New insights into the phenotypes of atopic dermatitis linked with allergies and asthma in children: An overview.

Atopic dermatitis (AD) is a complex disease with multiple causes and complex mechanistic pathways according to age of onset, severity of the illness, ethnic modifiers, response to therapy and triggers. A group of difficult-to-manage patients characterized by early-onset AD and severe lifelong disease associated with allergic asthma and/or food allergy (FA) has been identified. In this study, we focus on these severe phenotypes, analysing their links with other atopic comorbidities, and taking into account the results from recent cohort studies and meta-analyses. The main hypothesis that is currently proposed to explain the onset of allergic diseases is an epithelial barrier defect. Thus, the atopic march could correspond to an epithelial dysfunction, self-sustained by a secondary allergenic sensitization, explaining the transition from AD to allergic asthma. Furthermore, AD severity seems to be a risk factor for associated FA. Results from population-based, birth and patient cohorts show that early-onset and severe AD, male gender, parental history of asthma, and early and multiple sensitizations are risk factors leading to the atopic march and the development of asthma. The importance of environmental factors should be recognized in these high-risk children and prevention programs adapted accordingly. Effective targeted therapies to restore both barrier function and to control inflammation are necessary; early emollient therapy is an important approach to prevent AD in high-risk children. Clinicians should also keep in mind the specific risk of atopic comorbidities in case of filaggrin loss-of-function mutations and the rare phenotypes of orphan syndromes due to heritable mutations in skin barrier components.

Clinical phenotypes in asthma during childhood.

Asthma is a heterogeneous disease characterized by numerous phenotypes relating to age of onset, triggers, comorbidities, severity (assessed by multiple exacerbations, lung function pattern) and finally the inflammatory cells involved in the pathophysiologic pathway. These phenotypes can vary over time in relation to changes in the principal triggers involved in the aetiology of the disease. Nevertheless, in a patient with multiple allergies and early-onset disease (defined as multiple sensitizations and allergic comorbidities), the prognosis of asthma is poor with a high risk of persistence and severity of the disease during childhood. Future research will focus on classifying phenotypes into groups based on pathophysiologic mechanisms (endotypes) and the biomarkers attached to these endotypes, which could predict prognosis and lead to targeted therapy. Currently, these biomarkers are related to inflammatory cells associated with the asthma endotype, essentially eosinophils and neutrophils (and related cytokines) attached to Th-2 and non Th-1 pathways, respectively. The most severe asthma (refractory asthma) is linked to neutrophil-derived inflammation (frequently associated with female sex, obesity and possibly disorganized airway microbiota) encountered in very young children or teenagers. Severe asthma is also linked to or a marked eosinophil inflammatory process (frequently associated with multiple atopy and, more rarely, with non-atopic hypereosinophilic asthma in children) and frequently encountered in teenagers. Severe phenotypes of asthma could also play a role in the origin of chronic obstructive pulmonary disease in adult life.

[Single center analysis of the dermatosurgical patient cohort of a tumor center in Germany]. / Betrachtung des dermatochirurgischen Patientenkollektivs an einem Hauttumorzentrum in Deutschland.

BACKGROUND: The incidence of skin cancer continues to increase. However, little is known about the dermatosurgical characteristics of the patients. PATIENTS AND METHODS: In this single center, retrospective study, dermatosurgical reports of all patients treated because of basal cell carcinomas (BCC), squamous cell carcinomas (SCC), and malignant melanoma (MM) between 2004 and 2013 were analyzed. RESULTS: During the observed period, the number of operated BCC rose by a factor of 1.86 and the number of MM by a factor of 2.3. In comparison to BCC/MM, there was a disproportionately high increase of SCC by a factor of 4.02. The average age was 71.5 ± 13.4 years (minimum: 14 years; maximum: 104 years), whereupon a significant increase of male age and a significant decrease of female age occurred. Almost 70% of all tumors were located in the head and neck area. The nose was most commonly treated. CONCLUSIONS: During the last 10 years, the cohort of dermatosurgical patients changed in the tumor center. This should be verified in multicenter studies.

Prevalence and risk factors for carriage of ESBL-producing Enterobacteriaceae in Amsterdam.

OBJECTIVES: The objectives of this study were to determine the prevalence of carriage of ESBL-producing Enterobacteriaceae (ESBL-E) in a representative sample of the general adult Dutch community, to identify risk factors and to gain understanding of the epidemiology of these resistant strains. METHODS: Adults enrolled in five general practices in Amsterdam were approached by postal mail and asked to fill in a questionnaire and to collect a faecal sample. Samples were analysed for the presence of ESBL-E. ESBL genes were characterized by PCR and sequencing. Strains were typed using MLST and amplified fragment length polymorphism (AFLP) and plasmids were identified by PCR-based replicon typing. Risk factors for carriage were investigated by multivariate analysis. RESULTS: ESBL-E were found in 145/1695 (8.6%) samples; 91% were Escherichia coli. Most ESBL genes were of the CTX-M group (blaCTX-M-1 and blaCTX-M-15). MLST ST131 was predominant and mainly associated with CTX-M-15-producing E. coli. One isolate with reduced susceptibility to ertapenem produced OXA-48. In multivariate analyses, use of antimicrobial agents, use of antacids and travel to Africa, Asia and Northern America were associated with carriage of ESBL-E, in particular strains with blaCTX-M-14/15. CONCLUSIONS: This study showed a high prevalence of ESBL-E carriage in the general Dutch community. Also, outside hospitals, the use of antibiotics was a risk factor; interestingly, use of antacids increased the risk of carriage. A major risk factor in the general population was travel to countries outside Europe, in particular to Asia, Africa and Northern America.

Fully integrated hybrid silicon two dimensional beam scanner.

In this work we present the first fully-integrated free-space beam-steering chip using the hybrid silicon platform. The photonic integrated circuit (PIC) consists of 164 optical components including lasers, amplifiers, photodiodes, phase tuners, grating couplers, splitters, and a photonic crystal lens. The PIC exhibited steering over 23° x 3.6° with beam widths of 1° x 0.6°.

Risk factors for sporadic Shiga toxin-producing Escherichia coli O157 and non-O157 illness in The Netherlands, 2008-2012, using periodically surveyed controls.

Shiga toxin-producing Escherichia coli (STEC) infections have been associated with severe illness. Ruminants are seen as the main reservoir and the major transmission route is considered to be foodborne. In The Netherlands, a case-control study was conducted, using data collected during 2008-2012. Patients were interviewed and controls completed a self-administered questionnaire. Patients travelling abroad were excluded from the analyses. STEC O157 and non-O157 were examined separately and differentiated into two age groups (<10 years, ⩾10 years). We included 130 O157 cases, 78 non-O157 cases and 1563 controls. In both age groups of O157 patients, raw spreadable sausage was the main risk factor for infection. For STEC non-O157 cases aged <10 years, contact with farm animals was the main risk factor and in non-O157 cases aged ⩾10 years, consumption of beef was the main risk factor. During 2008-2012, risk factors for STEC infections in the Dutch population differed between age groups and serogroup categories, and were related to eating meat and contact with farm animals. Advising the public about the risks of consuming raw or undercooked meat (products) and hygiene habits in case of contact with farm animals, could help in the prevention of STEC infections.

Risk factors for sporadic listeriosis in the Netherlands, 2008 to 2013.

Although the disease burden of listeriosis on population level is low, on individual level the impact is high, largely due to severe illness and a high case fatality. Identification of risk factors supports and specifies public health actions needed for prevention. We performed a case­control study to determine host- and food-related risk factors for non-perinatal listeriosis in the Netherlands. Patients with non-perinatal listeriosis reported between July 2008 and December 2013 were compared with controls from a periodic control survey who completed a questionnaire in the same period. Higher age, male sex, underlying disease, especially cancer and kidney disease, and use of immunosuppressive medicine were strong risk factors for acquiring non-perinatal listeriosis. Analysis of the food consumption in the group of cases and controls with underlying diseases did not reveal any high-risk food products. Information and advice should continue to be given to persons at risk of severe listeriosis. Univariate analyses indicate that patients using gastric acid inhibitors are at risk. It is worth adding these patients to the group of susceptible persons.

Mutant PIK3CA controls DUSP1-dependent ERK 1/2 activity to confer response to AKT target therapy.

BACKGROUND: Alterations in the phosphoinositide 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) signalling pathway are frequent in urothelial bladder cancer (BLCA) and thus provide a potential target for novel therapeutic strategies. We investigated the efficacy of the AKT inhibitor MK-2206 in BLCA and the molecular determinants that predict therapy response. METHODS: Biochemical and functional effects of the AKT inhibitor MK-2206 were analysed on a panel of 11 BLCA cell lines possessing different genetic alterations. Cell viability (CellTiter-Blue, cell counts), apoptosis (caspase 3/7 activity) and cell cycle progression (EdU incorporation) were analysed to determine effects on cell growth and proliferation. cDNA or siRNA transfections were used to manipulate the expression of specific proteins such as wild-type or mutant PIK3CA, DUSP1 or CREB. For in vivo analysis, the chicken chorioallantoic membrane model was utilised and tumours were characterised by weight and biochemically for the expression of Ki-67 and AKT phosphorylation. RESULTS: Treatment with MK-2206 suppressed AKT and S6K1 but not 4E-BP1 phosphorylation in all cell lines. Functionally, only cell lines bearing mutations in the hotspot helical domain of PIK3CA were sensitive to the drug, independent of other genetic alterations in the PI3K or MAPK signalling pathway. Following MK-2206 treatment, the presence of mutant PIK3CA resulted in an increase in DUSP1 expression that induced a decrease in ERK 1/2 phosphorylation. Manipulating the expression of mutant or wild-type PIK3CA or DUSP1 confirmed that this mechanism is responsible for the induction of apoptosis and the inhibition of tumour proliferation in vitro and in vivo, to sensitise cells to AKT target therapy.Conclusion or interpretation:PIK3CA mutations confer sensitivity to AKT target therapy in BLCA by regulating DUSP1 expression and subsequent ERK1/2 dephosphorylation and can potentially serve as a stratifying biomarker for treatment.

Heterogeneous lasers and coupling to Si3N4 near 1060 nm.

A III-V/Si3N4 platform on silicon is presented capable of broad-spectral performance with initial heterogeneous lasers near 1060 nm. Continuous wave Fabry-Perot laser results for heterogeneous InGaAs/GaAs multiple quantum well (MQW) laser with output power approaching 0.25 mW on Si is demonstrated. Taper transmission loss measurements from III-V to Si3N4 are measured to be 2.5±0.75 dB.

Heterogeneously integrated III-V-on-silicon multibandgap superluminescent light-emitting diode with 290 nm optical bandwidth.

A broadband superluminescent III-V-on-silicon light-emitting diode (LED) was realized. To achieve the large bandwidth, quantum well intermixing and multiple die bonding of InP on a silicon photonic waveguide circuit were combined for the first time, to the best of our knowledge. The device consists of four sections with different bandgaps, centered around 1300, 1380, 1460, and 1540 nm. The fabricated LEDs were connected on-chip in a serial way, where the light generated in the smaller bandgap sections travels through the larger bandgap sections. By balancing the pump current in the four LEDs, we achieved 292 nm of 3 dB bandwidth and an on-chip power of -8 dBm.

Large outbreak of Salmonella Thompson related to smoked salmon in the Netherlands, August to December 2012.

On 15 August 2012, an increase in the number of Salmonella Thompson cases was noticed by the Salmonella surveillance in the Netherlands. A case­control study was performed, followed by a food investigation. In total 1,149 cases were laboratory-confirmed between August and December 2012 of which four elderly (76­91 years) were reported to have died due to the infection. The cause of the outbreak was smoked salmon processed at a single site. The smoked salmon had been continuously contaminated in the processing lines through reusable dishes, which turned out to be porous and had become loaded with bacteria. This is the largest outbreak of salmonellosis ever recorded in the Netherlands. The temporary closure of the processing site and recall of the smoked salmon stopped the outbreak. An estimated four to six million Dutch residents were possibly exposed to the contaminated smoked salmon and an estimated 23,000 persons would have had acute gastroenteritis with S. Thompson during this outbreak. This outbreak showed that close collaboration between diagnostic laboratories, regional public health services, the national institute for public health and the food safety authorities is essential in outbreak investigations.

Cytotoxic and mutagenic effects of iodine-131 and radioprotection of acerola (Malpighia glabra L.) and beta-carotene in vitro.

The radioisotope iodine-131 [(131)I] can damage DNA. One way to prevent this is to increase the amount of antioxidants via dietary consumption. The goal of this study was to evaluate the radioprotective effect of fresh acerola pulp and synthetic beta-carotene in Rattus norvegicus hepatoma cells (HTC) in response to [(131)I] exposure in vitro. Cellular DNA damage was subsequently assessed using a cytokinesis block micronucleus assay. The mutagenic and cytotoxic activities of doses of [(131)I] (0.1, 0.5, 1, 5, and 10 µCi), acerola (0.025, 0.125, and 0.25 g acerola pulp/mL), and beta-carotene (0.2, 1, and 2 µM) were evaluated. Radioprotective tests were performed by simultaneous treatment with acerola (0.25 g/mL) plus [(131)I] (10 µCi) and beta-carotene (0.2 µM) plus [(131)I] (10 µCi). Acerola, beta-carotene, and low concentrations of [(131)I] did not induce micronucleus formation in HTC cells; in contrast, high concentrations of [(131)I] (10 µCi) were mutagenic and induced DNA damage. Moreover, neither acerola nor beta-carotene treatment was cytotoxic. However, acerola reduced the percentage of [(131)I]-induced damage, although beta-carotene did not show a similar effect. Thus, our results suggest that acerola diet supplementation may benefit patients who are exposed to [(131)I] during thyroid diagnostics and therapy.

Antibody landscape of C57BL/6 mice cured of B78 melanoma via immunotherapy.

Hoefges et al. utilized a whole-proteome peptide array approach to show that C57BL/6 mice develop a large repertoire of antibodies against linear peptide sequences of their melanoma after receiving a curative immunotherapy regimen consisting of radiation and an immunocytokine. Antibodies can play an important role in innate and adaptive immune responses against cancer, and in preventing infectious disease. Flow cytometry analysis of sera of immune mice that were previously cured of their melanoma through a combined immunotherapy regimen with long-term memory showed strong antibody-binding against melanoma tumor cell lines. Using a high-density whole-proteome peptide array, we assessed potential protein-targets for antibodies found in immune sera. Sera from 6 of these cured mice were analyzed with this high-density, whole-proteome peptide array to determine specific antibody-binding sites and their linear peptide sequence. We identified thousands of peptides that were targeted by 2 or more of these 6 mice and exhibited strong antibody binding only by immune, not naive sera. Confirmatory studies were done to validate these results using 2 separate ELISA-based systems. To the best of our knowledge, this is the first study of the "immunome" of protein-based epitopes that are recognized by immune sera from mice cured of cancer via immunotherapy.

Comparison of SpectraCell RA typing and multilocus sequence typing for extended-spectrum-ß-lactamase-producing Escherichia coli.

Multilocus sequence typing (MLST) is one of the most reliable methods for typing of Escherichia coli, including extended-spectrum-ß-lactamase-producing E. coli (ESBL-EC). We investigated the performance of a new typing method, SpectraCell RA (River Diagnostics, Madison, WI), in comparison on MLST on a well-defined collection of ESBL-EC isolates obtained from chicken meat and humans. Ninety-two ESBL-EC isolates obtained from meat and 59 ESBL-EC isolates obtained from human rectal swabs and clinical blood cultures were typed using MLST and SpectraCell RA. The sensitivity and specificity of SpectraCell RA were calculated, using MLST as a reference method. Subsequently, the results of SpectraCell RA were used to determine the relatedness of ESBL-EC isolates from chicken and humans. Using MLST as the gold standard, the performance of SpectraCell RA was evaluated for 3 different cutoff values: 0.99975, 0.99955, and 0.99935. Depending on the cutoff value, the sensitivity was mediocre to unacceptably low, with values of 9.4%, 43.9%, and 66.7%, respectively. When sensitivity increased, the specificity decreased rapidly, from 95.6% to 69.8% and 34.4%, respectively. Also, the number of clusters containing both human and meat samples varied from 0 (0.0%) to 14 (38.9%). Our study shows that SpectraCell RA is not a suitable typing method for ESBL-EC when evaluating relationships of ESBL-EC at the population level.

Dual-wavelength passive and hybrid mode-locking of 3, 4.5 and 10 GHz InAs/InP(100) quantum dot lasers.

We present an investigation of passive and hybrid mode-locking in Fabry-Pérot type two-section InAs/InP(100) quantum dot lasers that show dual wavelength operation. Over the whole current and voltage range for mode-locking of these lasers, the optical output spectra show two distinct lobes. The two lobes provide a coherent bandwidth and are verified to lead to two synchronized optical pulses. The generated optical pulses are elongated in time due to a chirp which shows opposite signs over the two spectral lobes. Self-induced mode-locking in the single-section laser shows that the dual-wavelength spectra correspond to emission from ground state. In the hybrid mode-locking regime, a map of locking range is presented by measuring the values of timing jitter for several values of power and frequency of the external electrical modulating signal. An overview of the systematic behavior of InAs/InP(100) quantum dot mode-locked lasers is presented as conclusion.

Hybrid III/V silicon photonic source with integrated 1D free-space beam steering.

A chip-scale optical source with integrated beam steering is demonstrated. The chip was fabricated using the hybrid silicon platform and incorporates an on-chip laser, waveguide splitter, amplifiers, phase modulators, and surface gratings to comprise an optical phased array with beam steering across a 12° field of view in one axis. Tuning of the phased array is used to achieve 1.8°(steered axis)×0.6°(nonsteered axis) beam width with 7 dB background suppression for arbitrary beam direction within the field of view.

Expression of the T-cell regulatory marker FOXP3 in primary cutaneous large B-cell lymphoma tumour cells.

BACKGROUND: Primary cutaneous B-cell lymphomas (PCBCL) are subdivided into the aggressive form, primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL, LT) and two subtypes of indolent behaviour (primary cutaneous follicle centre lymphoma and primary cutaneous marginal zone B-cell lymphoma). The difference in clinical behaviour can be explained by the tumour cell itself, or the lymphoma microenvironment including the antitumour immune response. OBJECTIVES: To investigate the presence of regulatory T cells (Treg), CD4+CD25+FOXP3+, in the microenvironment of PCBCL in correlation with clinical outcome. METHODS: Tumour specimens of 55 consecutive cases of PCBCL were blinded and analysed for FOXP3, CD4 and CD25 expression by immunohistochemistry. Confocal images were taken with a Leica SP5. Statistical analyses were performed to determine significance. The test was considered significant when P<0.05. RESULTS: The CD4 and FOXP3 expression as well as the CD4/FOXP3 ratio were significantly increased in PCBCL of indolent behaviour in contrast to PCLBCL, LT (P=0.0002 for CD4, P<0.0001 for FOXP3 and P=0.0345 for FOXP3/CD4 ratio). CD25 expression did not differ in the three groups (P=0.9414). Within the group of patients with PCLBCL, LT we identified a subgroup with FOXP3+ tumour cells as demonstrated by CD20/FOXP3 double stainings. Patients with FOXP3+ PCLBCL, LT tumour cells showed a better prognosis on Kaplan-Meier analysis. CONCLUSION: High numbers of Treg in the lymphoma microenvironment correlate with a better prognosis in PCBCL. In PCLBCL, LT the presence of FOXP3+ tumour cells is beneficial for prognosis suggesting that FOXP3 expression of PCLBCL, LT tumour cells might serve as a tumour suppressor.

Outbreak of Salmonella Thompson in the Netherlands since July 2012.

An ongoing outbreak of salmonellosis due to Salmonella Thompson is affecting the Netherlands. Between 2 August and 19 October 2012, 866 cases were confirmed. Their median age was 44 years (range: 0-95 years), 63% were female and 36% were hospitalised. A matched case-control study suggested smoked salmon as the vehicle. Salmonella Thompson was confirmed in four of nine batches of smoked salmon from one producer. A recall of all concerned smoked salmon products was executed starting end of September.

[Foam sclerotherapy. Uses and indications in dermatology and phlebology]. / Schaumsklerosierung. Anwendung und Indikation in der Dermatologie und Phlebologie.

Foam sclerotherapy is a minimally invasive, effective technique for the treatment of varicoses up though venous malformations. This efficient therapy can be easily integrated in daily clinical practice and shows only minor side effects. It provides an alternative to invasive therapies like vein stripping, endovenous laser therapy or endovenous radiofrequency ablation, but without the need for anesthesia. The treatment can be performed in an outpatient setting and the patient is able to return quickly to everyday life.