Disparate effects of adalimumab and fumaric acid esters on cardiovascular risk factors in psoriasis patients: results from a prospective, randomized, observer-blinded head-to-head trial.

BACKGROUND: The effect of adalimumab and fumaric acid esters (FAE) on the cardiovascular risk associated with psoriasis has only been investigated scarcely in randomized controlled studies. OBJECTIVE: The aim of this prospective, randomized controlled head-to-head trial was to compare the influence of adalimumab and FAE on cardiovascular disease markers in psoriasis patients. METHODS: Sixty-five patients with moderate to severe plaque psoriasis were randomly assigned to adalimumab or FAE treatment for 6 months. Cardiovascular haemodynamic parameters [flow-mediated dilation (FMD), nitro-glycerine mediated dilation (NMD) and carotid intima-media thickness (CIMT), blood pressure] were assessed at baseline (v0) and after 6 months (v6). Cutaneous disease severity, inflammatory and lipid cardiovascular risk markers were analysed at baseline(v0), after 3 (v3) and 6 months (v6). RESULTS: After 6 months of treatment FMD in the adalimumab group increased significantly [v0 5.9% (6.4% SD), v6 8.0% (4.8% SD), P = 0.048) but not in the FAE group. (v0 7.0% (4.1% SD), v6 8.4% (6.1% SD), P = 0.753]. This was paralleled by a significant decrease of high sensitive C-reactive protein (hsCRP) in the adalimumab group in comparison to the FAE group (v0: 0.39 mg/dL (0.38 SD), v6: 0.39 mg/dL (0.48 SD), P = 0.043). No significant changes were observed in any other haemodynamic parameters. FAE, however, additionally decreased total cholesterol (P = 0.046) and apolipoprotein B (P = 0.041) levels compared to adalimumab. Mean Psoriasis Area and Severity Index (psoriasis area severity score) reduction was greater but not significant (P = 0.116) under adalimumab treatment compared to FAE treatment [-71.1% (29.9 SD) vs. -54.6% (45.7%)]. CONCLUSION: In our study, both treatments were documented to exert effects on the cardiovascular system. While adalimumab showed anti-inflammatory effects and improved FMD, FAE interacted favourably with the cholesterol metabolism.

Microstructural analysis of subchondral bone in knee osteoarthritis.

The results of this study show increased formation of bone in the subchondral areas in advanced stages of osteoarthritis of the knee. These changes seem to be influenced by mechanical factors. INTRODUCTION: Subchondral bone changes seem to contribute to the progression of knee osteoarthritis (OA). This study aimed to analyze subchondral bone microstructure in specimens of late-stage knee OA in respect to articular cartilage damage, meniscus integrity, and knee joint alignment. METHODS: Thirty proximal tibiae of 30 patients (20 female and 10 male) with late-stage OA retrieved during total knee arthroplasty were scanned using a high-resolution micro-computed tomography. The scans were semi-automatically segmented into five volumes of interest. The volumes of interest were then further analyzed using commercially available software. The degree of articular cartilage damage was assessed semi-quantitatively by magnetic resonance imaging before surgery. RESULTS: The mean bone fraction volume (bone volume/total volume (BV/TV)) in all weight-bearing locations was significantly higher compared to the non-weight-bearing reference point below the anterior cruciate ligament (p = 0.000). The mean BV/TV in the medial compartment was significantly higher compared to the lateral compartment (p = 0.007). As for the BV/TV in intact menisci, there was a significantly lower subchondral bone fraction volume compared to subluxated or luxated menisci in the medial (p = 0.020) and lateral compartment (p = 0.005). Varus alignment had a significantly higher subchondral BV/TV in the medial compartment, whereas valgus alignment had a significantly higher subchondral BV/TV in the lateral compartment (p = 0.011). CONCLUSIONS: The results show significant differences of subchondral bone microstructural parameters in respect to cartilage damage, meniscus' structural integrity, and knee joint alignment. Therefore, subchondral bone changes seem to be a secondary process in the late-stage OA of the knee caused by mechanical changes.

Bone health in childhood cancer: review of the literature and recommendations for the management of bone health in childhood cancer survivors.

In the past decades, new cancer treatment approaches for children and adolescents have led to a decrease in recurrence rates and an increase in long-term survival. Recent studies have focused on the evaluation of the late effects on bone of pediatric cancer-related treatments, such as chemotherapy, radiation and surgery. Treatment of childhood cancer can impair the attainment of peak bone mass, predisposing to premature onset of low bone mineral density, or causing other bone side-effects, such as bone quality impairment or avascular necrosis of bone. Lower bone mineral density and microarchitectural deterioration can persist during adulthood, thereby increasing fracture risk. Overall, long-term follow-up of childhood cancer survivors is essential to define specific groups at higher risk of long-term bone complications, identify unrecognized long-term adverse effects, and improve patient care. Children and adolescents with a cancer history should be carefully monitored, and patients should be informed of possible late complications of their previous medical treatment. The International Osteoporosis Foundation convened a working group to review the bone complications of pediatric cancer survivors, outlining recommendations for the management of bone health, in order to prevent and treat these complications.

Randomized controlled trial comparing 35% trichloroacetic acid peel and 5-aminolaevulinic acid photodynamic therapy for treating multiple actinic keratosis.

BACKGROUND: Photodynamic therapy (PDT) and chemical peels with trichloroacetic acid (TCA) can be applied to large skin areas and thus are suitable treatment options for patients with multiple actinic keratosis (AK). However, despite its long use, TCA has been investigated only rarely in this indication. OBJECTIVES: This randomized, observer-blinded, intrapatient comparative study sought to investigate the efficacy and safety of 35% TCA vs. aminolaevulinic acid 20% (ALA) PDT in patients with extensive field cancerization and multiple AKs in the face or on the scalp. METHODS: Twenty-eight patients with at least five AKs in two comparable anatomical areas on the head were treated with 35% TCA and ALA PDT randomly assigned to each area. Their therapeutic efficacy, adverse events and cosmetic outcome were assessed by a blinded investigator at 1, 3, 6 and 12 months after treatment. RESULTS: After 12-months' follow-up TCA and ALA PDT reduced the total lesion count, the primary outcome, by 31% and 58%, respectively (P = 0·006). Complete clearance of pre-existing AKs were 49% for TCA and 74% for ALA PDT (P = 0·011). Treatment failure (number of AKs greater than 50% of the baseline count) was observed in seven patients (25%) after TCA and in two patients (7%) after PDT treatment. Treatment-related pain was significantly higher for ALA PDT (visual analogue scale 7·5 ± 2·3 vs. TCA: 5·1 ± 2·6; P = 0·04), whereas scarring (n = 6, 21%) was seen only in TCA treated patients. CONCLUSIONS: ALA PDT provided better clinical results than TCA in the treatment of patients with extensive field cancerization and multiple AKs.

[Cutaneous manifestations of metabolic syndrome]. / Hautmanifestationen beim metabolischen Syndrom.

BACKGROUND: Metabolic syndrome (MetS) is a cluster of risk factors which increase the risk of developing cardiovascular diseases and type II diabetes mellitus. High blood pressure, hyperglycemia, dyslipidemia, and central obesity are the main risk factors. While MetS is not a dermatological diagnosis per se, several cutaneous manifestations can serve as a clinical indicator for impending MetS and facilitate an early diagnosis and therapy in order to prevent its long-term sequelae. CUTANEOUS MANIFESTATIONS: Acanthosis nigricans and multiple skin tags can be signs of insulin resistance and impaired glucose tolerance, xanthoma and xanthelasma signs of dyslipidemia. Patients with type II diabetes can display numerous more or less specific dermatoses. Psoriasis and Hidradenitis suppurativa are frequently associated with MetS and obesity. Acne and hirsutism are highly prevalent signs of cutaneous hyperandrogenism due to polycystic ovary syndrome (PCOS). Hyperinsulinemia plays a major pathophysiological role in PCOS; MetS is thus an integral part of PCOS CONCLUSION: Emerging scientific evidence points to close associations between MetS and common dermatological diseases necessitating to integrate this perspective into clinical management of these diseases. The dermatologist is a key player in early detection of MetS.

Imaging of highly malignant osteosarcoma with iodine-123-vascular endothelial growth factor.

OBJECTIVE: Vascular endothelial growth factor (VEGF) is an important angiogenic factor, and its receptors have been shown to be overexpressed in various human carcinomas. In this study, we investigated the role of scanning with iodine-123 ((123)I)-labelled VEGF(165) in patients with highly malignant osteosarcoma. METHODS: Two patients (a 15-year-old female and a 14-year-old male) with osteosarcoma were injected with 140 MBq [<130 pmol (<5 µg) VEGF(165) per patient] of (123)I-VEGF(165). Dynamic acquisition was initiated immediately after administration and carried out until 30 min after injection. Whole-body images were done in anterior and posterior views at various time points. All patients underwent single-photon emission tomography imaging. RESULTS: (123)I-VEGF(165) scans were positive in these patients. Sequential images clearly showed increased (123)I-VEGF(165) activity in osteosarcoma lesions. The tumour lesions were still visualized in whole-body images and single-photon emission tomography examinations 2 h after injection. Intravenous injection of (123)I-VEGF(165) did not cause any side effects. CONCLUSION: Our results suggest that (123)I-VEGF(165) receptor scintigraphy may be useful for the visualization of highly malignant osteosarcoma and/or metastasis and the angiogenic activity of the tumour.

5-Methoxypsoralen plus ultraviolet (UV) A is superior to medium-dose UVA1 in the treatment of severe atopic dermatitis: a randomized crossover trial.

BACKGROUND: Ultraviolet (UV) A1 and psoralen plus UVA (PUVA) are effective treatment options for severe atopic dermatitis (AD); however, their relative efficacy has not yet been determined in a head-to-head study. OBJECTIVES: To compare UVA1 and oral 5-methoxypsoralen (5-MOP) plus UVA with respect to efficacy, tolerability and duration of response in patients with severe generalized AD. METHODS: Forty patients were included in this randomized observer-blinded crossover trial. The patients received either 15 exposures to medium-dose UVA1 as the first treatment and, in cases of relapse, another 15 exposures to 5-MOP plus UVA as the second treatment, or vice versa. All patients were followed until 12 months after discontinuation of the last treatment. The SCORAD score was determined by a blinded investigator at baseline, after 10 and 15 treatments each and during the follow-up period. In addition, all adverse events were recorded during the whole study period. RESULTS: Twenty-three patients completed the crossover treatment. Both phototherapies resulted in clinical improvement; however, PUVA reduced the baseline SCORAD score to a significantly greater extent than UVA1 (mean +/- SD 54.3 +/- 25.7% vs. 37.7 +/- 22.8%; P = 0.041). The median length of remission was 4 weeks (interquartile range 4-12) after UVA1 and 12 weeks (interquartile range 4-26) after PUVA therapy (P = 0.012). CONCLUSIONS: PUVA provides a better short- and long-term response than medium-dose UVA1 in patients with severe AD.

Photoepilation with variable pulsed light in non-facial body areas: evaluation of efficacy and safety.

BACKGROUND: Variable Pulsed Light (VPL) is a new intensity pulse light (IPL) system. We evaluated VPL for safety and long-term efficacy in non-facial hair removal. STUDY DESIGN/MATERIAL AND METHODS: The Variable Pulsed Light [VPL System (Energist Limited, UK), 610-950 nm] system was used for the removal of unwanted non-facial dark pigmented body hair in 42 volunteers (40 females, two males, age: 18-43 years, mean: 30.4 +/- 7.4 years) with Fitzpatrick skin phototype (SPT) II (33.3%), III (38.1%) and IV (28.6%), and brown (43.8%) or black (56.2%) fine (19.0%), medium (47.6%) or coarse (9.4%) body hair. Minimum follow-up period was 12 months (mean: 13.14 +/- 2.38). Treatment parameters were as follows: number x duration of micropulses: 15 x 5-15 x 7 ms, pulse delay: 1-8 ms, fluence: 30-45 J/cm(2). RESULTS: Very good (> or =76% hair reduction) and good treatment efficacies (hair reduction: 51-75%) were observed in the majority of treated patients (n = 18; 42.9%; n = 14; 33.3% respectively), four patients (9.5%) had only moderate (hair reduction: 26-50%) and six (14.3%) patients had no (hair reduction < or =25%) treatment response. Side-effects (reversible erythema, leukotrichia) were sparse. More favourable long-term therapy outcomes were observed for higher SPT (III and IV), medium or coarse black hair and younger patients. CONCLUSION: The VPL System is a relatively efficient and safe treatment for long-term hair removal. Higher SPT (III and IV) with black and medium to coarse hair, and younger age of the patients appear to be factors of significant importance predicting long-term efficacy.

Long-chain diols: a new class of membrane lipids from a thermophilic bacterium.

Glycerol-derived membrane lipids are essentially absent in the thermophilic bacterium Thermomicrobium roseum. A series of straight chain and internally methyl-branched 1,2-diols of carbon numbers C(18) to C(23) were found to replace glycerolipids in this bacterium. Fatty acids were present but were ester-linked to the diols or amide-linked to polar heads groups and not to glycerol. This thermophile has evolved the integration of diols as a novel approach for the construction of its cytoplasmic membrane.

[Bisphosphonates for malignant bone tumors]. / Bisphosphonate bei malignen Knochentumoren.

Bisphosphonates (BPs) are able to prevent, reduce, or delay skeletal complications caused by tumors. Since the introduction of BPs, there has been a marked reduction of skeletal events. Today we can choose from a variety of BPs with different potency, efficacy, dosing, and administration regimens, as well as BPs for different indications. For patients with tumors who have a risk of developing osteoporosis induced by the tumor or antitumor treatment, we should think of prevention. In general, BPs are well tolerated. But there are also side effects: flulike syndrome, arthralgias, or, when administered orally, gastrointestinal symptoms. In a number of cases, the dosing regime must be adjusted according to renal function and baseline creatinine clearance. This paper reviews the current evidence-based use of BPs in solid tumors and the recommendations for treatment.

Evaluation of safety and efficacy of variable pulsed light in the treatment of unwanted hair in 77 volunteers.

BACKGROUND: Several studies on hair removal with intense pulsed light (IPL) and various laser sources have been done, but adequate data on long-term follow up are scarce. The present uncontrolled prospective pilot study evaluated safety and long-term efficacy of variable pulsed light (VPL) on hair removal in the face for medical and/or cosmetic indications. STUDY DESIGN/MATERIAL AND METHODS: The VPL system (Energist Ltd, UK) was used for the treatment of hypertrichosis in the face, mainly hirsutism, in 77 female volunteers. The minimum follow-up time after the last treatment was 9 months (mean: 12.74 +/- 2.87 months). RESULTS: Over 50% of hair clearance was observed in 68 (88.3%) of all cases. Erythema and leucotrichia were the most often associated side-effects encountered. Transient pigmentary changes were not reported. CONCLUSION: The VPL System presents as a relatively efficient and safe treatment alternative for long-term removal of unwanted hair. It seems to be particularly effective in fair-skinned patients with dark hair (skin types II-III-IV). Adverse effects were minimal and transient and, in no patient, significant enough to interrupt treatment.

Characterization of the vaccinia MVA hemagglutinin gene locus and its evaluation as an insertion site for foreign genes.

The 'Modified Vaccinia Ankara' (MVA) strain is a potential live vaccine vector. The use of the hemagglutinin (ha) gene of the MVA strain as an insertion site for foreign genes was evaluated. To identify the molecular basis of the hemagglutinin-negative (HA-) phenotype of MVA, the ha gene and the region around this gene were sequenced. Amino acid (aa) sequence comparisons with functional hemagglutinins of other vaccinia strains predicted a functional polypeptide. The late part of the promoter region of the ha gene, however, was deleted, causing the apparent loss of the ha gene function. Nevertheless, insertion of foreign DNA into the ha gene allowed generation of functional recombinant viruses, indicating that the ha-gene region is a suitable insertion site.

Vaccinia viral/retroviral chimeric vectors.

Retroviral vectors have become important tools in gene therapy due to a number of desirable properties, including efficient gene delivery and stable genomic integration. Some shortcomings, however, still remain to be solved. Retroviral vectors cannot be grown to as high titers as for example adenoviruses or vaccinia viruses, they tend to be unstable and are sensitive to lysis by complement when transfused into patients. The search for more robust retroviral delivery systems has led to the development of hybrid viral vectors trying to combine the broadly estimated features of retroviral vectors with advantageous properties of a second viral vector system. Chimeric systems with retroviruses and adeno-alphavirus and herpesviruses have been reported. This review is dedicated to vaccinia virus, a widely used vector in molecular and cell biology, as a chimeric carrier for retroviral vector units. In the first poxviral/retroviral constructs, retroviral vector units integrated into a defective vaccinia vector, gave rise to transduction competent particles. Due to the high insertion capacity of the vaccinia system, also the packaging components could be inserted into the carrier virus resulting in a system that is independent of retroviral packaging cell lines. Moreover, since vaccinia is a cytoplasmic virus that does not recognize nuclear transcription and processing signals, retroviral vectors with introns and internal transcription stops could be constructed that transduce complex gene cassettes. The topic of this review is the vaccinia viral / retroviral vector system and possible applications to gene therapy.

Clinical and serologic follow-up in patients with neuroborreliosis.

The authors performed a clinical and serologic follow-up study after 4.2 +/- 1.2 years in 44 patients with clinical signs of neuroborreliosis and specific intrathecal antibody production. All patients had been treated with ceftriaxone 2 g/day for 10 days. Although neurologic deficits decreased significantly, more than half the patients had unspecific complaints resembling a chronic fatigue syndrome and showed persisting positive immunoglobulin M serum titers for Borrelia in the Western blot analysis.

Serum antibodies against the heat shock protein 60 are elevated in patients with osteosarcoma.

Osteosarcoma is the most frequent malignant bone tumor, mainly occurring in the second and third decade of life. Diagnosis is limited to clinical symptoms, radiology and histology, but so far no diagnostic laboratory tests are available. Heat shock proteins (hsp), highly conserved proteins performing vital intracellular chaperoning functions and preventing cells from death, have been shown to be involved in tumor immunity. We analyzed 75 sera from 23 patients with high-grade osteosarcoma, 8 patients with chondrosarcoma, 10 patients with Ewing's sarcoma, 5 patients with soft tissue sarcoma, 11 patients with benign bone tumors at the time of diagnosis and from 18 healthy controls with an indirect one-site enzyme linked immunosorbent assay (ELISA) for the presence of anti-hsp60 and 70 antibodies. In these assays 10/23 osteosarcoma patients (43%) had anti-hsp60 antibodies with a mean +/- S.D. titer of 0.382 +/- 0.243 U/ml. Only one of the 18 healthy controls (1/18, 5.6%; titer 0.22 U/ml), two of the Ewing's sarcoma patients (2/10, 20%; titer 0.2 +/- 0.09 U/ml), two of the patients with a benign bone tumor (2/11, 18%; titer 0.22 +/- 0.16 U/ml) and one of the chondrosarcoma patients (1/8, 12.5%; titer 0.14 U/ml) were positive, whereas all others, including all soft tissue sarcomas were negative throughout. Anti-hsp60 antibodies in patients with osteosarcoma are therefore significantly increased (p < 0.05). 19/23 (83%) of osteosarcoma biopsy specimens expressed hsp60 immunohistochemically and all specimens from patients with a positive anti-hsp60 serum titer expressed hsp60. The level of the anti-hsp60 antibodies did not correlate with clinical parameters such as response to preoperative chemotherapy, duration of symptoms, age, gender, tumor size, serum alkaline-phosphatase levels and metastases. Although no difference in anti-hsp70 antibodies could be observed between sera from patients and healthy controls, a positive correlation was found for the presence of anti-hsp70 serum antibodies and lung metastases at the time of diagnosis in osteosarcoma patients. These data suggest an increase of anti-hsp60 antibodies at the time of first diagnosis of osteosarcoma. These findings should therefore give rise to further investigations on a group of new markers for the diagnosis of osteosarcoma.

Immunological differentiation between neuroborreliosis and multiple sclerosis.

Neuroborreliosis, a tick-borne spirochaetosis of the central nervous system, is diagnosed by the presence of intrathecally synthesized Borrelia burgdorferi-specific antibodies. Multiple sclerosis and neuroborreliosis can show similarities in clinical symptoms as well as lymphocytic cell reactions and oligoclonal bands in the isoelectric focusing of cerebrospinal fluid. To differentiate between multiple sclerosis and neuroborreliosis we tested intrathecally synthesized IgM and virus antibodies. The IgM indices were higher for most of the neuroborreliosis patients studied than for those with multiple sclerosis, and cell counts were also significantly higher in the acute stage of the disease. In 84% of multiple sclerosis patients we were able to demonstrate intrathecal antibody production against measles, rubella or mumps virus. Neuroborreliosis patients had no intrathecal virus antibody synthesis. The specification of oligoclonal bands resulting from isoelectric focusing of cerebrospinal fluid with an ELISA for B. burgdorferi can further substantiate the diagnosis of neuroborreliosis or help to rule it out in multiple sclerosis patients with positive borrelia-specific serology.

Quantitative evaluation of functional capacity during isoniazid therapy in Huntington's disease.

Eleven patients with Huntington's disease were treated with high doses of isoniazid. In addition to clinical assessment, the functional capacity was evaluated quantitatively. The symptoms of four of the patients showed a marked improvement and their functional capacity increased. The condition of one patient with the rigid form (Westphal's variant) deteriorated, and the remaining six patients showed no change. Patients with prominent mental disturbances appeared to respond best to isoniazid therapy.

Hypergonadotropic hypogonadic amenorrhea (World Health Organization III) and osteoporosis.

OBJECTIVE: To assess the bone mineral density in World Health Organization (WHO) III women after hormone replacement therapy. DESIGN: We studied the bone mineral density of 41 women with premature ovarian failure (hypergonadotropic hypogonadic amenorrhea--WHO III) before and during hormone replacement therapy. SETTING: All WHO III women were recruited from the Outpatient Department of the First Department of Gynecology and Obstetrics, University of Vienna Medical School, Austria, a public University Hospital. PATIENTS, PARTICIPANTS: Forty-one patients, 30 healthy women. INTERVENTIONS: Twenty-eight of 41 WHO III women received cyclic hormone replacement therapy consisting of 0.625 mg conjugated estrogen (days 1 to 30) and 5 mg medrogeston (days 20 to 30) in addition, with a 7-day interval. MAIN OUTCOME MEASURE: The bone mineral density was evaluated by single photon absorptiometry and dual energy x ray absorptiometry every 6 months (single photon absorptiometry six times, dual energy x ray absorptiometry four times). RESULTS: The bone mineral density in young women with hypergonadotropic hypogonadic amenorrhea (WHO III) was lower than in age-matched controls. Hormone replacement therapy produced an increase in bone mineral density in 28 WHO III women, whereas bone mineral density remained quite constant in the women without therapy. CONCLUSION: Hormone replacement therapy increases the bone mineral density of women with hypergonadotropic hypogonadic amenorrhea. Hormones should be substituted early and consistently in affected patients.

Serum concentrations of APO-1/Fas and interleukin-1beta-converting enzyme in osteosarcoma correlate with response to chemotherapy.

BACKGROUND: Cytotoxic drugs used in neoadjuvant chemotherapy may exert their effect by activation of apoptosis. Both APO-1/Fas and Interleukin-1beta-converting (ICE)/caspase-1 are believed to act as mediators of apoptotic cell death. PATIENTS AND METHODS: The sera of 21 patients with high-grade osteosarcoma were tested at the time of diagnosis by ELISA and compared with clinical data. RESULTS: The mean APO-1 serum levels were 844 +/- 344 pg ml(-1) and the mean ICE serum levels were 212 pg ml(-1) +/- 155 pg ml(-1) for all patients. Furthermore, both serum levels were found to be statistically significantly higher in patients with good regression grades compared to those in patients with bad regression grades. CONCLUSION: In highly-malignant osteosarcoma elevated serum levels of both APO-1 and ICE seem to be predictive of good response to chemotherapy.