Safety and efficacy of the combination of pegylated interferon-α2b and dasatinib in newly diagnosed chronic-phase chronic myeloid leukemia patients.

Dasatinib (DAS) and interferon-α have antileukemic and immunostimulatory effects and induce deep responses in chronic myeloid leukemia (CML). We assigned 40 newly diagnosed chronic-phase CML patients to receive DAS 100 mg o.d. followed by addition of pegylated interferon-α2b (PegIFN) after 3 months (M3). The starting dose of PegIFN was 15 µg/week and it increased to 25 µg/week at M6 until M15. The combination was well tolerated with manageable toxicity. Of the patients, 84% remained on PegIFN at M12 and 91% (DAS) and 73% (PegIFN) of assigned dose was given. Only one patient had a pleural effusion during first year, and three more during the second year. After introduction of PegIFN we observed a steep increase in response rates. Major molecular response was achieved in 10%, 57%, 84% and 89% of patients at M3, M6, M12 and M18, respectively. At M12, MR(4) was achieved by 46% and MR(4.5) by 27% of patients. No patients progressed to advanced phase. In conclusion, the combination treatment appeared safe with very promising efficacy. A randomized comparison of DAS±PegIFN is warranted.

Histamine suppresses epidermal keratinocyte differentiation and impairs skin barrier function in a human skin model.

BACKGROUND: Defects in keratinocyte differentiation and skin barrier are important features of inflammatory skin diseases like atopic dermatitis. Mast cells and their main mediator histamine are abundant in inflamed skin and thus may contribute to disease pathogenesis. METHODS: Human primary keratinocytes were cultured under differentiation-promoting conditions in the presence and absence of histamine, histamine receptor agonists and antagonists. The expression of differentiation-associated genes and epidermal junction proteins was quantified by real-time PCR, Western blot, and immunofluorescence labeling. The barrier function of human skin models was tested by the application of biotin as tracer molecule. RESULTS: The addition of histamine to human keratinocyte cultures and organotypic skin models reduced the expression of the differentiation-associated proteins keratin 1/10, filaggrin, and loricrin by 80-95%. Moreover, the addition of histamine to skin models resulted in the loss of the granular layer and thinning of the epidermis and stratum corneum by 50%. The histamine receptor H1R agonist, 2-pyridylethylamine, suppressed keratinocyte differentiation to the same extent as did histamine. Correspondingly, cetirizine, an antagonist of H1R, virtually abrogated the effect of histamine. The expression of tight junction proteins zona occludens-1, occludin, claudin-1, and claudin-4, as well as that of desmosomal junction proteins corneodesmosin and desmoglein-1, was down-regulated by histamine. The tracer molecule biotin readily penetrated the tight junction barrier of skin cultures grown in the presence of histamine, while their diffusion was completely blocked in nontreated controls. CONCLUSIONS: Our findings suggest a new mechanism by which mast cell activation and histamine release contribute to skin barrier defects in inflammatory skin diseases.

Freckles and solar lentigines have different risk factors in Caucasian women.

BACKGROUND: To date, few epidemiological data on the relationships between solar lentigines, freckles and behavioural and constitutional risk factors in Caucasian populations exist. OBJECTIVES: To investigate the potential impact of behavioural and phenotypic variables, as well as the MC1R genetic background, on the history of facial freckles and the severity of solar lentigines in Caucasian women. METHODS: The severity of solar lentigines was graded from facial digital images of 523 French middle-aged women by a dermatologist and summarized by a score afterwards. The history of facial freckles was assessed and the sun-exposure behaviour was characterized using a six-category typology. Risk factors including MC1R polymorphism were evaluated using logistic regression models. RESULTS: Two constitutive host factors were found to be independently associated with a history of facial freckles: frequent sunburns and the presence of diminished function variants of the MC1R gene. In addition to age, five factors were independently associated with solar lentigines: constitutive host factors (dark skin colour and tanning capacity), a history of freckles, sun-exposure behaviour and current intake of oral contraceptive or progestogen treatments. CONCLUSION: These results strengthen the hypothesis that solar lentigines are markers of photoaging, whereas freckles are mainly determined by genetic factors. The finding that hormonal treatment is associated with a higher risk for solar lentigines merits further investigations.

Acute-onset migrainous aura mimicking acute stroke: MR perfusion imaging features.

BACKGROUND AND PURPOSE: In a very limited number of cases, acute migrainous aura may mimic acute brain infarction. The aim of this study was to recognize patterns of MR perfusion abnormalities in this presentation. MATERIALS AND METHODS: One thousand eight hundred fifty MR imaging studies performed for the suspicion of acute brain infarction were analyzed retrospectively to detect patients with acute migrainous aura not from stroke. All patients were examined clinically by 2 neurologists and underwent a standard stroke MR imaging protocol, including PWI. Two radiologists reviewed the perfusion maps visually and quantitatively for the presence, distribution, and grade of perfusion abnormalities. RESULTS: Among 1850 MR imaging studies, 20 (1.08%) patients were found to have acute migrainous aura. Hypoperfusion was found in 14/20 patients (70%) with delayed rMTT and TTP, decreased rCBF, and minimal decrease in rCBV. In contrast to the typical pattern in stroke, perfusion abnormalities were not limited to a single vascular territory but extended to >1. Bilateral hypoperfusion was seen in 3/14 cases. In 11/14 cases, hypoperfusion with a posterior predominance was found. TTP and rMTT were the best maps to depict perfusion changes at visual assessment, but also rCBF maps demonstrated significant hypoperfusion in quantitative analysis. In all patients, clinical and imaging follow-up findings were negative for stroke. CONCLUSIONS: Acute migrainous aura is rare but important in the differential diagnosis among patients with the suspicion of acute brain infarction. Atypical stroke perfusion abnormalities can be seen in these patients.

[MC1R polymorphisms and facial photoaging]. / Polymorphismes du MC1R et photovieillissement du visage.

BACKGROUND: The objective of this study was to assess the association between melanocortin-1 receptor (MC1R) variants and the severity of facial skin photoaging. METHODS: The study population comprised 530 French middle-aged women between 44 and 70 years. A trained dermatologist graded the severity of facial skin photoaging from photographs using Larnier's global scale. Logistic regressions were performed to assess the influence of MC1R polymorphism on severe photoaging (grades 1-3 vs. 4-6), with adjustment for possible confounders (demographic and phenotypic data, and sun exposure intensity). RESULTS: Overall, 35% of the women were wild-type homozygotes, 49% had one variant, 15% had two variants, and 1% had at least one rare variant. After adjustment for possible confounders, the presence of two major diminished function variants was found to be a risk factor for photoaging (adjusted odds ratio=5.61; 95% confidence interval [1.43-21.96]). DISCUSSION: Our results suggest that genetic variations of MC1R are important determinants for severe photoaging.

Reliability of the noninvasive sequence methods to estimate baroreflex function using the paradigm of brain death.

BACKGROUND: Various techniques have been developed to estimate spontaneous baroreflex sensitivity noninvasively. However, in the EuroBaVar study it has been shown that they yield differing results. AIM OF THE STUDY: To investigate the reliability of these methods further we compared the results of the most common sequence techniques. We used the paradigm of brain death with the absence of any baroreflex function. METHODS: In a prospective study we recorded breathing pattern, ECG and continuous blood pressure in 10 consecutive brain dead subjects of a neurointensive care unit. EuroBaVar sequence techniques 12-18 (ST12-ST18) were applied to the data sets and the number of sequences compared. RESULTS: Techniques which are based on thresholds in terms of blood pressure or R-R interval changes yielded the least false positive results: technique ST12, ST13, and ST14 detected very few sequences, while ST18 detected no sequence at all. Techniques using a correlation threshold (ST15-ST17) found a high number. CONCLUSION: This study demonstrates clearly that many of the sequence techniques used to estimate baroreflex sensitivity render false positive results in the unique paradigm of brain death. Thus, the method should be selected with regard to the biological signal and the pathophysiological background.

[Deformity-associated treatment of the hallux valgus complex]. / Deformitätsassoziierte Behandlung des Hallux-valgus-Komplexes.

Hallux valgus represents a combined deformity with malpositioning of the big toe in the metatarsophalangeal joint and metatarsal splaying due to metatarsus primus varus formation. It is defined on the basis of joint condition of the metatarsophalangeal and tarsometatarsal (TMT) joints, the extent and congruence or incongruence of malposition, mobility of the metatarsophalangeal joint and TMT stability. Basic resection appears to be indicated only in exceptional cases. Depending on the degree of severity, deformities can be corrected by means of distal, diaphyseal or proximal osteotomies and TMT arthrodeses. Any correction requires the use of subtle soft tissue surgery with recentering of the tendon, tightening of the medial capsule and abductor hallucis and releasing the lateral capsule. A check-list-like analysis of hallux valgus deformity helps determine the ideal procedure and avoid over- or under-treatment.

Airway inflammation induced after allergic poly-sensitization can be prevented by mucosal but not by systemic administration of poly-peptides.

BACKGROUND: Patients with multiple sensitizations require alternative forms of treatment, as the efficacy of conventional immunotherapy is unsatisfactory. OBJECTIVE: In the present study, we sought to compare the efficacy of a subcutaneously (s.c.) and a mucosally applied polyvalent vaccine to reduce allergic immune responses within airway and lung tissues. METHODS: Female BALB/c mice were intraperitoneally immunized with recombinant (r)Bet v 1, rPhl p 1 and rPhl p 5, followed by an aerosol challenge of birch and phleum pollen extract. For tolerance induction, either a mixture of the immunodominant peptides or a hybrid peptide of the respective antigens was s.c. injected or intranasally applied before poly-sensitization. RESULTS: Mucosal but not systemic pre-treatment with poly-peptides led to significant suppression of eosinophils and IL-5 production in bronchoalveolar lavages, as well as IL-5, IL-4, IL-13 and eotaxin levels in lung cell cultures. Lung histology showed a clear reduction of cellular infiltration and mucus production only in intranasally pre-treated mice. In accordance, also the systemic immune response, characterized by IgE-dependent basophil degranulation and IL-4 levels in vitro, was significantly reduced by mucosal antigen application, but only marginally influenced by subcutaneous pre-treatment. Both treatment routes led to up-regulated CTLA4 expression in splenocytes, whereas only after mucosal pre-treatment Foxp3 expression levels were enhanced in lung CD3(+) T cells. Furthermore, intranasal but not subcutaneous application of the peptides enhanced IL-10 levels in the lungs, indicating regulatory mechanisms operating in local tolerance induction. CONCLUSION: Mucosal application of peptides is superior to systemic application in preventing both local and systemic poly-allergic T helper2 immune responses, suggesting mucosal tolerance induction as an attractive strategy for the primary and secondary prevention of allergic multi-sensitization and lung pathology.

Intermediate-term results of the Ludloff osteotomy in one hundred and eleven feet.

BACKGROUND: The modified Ludloff proximal first metatarsal osteotomy is indicated for the surgical correction of moderate-to-severe hallux valgus deformity associated with metatarsus primus varus. We report the intermediate-term results of this procedure. METHODS: Ninety-nine patients (111 feet) with a mean age of fifty-six years underwent a modified Ludloff proximal first metatarsal osteotomy and a distal soft-tissue procedure at two institutions for the treatment of a moderate-to-severe hallux valgus deformity. The American Orthopaedic Foot and Ankle Society score and weight-bearing radiographs of the foot were assessed preoperatively and after a mean duration of follow-up of thirty-four months. Clinical and radiographic outcome was also compared between younger and older patients, with the arbitrarily chosen age of sixty years dividing the two groups. RESULTS: The mean American Orthopaedic Foot and Ankle Society score improved significantly (p < 0.0001) from 53 points preoperatively to 88 points at the time of the most recent follow-up. The mean American Orthopaedic Foot and Ankle Society score for patients who were sixty years of age or less was significantly higher than that for patients who were more than sixty years of age (91 compared with 83 points; p = 0.0057). The mean hallux valgus angle decreased significantly from 35 degrees preoperatively to 9 degrees at the time of the most recent follow-up (p < 0.0001), and the mean intermetatarsal angle decreased significantly from 17 degrees to 8 degrees (p < 0.0001). All osteotomy sites united without dorsiflexion malunion but with a mean first metatarsal shortening of 2.2 mm. CONCLUSIONS: To our knowledge, the present report describes the largest cohort of patients undergoing a modified Ludloff osteotomy for the correction of hallux valgus deformity that has been reported in the literature. Our intermediate-term results demonstrate that the procedure achieves significant correction of moderate-to-severe hallux valgus deformity, significant reduction in forefoot pain, and significant improvement in functional outcome. Patients with an age of sixty years or less appear to have a more favorable outcome.

Alterations in antral cytokine gene expression in peptic ulcer patients during ulcer healing and after Helicobacter pylori eradication.

Earlier studies have shown that the antral immune response in Helicobacter pylori infection has a mixed Th1-Th2-T-regulatory profile. After eradication, a chronic inflammation remains in some patients, but a follow-up study with a comprehensive cytokine profile in has not previously been published. Twelve patients with H. pylori positive peptic ulcer disease (five antral and seven duodenal) were enrolled and cytokine gene expressions in antral biopsies were determined (1) at entry, (2) after resolving the ulcer with proton pump inhibitor (PPI) treatment and (3) after eradication. The second endoscopy was performed 4 weeks after ending the PPI treatment, and the third endoscopy was performed after a mean of 10 months after eradication. Inflammation was graded according to the updated Sydney system. Interleukin (IL)1beta, IL8, IL12A, IL18, TNFalpha, IFNgamma, IL4, IL6 and IL10 expression levels were analysed by real-time RT-PCR. Mixed mononuclear and neutrophil infiltrates were seen at entry and after ulcer healing. After eradication, low-grade mononuclear infiltrates were found. The cytokine expression levels after ulcer healing (H. pylori positive gastritis) were not significantly different from the levels at entry (ulcer). After eradication, attenuation of the Th1 cytokines except for TNFalpha and a persisting increase of IL4 levels were observed, whereas the IL10 expression was markedly reduced. The present data did not indicate a specific ulcer promoting cytokine gene regulation profile. However, after eradication a chronic low-grade inflammation was seen with reduced Th1, prolonged Th2 and disappearance of the T-regulatory response.

High tissue factor-expressing human monocytes carry low surface CD36: application to intersubject variability.

BACKGROUND: The 'high and low responder' phenomenon describes an intersubject variability in mononuclear cell (MNC) prothrombotic reactivity to lipopolysaccharide (LPS) stimulation. Because alterations in surface CD36 expression in monocytes were associated with impaired monocyte function, we studied the relationship between the levels of surface CD36 presentation and the prothrombotic reactivity of monocytes from high-responder (HR) and low-responder (LR) individuals. METHODS AND RESULTS: The relationship between levels of tissue factor (TF) expression and surface CD36 presentation in MNCs from HR individuals (n = 7) and LR individuals (n = 8) was investigated. Resting MNCs from HR individuals contained significantly more TF mRNA but levels of TF antigen and procoagulant activity similar to MNCs from LR individuals. Resting CD14+ MNCs from HR individuals expressed significantly lower surface CD36, as mean fluorescence intensities (MFIs) were 70.4 +/- 6.3 vs. 132.0 +/- 14.5 arbitrary units (AU) in HR and LR individuals, respectively. MFI from surface TF negatively correlated with surface CD36 in the population of resting (r = -0.598, P = 0.031) and LPS-stimulated (r = -0.672, P = 0.009) CD14+ cells. LPS-stimulated MNCs from HR individuals contained significantly more TF in a surface pool (2079 +/- 199 vs. 786 +/- 57 AU) along with higher TF procoagulant activity (57.3 +/- 15.2 vs. 21.1 +/- 4.5 mU 10(6) cells(-1)) as compared with LR individuals. CD14+ MNCs from HR individuals expressed less surface CD36 during a 2-h LPS challenge. CONCLUSIONS: A novel phenotype of monocytes characterized by high TF and low CD36 presentation could be further developed for use as a marker for detection of HR individuals prone to developing prothrombotic conditions.

Adaptation to high salinity in poplar involves changes in xylem anatomy and auxin physiology.

To investigate the physiological basis of salt adaptation in poplar, we compared the effect of salt stress on wood anatomy and auxin physiology of the salt-resistant Populus euphratica and salt-sensitive Populus x canescens. Both poplar species showed decreases in vessel lumina associated with increases in wall strength in response to salt, however, in P. euphratica at three-fold higher salt concentrations than in P. x canescens. The predicted hydraulic conductivity of the wood formed under salt stress decreased in P. x canescens, while in P. euphratica, no significant effects of salt on conductivity and transpiration were observed. The concentration of free indole-3-acetic acid (IAA) decreased under salt stress in the xylem of both poplar species, but to a larger extent in P. x canescens than in P. euphratica. Only salt-treated P. euphratica exhibited an increase in IAA-conjugates in the xylem. Genes homologous to the auxin-amidohydrolase ILL3 were isolated from the xylems of P. euphratica and P. x canescens. For functional analysis, the auxin-amidohydrolase from P. x canescens was overexpressed in Arabidopsis. Transgenic Arabidopsis plants were more resistant to salt stress than the wild-type plants. Increased sensitivity of the transgenic Arabidopsis to IAA-Leu showed that the encoded hydrolase used IAA-Leu as a substrate. These results suggest that poplar can use IAA-amidoconjugates in the stem as a source of auxin to balance the effects of salt stress on auxin physiology.

[The modified Ludloff osteotomy for correction of severe metatarsus primus varus with hallux valgus deformity]. / Die modifizierte Ludloff-Osteotomie zur Korrektur der schweren Spreizfussdeformität mit Hallux valgus-Fehlstellung.

AIM: The present study investigates the clinical and radiological mid-term results of the modified Ludloff osteotomy, a proximal metatarsal osteotomy for surgical correction of severe metatarsus primus varus with hallux valgus deformity. METHOD: 70 feet in 67 patients from 25 to 78 years (average age 56 years) were included in this prospective study. The patients were evaluated with the American Orthopaedic Foot and Ankle Society (AOFAS) forefoot metatarsophalangeal interphalangeal score, which was used preoperatively and at an average follow-up of 37 +/- 6 months. Weight-bearing foot radiographs were analysed according to AOFAS guidelines and statistical evaluation was made with the Wilcoxon signed-rank test. RESULTS: The average AOFAS score improved significantly (p < 0.0001) from 55.2 +/- 15.2 points preoperatively to 86.6 +/- 15.2 points at follow-up. Preoperatively, all patients complained of pain (20.2 +/- 9.6 points) which had improved significantly (p < 0.0001) at the latest follow-up (37.3 +/- 5.7 points). The average hallux valgus angle (HVA) was 37 +/- 8 degrees preoperatively and improved significantly to 12 +/- 11 degrees at follow-up (p = 0.0001). The intermetatarsal angle (IMA) improved significantly from 18 +/- 2 degrees preoperatively to 8 degrees +/- 4 degrees after 37 +/- 6 months (p = 0.0002). The sesamoid position improved significantly from preoperative to follow-up (p = 0.0003). Radiographic evaluation of the patients indicated that all examined osteotomies had healed after 37 +/- 6 months. CONCLUSION: This prospective investigation at intermediate follow-up using currently available outcome measures suggests that the Ludloff osteotomy is a suitable procedure for the surgical correction of severe metatarsus primus varus (IMA > 15 degrees ) with hallux valgus deformity.

The Weil osteotomy: a seven-year follow-up.

We prospectively evaluated the one- and seven-year results of the Weil osteotomy for the treatment of metatarsalgia with subluxed or dislocated metatarsophalangeal joints in 25 feet of 24 patients. Good to excellent results were achieved in 21 feet (84%) after one year and in 22 (88%) after seven years. The American Orthopaedic Foot and Ankle Society score significantly improved from 48 (SD 15) points before surgery to 75 (SD 24) at one year, and 83 (SD 18) at seven years. The procedure significantly reduced pain, diminished isolated plantar callus formation and increased the patient's capacity for walking. Redislocation of the metatarsophalangeal joint was seen in two feet (8%) after one year and in three (12%) after seven years. Although floating toes and restricted movement of the metatarsophalangeal joint may occur, the Weil osteotomy is safe and effective.

Selecting and deselecting imatinib-resistant clones: observations made by longitudinal, quantitative monitoring of mutated BCR-ABL.

Resistance to imatinib during the treatment of chronic myeloid leukaemia (CML) is frequently associated with point mutations in the ABL gene encoding the ATP binding region likely to cause disease relapse. Early diagnosis and monitoring of these mutations may be important in order to prevent rapid expansion of resistant clones. We describe a quantitative mutation-specific PCR assay based on the readily available Taqman platform. Selectivity for the mutated target is conferred by mutation-specific primers destabilised by additional mismatches. The assay can be carried out in parallel to standard BCR-ABL quantification and is therefore more quickly compared to standard sequencing procedures. The sensitivity of the assay reaches 0.1%. It also allows for quantitative assessment of mutated clones. By analysing sequential samples of resistant subjects, we show how mutated clones were selected, maintained or deselected depending on the individual treatment setting. The high sensitivity and practical merits of this method makes it a good candidate for prospective molecular surveillance of patients at high risk for imatinib resistance.

Delayed onset of warts over tattoo mark provoked by sunburn.

Multiple warts in a 32-year-old-man are reported that developed after tattooing and remaining exclusively confined to that area. The tattooing was done 2.5 years earlier by a professional tattoo artist. It was previously a lesion-free tattoo, but when damaged by sunburn developed multiple skin warts. The ability of a latent virus to induce warts after cutaneous ultraviolet exposure was discussed.

Perforin expression is upregulated in the epidermis of psoriatic lesions.

BACKGROUND: There are currently very few data regarding the role of cell-mediated cytotoxicity in psoriasis. Both cytotoxic T lymphocytes and natural killer (NK) cells mediate cytotoxicity reactions, mainly by two distinct pathways, the perforin/granzyme and the Fas/Fas ligand pathway. OBJECTIVES: To study the expression and distribution of perforin, T- and NK-cell subsets in psoriatic lesional and nonlesional skin. METHODS: Skin biopsy specimens from both lesional and nonlesional skin of 11 patients with chronic plaque psoriasis and eight healthy controls were analysed by immunohistochemistry. RESULTS: We found a significant increase in CD4+ and CD8+ cells in psoriatic lesions compared with nonlesional and healthy skin. The expression of CD16+ NK cells was significantly lower in lesions compared with healthy skin. Perforin expression was significantly enhanced in the epidermis of psoriatic lesions. CONCLUSIONS: Perforin expression is upregulated in the epidermis of psoriatic lesions, suggesting a potential role for perforin in the creation of the psoriatic plaque.