences for "optimal" and "average" noses as compared to the "most unpleasant" noses. In assessing their own noses, women were significantly less satisfied with their appearance in general (p=0.001) as compared to men. CONCLUSIONS: In comparison to men, women are more critical in assessing the appearance of their own nose as opposed to the noses of other people. The implications of this for rhinoplasty, so far as considering the degree of influence of the gender of a person assessing a prospective patient's nose remains a matter of conjecture.

Melanocytic schwannoma of the cutaneous and subcutaneous tissues: three cases and a review of the literature.

Melanocytic schwannoma is a rare soft-tissue tumor, which arises most commonly in the paraspinal sympathetic chain. In general, 25% of the patients develop metastasis. To date, only 17 cases of a cutaneous and subcutaneous melanocytic schwannoma have been reported. None of these patients developed metastasis. Three cases of cutaneous melanocytic schwannoma, diagnosed in our institution are reported. For further literature overview we performed a search on Medline using the terms 'melanocytic schwannoma' or 'melanotic schwannoma' or 'Carney complex' combined with 'skin' or 'cutaneous', for the period 1970-2007. Seventeen patients were described to have melanocytic schwannoma of the skin or subcutaneous tissues. These papers were reviewed for clinical data. Two of the three patients showed metastatic disease, one of them died of disseminated metastases. In contrast, none of the reported cases of cutaneous or subcutaneous melanocytic schwannomas was characterized by a malignant course. The differential diagnosis, especially with regard to malignant melanoma, is made by histology and by its clinical course, which differs from melanoma in its tendency to recur at the site of excision and slow rate of growth. Commonly misdiagnosed as melanoma, this tumor reveals insights into the origin of both melanocytes and Schwann cells. It is likely that the biological bases for melanoma and melanocytic schwannoma differ. It is necessary to differentiate this tumor from melanoma because of the differing prognosis and the association of melanocytic schwannoma with the Carney complex. Owing to the lack of clinical trials, we recommend that patients be treated according to the existing guidelines for melanoma.

Penicillin compared with other advanced broad spectrum antibiotics regarding antibacterial activity against oral pathogens isolated from odontogenic abscesses.

OBJECTIVES: We examined the spectrum of oral pathogens found in odontogenic abscesses and their susceptibility to penicillin as well as to amoxicillin with clavulanic acid, doxycycline, clindamycin and moxifloxacin. The in vitro results were compared with clinical observations. PATIENTS AND METHODS: One hundred and eighty eight swabs were obtained from 94 patients with odontogenic abscesses. Bacterial strains were isolated for susceptibility tests. The same patients were investigated for their clinical outcome after standard therapy. RESULTS: A total of 517 bacterial strains were isolated from 94 patients. Ninety eight per cent of abscesses were polymicrobial. The most prevalent bacteria were Viridans streptococci representing 54% of the aerobic/facultative anaerobic bacteria. Prevotella spp. comprised 53% of the anaerobes. No multiresistant strains were detected. Susceptibility testing revealed a sensitivity of over 99% of aerobes/facultative aerobes and 96% of anaerobes sensitivity for moxifloxacin. The corresponding values for penicillin were lowest at 61% and 79%, respectively. In the clinical collective, patients with minor abscesses and no risk of further progression received surgical treatment without antibiotics (36%). Penicillin was administered additionally in 30%. Amoxicillin with clavulanic acid was given in 18% and clindamycin in 15%. Ninety two of the 94 patients showed significant recovery with the described treatment. Only in two cases was a change to the latest broader spectrum antibiotics necessary. CONCLUSION: In contrast to the moderate in vitro results, penicillin successfully treated the pathogens derived from odontogenic abscess sufficiently when adequate surgical treatment was provided. One third of the patients was treated successfully with incision and drainage only. We suggest that one good reason for its clinical efficacy is the susceptibility of the dominant aerobe/facultative aerobe and anaerobe strains to penicillin.

Long-term efficacy of subcutaneous sweat gland suction curettage for axillary hyperhidrosis: a prospective gravimetrically controlled study.

BACKGROUND: Subcutaneous sweat gland suction curettage (SSGSC) is gaining acceptance as a therapy for axillary hyperhidrosis. Despite its acceptance, there remains a lack of prospective data describing the efficacy and long-term outcome of SSGSC. OBJECTIVE: We examined the sweat rates and patients' satisfaction of 12 months following SGSC in 28 patients with axillary hyperhidrosis. METHODS: Axillary sweat rates were determined by semiquantitative gravimetry. A questionnaire was used to determine patients' satisfaction. RESULTS: A 58% reduction in sweat rate under resting conditions and an 85% reduction during aerobic exercise in sweat rates was observed. A subdivision of patients into three groups based on their baseline preoperative sweat rates (<25, 25-50, and >50 mg/min) showed that patients with resting sweat rates over 25 mg/min benefited particularly from this procedure, whereas patients with less than 25 mg/min did not. CONCLUSION: SSGSC produces a significant reduction in the preoperative sweat rates. A low complication rate and a high degree of patient satisfaction were observed. Long-term follow-up evaluations demonstrate a low number of relapses, making SSGSC a convenient and satisfactory method of treating axillary hyperhidrosis. It should be considered in patients refractory to conventional therapies with baseline sweat rates greater than 25 mg/min. The authors have indicated no significant interest with commercial supporters.

"Bis-phossy jaws" - high and low risk factors for bisphosphonate-induced osteonecrosis of the jaw.

INTRODUCTION: Bisphosphonates (BPs) have transformed our ability to treat certain malignancies, osteoporosis and hypercalcaemia. This class of drug is assumed to be well tolerated by most. There are some important caveats to this assumption, however, one of the significances being the risk of osteonecrosis of the jaw (ONJ). MATERIAL AND METHODS: This multi-centre retrospective study examined the role of different BPs on the development of ONJ, its clinical presentation and the efficacy of various treatment modalities, comparing these findings with the available literature. RESULTS: A total of 78 patients from 17 centres were identified with ONJ. A majority of patients identified with ONJ had used Pamidronate or Zoledronate (93.6%) intravenously. 94.9% of patients had received BP in the course of treatment for malignancies and a majority had also received prior chemotherapy or exogenous steroids. 82.1% of patients had received BP for more than 1 year. The mean time from the introduction of BP to the development of ONJ in 24 patients from our department was 31.8 months. CONCLUSIONS: The most common intraoral manifestation was exposed necrotic jawbone. Tooth extractions and oral surgical intervention appear to place patients on BP therapy at risk of ONJ, especially after intravenous BP treatments. ONJ proved in this study to be remarkably refractory to treatment, with radical resection being the only curative approach. We recommend that all patients receive necessary dental treatment prior to commencing BP therapy.

Gender and nasal shape: measures for rhinoplasty.

BACKGROUND: Gender-specific nasal shapes are recommended for rhinoplasty. This study was conducted to clarify whether there truly are gender-related differences and to determine optimal nasal shapes in a Caucasian population. METHODS: The authors created female and male composite photographs of "average" (n = 128 each), "optimal" (n = 16 each), and "most unpleasant" (n = 8 each) noses stratified on the basis of each photographed subject's (n = 311) own evaluation of the attractiveness of her or his nose, using a visual analogue scale. These composites were also assessed by 308 independent judges. RESULTS: Optimal female noses showed a horizontally and vertically lower nasion and were concave to straight in profile as compared with optimal male noses, which had a vertically and horizontally higher nasion and a straight profile. A supratip break was not found in any of the composites. At least half of the judges rated average and optimal male composite noses as female. A significant majority mistook the composite of the most unpleasant female noses as male (frontal view, 62.0 percent; lateral view, 72.4 percent; p < 0.001). Optimal and average female and male noses were found to be independently significantly more attractive than the most unpleasant ones (p < 0.001, n = 308 judges). Women and men with a straight or concave profile were significantly (p = 0.017 and p = 0.006, respectively) more satisfied with the appearance of their nose than those with nasal humps. CONCLUSIONS: Gender-related differences in nasal shape appear to be subtle, with nasion position being one of the main factors. A nasal hump and a supratip break are not desirable.

Facial attractiveness: visual impact of symmetry increases significantly towards the midline.

Symmetry is thought to be a major prerequisite for an attractive face. Many faces are not symmetric, yet are still regarded as beautiful. What role, then, does asymmetry play in the perception of beauty? We studied the assessment of computer-manipulated images by independent judges (n = 200-250): part A: nevi located at different positions; part B: standardized changes of the orbital region. The results showed that slight lateral orbital and facial asymmetry does not impair attractiveness at all and that asymmetries close to the midline are significantly less attractive than those affecting the lateral aspect of the face (P < 0.001). A single nevus which is located laterally on the face is significantly more attractive than a nevus close to the midline (P < 0.001). Faces with a completely symmetric bilateral pair of nevi in the same lateral positions (perceived as attractive when alone), received the worst ratings (P < 0.001). Symmetry is a characteristic of the attractive face, but there are exceptions to the rule. Under certain conditions symmetry can be completely unattractive. The visual impact of symmetry on the perception of beauty increases significantly when approaching the midline.

Craniectomy and noggin application in an infant model.

INTRODUCTION: Noggin is an antagonist of bone morphogenetic proteins (BMP)-2, -4 and -7. Little data are available regarding its clinical utility. Two hypotheses were put forward: firstly, that spontaneous regeneration of calvarial defects with noggin protein would result in diminished bone volume when compared with calvarial defects not so treated. Secondly, that centrifugal cranial expansion would remain undisturbed whether noggin was applied or not. MATERIAL AND METHODS: A unilateral defect of the frontal and parietal bones (2x4cm) was generated by excising the right coronal suture in 2-month-old minipigs (n=10) and in group 1 (n=5) no further intervention was undertaken. In the second group (n=5), a collagen type I tissue fleece and noggin protein (1.05mg/ml) were applied. After 4 months the coronal suture regions of frontal sides were examined in each animal by computed tomography and non-decalcified histology. RESULTS: Bony gaps of equivalent size remained in animals of both groups. The differences in bone volumes of the experimental sides of group 1 were not statistically significantly different (p=0.117) when compared with those of group 2. A significant difference in the bone volumes of the experimental versus control (unoperated) sides was found in both group 1 (p=0.043) and group 2 (p=0.043). Internal skull diameters increased by 16.4% in both groups but the physiological centrifugal cranial expansion remained undisturbed. Bone densities of the experimental and control sides of groups 1 and 2 were not statistically significantly different (both p>0.05). CONCLUSIONS: The first hypothesis was contradicted: the quantity and quality of spontaneous bone regenerates was not altered by application of noggin protein. The second hypothesis was confirmed: no disruption of subsequent cranial development was seen. It may be that a single application of noggin protein in this study was insufficient. However, it may well be suggested that the continuous supplementation of noggin, for example by adenoviral noggin gene transfer may significantly reduce the quantity of spontaneous bone regeneration in a similar experiment.

A new method of monitoring osteomyelitis.

Chronic infections of bone such as osteomyelitis are frequent events, especially in immunocompromised or diabetic patients, and costly on a national level. Incorrect treatment or delayed diagnosis may lead to loss of the affected extremity or mandible. The aim of this study was to assess the possible value of urinary lysylpyridinoline (LP) and hydroxylysylpyridinoline (HP) concentrations in the monitoring of mandibular osteomyelitis. Patients were assigned to the following groups: group 1 (n=85), control; group 2a (n=38), patients with active disease; group 2b (n=25), patients of group 2a 6 months after successful treatment; group 2c (n=7), patients of group 2a with ongoing osteomyelitis 6 months after treatment. The range and upper limit of normal values (HP(max) and LP(max)) were determined in group 1. Levels of LP and HP were measured by high-performance liquid chromatography and fluorescence detection. There was a significant decrease (mean 45.43% for HP and 32.12% for LP) in samples of group 2b compared to 2a (P<0.001 for HP and LP). There was a significant increase in HP values in samples from group 2c compared to 2a (P=0.018). The urinary concentrations of HP and LP appear to act as a marker of disease activity, with a decrease reflecting treatment success and an increase or stable values indicating persistent disease. An inexpensive tool (US$5 per analysis) for the monitoring of osteomyelitis is described.

Man as living bioreactor: fate of an exogenously prepared customized tissue-engineered mandible.

In 2004, we reported a novel method of repairing a human mandible by in vivo tissue engineering. The patient served as his own bioreactor as the exogenously prepared customized mandible replacement was grown inside his latissimus dorsi muscle prior to transplantation to repair the existing defect. Our technique was developed through extensive experience with an animal model. We describe our and the patient's experiences with this procedure. We give details to the benefits and limitations of this technique as it stands and outline issues that should be addressed in future human clinical trials.