Lead Time from First Suspicion of Malignant Melanoma in Primary Care to Diagnostic Excision: a Cohort Study Comparing Teledermatoscopy and Traditional Referral to a Dermatology Clinic at a Tertiary Hospital.

INTRODUCTION: The increasing use of teledermatoscopy in clinical practice has led to demands to evaluate the effects of this new technology on traditional healthcare systems. OBJECTIVES: To study lead times from first consultation in primary care to diagnostic excision of suspected malignant melanoma lesions in traditional referrals to a tertiary hospital-based dermatology clinic compared with mobile teledermatoscopy referrals. METHODS: A retrospective cohort study design was used. Data on sex, age, pathology, caregivers, clinical diagnosis, date for first visit to primary care unit, and date for diagnostic excision were collected from medical records. Patients managed through traditional referral (n=53) were compared with patients managed at primary care units using teledermatoscopy (n=128) regarding lead time from first visit to diagnostic excision. RESULTS: Mean time from date of first visit at primary care unit to diagnostic excision did not differ between the traditional referral and teledermatoscopy groups (16.2 vs. 15.7 days, median 10 vs. 13 days, p=0.657). Lead times from date of referral to diagnostic excision did not significantly differ (15.7 vs. 12.8 days, median 10 vs. 9 days, p=0.464). CONCLUSIONS: Our study indicates that lead time to diagnostic excision for patients with suspected malignant melanoma managed by teledermatoscopy was comparable and not inferior to that of the traditional referral pathway. If teledermatoscopy is used at first consultation in primary care, it could potentially be more efficient than traditional referral.

Contribution of mutant HSC clones to immature and mature cells in MDS and CMML, and variations with AZA therapy.

Myelodysplastic neoplasms (MDSs) and chronic myelomonocytic leukemia (CMML) are clonal disorders driven by progressively acquired somatic mutations in hematopoietic stem cells (HSCs). Hypomethylating agents (HMAs) can modify the clinical course of MDS and CMML. Clinical improvement does not require eradication of mutated cells and may be related to improved differentiation capacity of mutated HSCs. However, in patients with established disease it is unclear whether (1) HSCs with multiple mutations progress through differentiation with comparable frequency to their less mutated counterparts or (2) improvements in peripheral blood counts following HMA therapy are driven by residual wild-type HSCs or by clones with particular combinations of mutations. To address these questions, the somatic mutations of individual stem cells, progenitors (common myeloid progenitors, granulocyte monocyte progenitors, and megakaryocyte erythroid progenitors), and matched circulating hematopoietic cells (monocytes, neutrophils, and naïve B cells) in MDS and CMML were characterized via high-throughput single-cell genotyping, followed by bulk analysis in immature and mature cells before and after AZA treatment. The mutational burden was similar throughout differentiation, with even the most mutated stem and progenitor clones maintaining their capacity to differentiate to mature cell types in vivo. Increased contributions from productive mutant progenitors appear to underlie improved hematopoiesis in MDS following HMA therapy.

Early post-operative nausea and vomiting: A retrospective observational study of 2030 patients.

BACKGROUND: The overall risk of post-operative nausea and vomiting (PONV) after general anaesthesia is reportedly 20%-40%. The first episode of PONV may occur early in the post-anaesthesia care unit (PACU) or later at the ward or after discharge at home in an ambulatory setting. This study aimed to investigate and describe the risk of early PONV in a PACU, and we hypothesised that patients and perioperative factors were associated with early PONV. METHODS: This single-centre retrospective observational study was conducted in a Swedish county hospital from January to June 2017 and included adult patients who underwent surgical procedures under general anaesthesia. Perioperative data were obtained by reviewing the local registry for surgical procedures, medical records and anaesthesia and post-operative charts. Early PONV was defined as PONV occurring up to 4 hours post-operatively at the PACU. Any notification in the medical records, perioperative charts or the registry regarding nausea, vomiting or PONV treatment was regarded as PONV. Univariate and multivariate analyses were performed for factors associated with early PONV. RESULTS: A total of 2030 patients were included in the study, of which 9.6% (n = 194) experienced early PONV. Factors associated with a high risk of early PONV were suboptimal PONV prophylaxis, need for opioids, female sex, body mass index >35 kg m-2 and major surgery and anaesthesia time ≥60 minutes. CONCLUSION: We found that every 10th patient under general anaesthesia experienced early PONV. Suboptimal PONV prophylaxis and previously acknowledged risk factors for PONV were associated with early PONV.

Association Between Atopic Dermatitis and Cardiovascular Disease: A Nationwide Register-based Case-control Study from Sweden.

The associations between atopic dermatitis (AD) and cardiovascular disease (CVD) are debated. The aim of this study was to investigate the association between AD and coronary artery disease or ischaemic stroke in a nationwide, register-based, case-control study (104,832 AD cases, 1,022,435 controls) based on linkage of Swedish national register data between 1968 and 2016. Patients were classified as having severe AD if they had received systemic pharmacotherapy for AD or had been treated in a dermatological ward with AD as the main diagnosis. Other AD was classified as non-severe. After multivariable adjustments for comorbidities and socioeconomic status, overall AD was associated with angina pectoris (adjusted odds ratio (aOR) 1.13, 95% confidence interval (CI) 1.08-1.19), but among males with severe AD this association was not found, compared with the general population. Male non-severe AD was associated with myocardial infarction (OR 1.15, 95% CI 1.07-1.23). Severe AD was associated with ischaemic stroke, with similar estimates in men and women (aOR 1.19, 95% CI 1.07-1.33). Subgroup analyses among women indicated smoking as an important risk factor among severe cases. Dia-betes mellitus, hyperlipidaemia, and hypertension were more prevalent in severe AD than in controls, and hyper-lipidaemia and hypertension were also more prevalent in non-severe AD than in controls. In conclusion, in this study, AD was associated with CVD, and this should be kept in mind, especially when managing patients with severe AD.

Severe Photo Toxicity Recalled by Docetaxel.

Photo-recall phenomenon is a rarely recognized adverse event of chemotherapeutic agents. The physiopathology of this entity is unclear. We have reported a 56-year old breast cancer patient with severe photo toxicity recalled 5 months after the initial sunburn by one course of adjuvant docetaxel treatment. However, being given right diagnosis and proper managements the patient could be able to complete her adjuvant chemotherapy according to the planed time schedule, without any delay. Our case may be explained by the theory that long-lived memory T-cells may remember former skin damage and cross-react with cytotoxic drugs. In addition, we have proved that weekly paclitaxel can still be the drug of option after docetaxel recalled severe photo toxicity.

Prognosis of Preschool Eczema and Factors of Importance for Remission.

Information on factors of importance for remission of eczema is scarce. This study explored factors related to the remission and course of preschool eczema (PSE) (eczema at 1, 2 and/or 4 years of age) to 16 years of age (n = 889) in a Swedish cohort. Half of the children were in complete remission by school age (at age 8, 12, and 16 years). In multivariate prognostic models, persistent PSE (eczema at 1, 2 and 4 years of age) (odds ratio 0.27 (95% confidence interval 0.18-0.41)), PSE with sleep disturbance (due to itch at least once a week at 1, 2 and/or 4 years of age) (0.59 (0.43-0.81)), parental allergy (0.73 (0.55-0.96)), parental smoking at child's birth (0.70 (0.50-0.99)) and filaggrin mutation (R501X, R2447X, 2282del4) (0.47 (0.26-0.85)) were inversely associated with complete remission by school age. Male sex (1.37 (1.03-1.82)) and exclusive breastfeeding ≥4 months (1.44 (1.01-2.05)) were positively associated with complete remission by school age. In conclusion, half of the children with PSE were in complete remission by school age. The most important prognostic factors were persistent PSE and PSE with sleep disturbance due to itch.

[Atopic eczema common at all ages]. / Atopiskt eksem vanligt i alla åldrar - Nya rön om samsjuklighet till atopiskt eksem.

Atopic eczema common at all ages Eczema (atopic dermatitis) is an inflammatory skin disorder with dry skin and recurrent episodes of inflammation and itch. Onset is most common the first two years of life, but also occurs among older children, adolescents and adults. The prevalence of eczema has increased in Sweden and other industrialized countries the last decades; 15-30% of children and 2-10% of adults are affected. Approximately half of children with eczema early in life are in remission in adolescence. However, many of these will relapse later in life, often as hand eczema. Children with eczema are at increased risk to develop IgE sensitization to common food- and airborne allergens, food allergy, asthma and rhinitis. In addition, recent studies have reported that having eczema is associated with non-allergic disorders such as ADHD, depression and anxiety, epilepsy, overweight and obesity, cardiovascular disease, and different kinds of malignancies. There are also studies that have not found an association between eczema and the above mentioned non-allergic comorbidities. Thus, the association between eczema and non-allergic comorbidities are still largely unknown.

Surface functionalization affects the zeta potential, coronal stability and membranolytic activity of polymeric nanoparticles.

Nano materials are commonly functionalized to boost their physicochemical properties. However, there is little known about the impact of these modifications on cellular systems. Herein, we synthesized eight types of polymeric nanoparticles (NPs) bearing different functional groups, and investigated their effects on interactions with cellular membranes. As models for particle membrane interactions, hemolysis assays using human red blood cells and culture with A549 cells were utilized. Under protein-free conditions, the NPs showed a wide distribution of zeta potentials (ζPs) which showed a good correlation with their hemolytic potential. However, in the presence of serum or lung lining fluid, the ζPs of all NPs coalesced towards a single common negative value and showed neither hemolytic activity nor cytotoxicity to A549 cells. Lipase and protease treatment of the coronated particles did not restore their reactivity. These result simply proves that particle functionalization influences the stability of the particle corona which, if intact, prevents hemolytic activity and membrane disrupture.

Shape engineering vs organic modification of inorganic nanoparticles as a tool for enhancing cellular internalization.

In nanomedicine, physicochemical properties of the nanocarrier affect the nanoparticle's pharmacokinetics and biodistribution, which are also decisive for the passive targeting and nonspecific cellular uptake of nanoparticles. Size and surface charge are, consequently, two main determining factors in nanomedicine applications. Another important parameter which has received much less attention is the morphology (shape) of the nanocarrier. In order to investigate the morphology effect on the extent of cellular internalization, two similarly sized but differently shaped rod-like and spherical mesoporous silica nanoparticles were synthesized, characterized and functionalized to yield different surface charges. The uptake in two different cancer cell lines was investigated as a function of particle shape, coating (organic modification), surface charge and dose. According to the presented results, particle morphology is a decisive property regardless of both the different surface charges and doses tested, whereby rod-like particles internalized more efficiently in both cell lines. At lower doses whereby the shape-induced advantage is less dominant, charge-induced effects can, however, be used to fine-tune the cellular uptake as a prospective 'secondary' uptake regulator for tight dose control in nanoparticle-based drug formulations.

Glycopeptide dendrimer colchicine conjugates targeting cancer cells.

Screening of a 65,536-member one-bead-one-compound (OBOC) combinatorial library of glycopeptide dendrimers of structure ((betaGal)(n)(+1)X(8)X(7)X(6)X(5))(2)DapX(4)X(3)X(2)X(1)(beta-Gal)(m) (betaGal=beta-galactosyl-thiopropionic acid, X(8-1)=variable amino acids, Dap=l-2,3-diaminopropionic acid, n, m=0, or 1 if X(8)=Lys resp. X(1)=Lys) for binding of Jurkat cells to the library beads in cell culture, resynthesis and testing lead to the identification of dendrimer J1 (betaGal-Gly-Arg-His-Ala)(2)Dap-Thr-Arg-His-Asp-CysNH(2) and related analogues as delivery vehicles. Cell targeting is evidenced by FACS with fluorescein conjugates such as J1F. The colchicine conjugate J1C is cytotoxic with LD(50)=1.5 microM. The beta-galactoside groups are necessary for activity, as evidenced by the absence of cell-binding and cytotoxicity in the non-galactosylated, acetylated analogue AcJ1F and AcJ1C, respectively. The pentagalactosylated dendrimer J4 betaGal(4)(Lys-Arg-His-Leu)(2)Dap-Thr-Tyr-His-Lys(betaGal)-Cys) selectively labels Jurkat cell as the fluorescein derivative J4F, but its colchicine conjugate J4C lacks cytotoxicity. Tubulin binding assays show that the colchicine dendrimer conjugates do not bind to tubulin, implying intracellular degradation of the dendrimers releasing the active drug.

Systemic reduction of functionally suppressive CD4dimCD25highFoxp3+ Tregs in human second trimester pregnancy is induced by progesterone and 17beta-estradiol.

CD4(+)CD25(high) regulatory T cells (Tregs) are implicated in the maintenance of murine pregnancy. However, reports regarding circulating Treg frequencies in human pregnancy are inconsistent, and the functionality and phenotype of these cells in pregnancy have not been clarified. The aim of this study was to determine the frequency, phenotype, and function of circulating Tregs in the second trimester of human pregnancy and the influence of progesterone and 17beta-estradiol on Treg phenotype and frequency. Based on expressions of Foxp3, CD127, and HLA-DR as determined by multicolor flow cytometry, we defined a proper CD4(dim)CD25(high) Treg population and showed, in contrast to most previous reports, that this population was reduced in second trimester of pregnancy. Unexpectedly, Foxp3 expression was decreased in the Treg, as well as in the CD4(+) population. These changes could be replicated in an in vitro system resembling the pregnancy hormonal milieu, where 17beta-estradiol, and in particular progesterone, induced, in line with the pregnancy situation, a reduction of CD4(dim)CD25(high)Foxp3(+) cells in PBMC from nonpregnant women. By coculturing FACS-sorted Tregs and autologous CD4(+)CD25(-) responder cells, we showed that Tregs from pregnant women still displayed the same suppressive capacity as nonpregnant women in terms of suppressing IL-2, TNF-alpha, and IFN-gamma secretion from responder cells while efficiently producing IL-4 and IL-10. Our findings support the view of hormones, particularly progesterone, as critical regulators of Tregs in pregnancy. Furthermore, we suggest that in the light of the results of this study, early data on circulating Treg frequencies in pregnancy need reevaluation.

Glycopeptide dendrimers with high affinity for the fucose-binding lectin LecB from Pseudomonas aeruginosa.

The fucose-specific lectin LecB is implicated in tissue binding and biofilm formation by the opportunistic pathogen Pseudomonas aeruginosa, which causes severe respiratory tract infections mainly in immunocompromised patients or cancer patients undergoing chemotherapy. With a view to developing multivalent LecB inhibitors as novel antibacterial agents, a combinatorial library containing 15 625 tetravalent C-fucosyl peptide dendrimers with the basic structure (CFuc-X(6)X(5)X(4))(4)(LysX(3)X(2)X(1))(2)LysIleHisNH(2) (CFuc=alpha-L-fucosyl acetic acid, X(1-6)=amino acids, Lys=lysine branching) was screened for lectin binding using on-bead binding assays. Ten tetravalent and three octavalent dendrimers derived from the identified sequences were prepared by solid-phase peptide synthesis (SPPS), cleaved from the resin, and purified by preparative HPLC. Relative affinities of these soluble ligands to LecB were determined by an enzyme-linked lectin assay (ELLA). Strong binding was observed for tetravalent and octavalent ligands, with up to 440-fold enhancement in potency over fucose for the octavalent cationic dendrimer 2G3 (CFuc-LysPro)(8)(LysLeuPhe)(4)(LysLysIle)(2)LysHisIleNH(2)). Mono- and divalent controls showed affinities similar to fucose, highlighting the importance of multivalency for binding. Docking studies showed that the C-fucosyl group of the dendrimers can adopt the same binding mode as fucose itself, with the peptide arms protruding from the binding pocket and establishing specific contacts with the lectin.

Development and initial evaluation of PEG-stabilized bilayer disks as novel model membranes.

We show in this study that stable dispersions dominated by flat bilayer disks may be prepared from a carefully optimized mixture of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-5000] [PEG-DSPE(5000)]. By varying the content of the latter component, the average diameter of the disks can be changed in the interval from about 15 to 60 nm. The disks show excellent long-term stability, and their size and structure remain unaltered in the temperature range between 25 and 37 degrees C. The utility of the disks as artificial model membranes was confirmed and compared to uni- and multilamellar liposomes in a series of drug partition studies. Data obtained by isothermal titration calorimetry and drug partition chromatography (also referred to as immobilized liposome chromatography) indicate that the bilayer disks may serve as an attractive and sometimes superior alternative to liposomes in studies aiming at the investigation of drug-membrane interactions. The disks may, in addition, hold great potential for structure/function studies of membrane-bound proteins. Furthermore, we suggest that the sterically stabilized bilayer disks may prove interesting as carriers for in vivo delivery of protein/peptide, as well as conventional amphiphilic and/or hydrophobic, drugs.