Guselkumab Treatment Outcomes and Persistence in a Nationwide Real-world Cohort of Patients with Plaque Psoriasis.

Guselkumab treatment outcomes and persistence were assessed in a real-world cohort of Finnish patients with difficult-to-treat plaque psoriasis over a median follow-up of 1 year. Data on 181 patients who initiated guselkumab at the 15 study centres were collected retrospectively from the patient charts. Prior exposure to biologic therapies was common, with 56% and 35% having used at least 1 and 2 biologics, respectively. Median guselkumab treatment duration was 11 months with 21 patients (12%) discontinuing treatment during follow-up. Of 85 patients with a follow-up duration of at least 1 year, 73 (86%) were still on guselkumab at 1 year. Significant improvements during follow-up were seen in the absolute Psoriasis Area and Severity Index (PASI) scores with 32 patients (80%) having absolute PASI ≤ 2 after a 9-14-month treatment. Guselkumab treatment was effective and treatment persistence was high in the nationwide Finnish real-life setting.

Management of Ocular Manifestations of Atopic Dermatitis: A Consensus Meeting Using a Modified Delphi Process.

There is a need for unified guidance on the management of ocular manifestations of atopic dermatitis and ocular manifestations associated with dupilumab in the Nordic region (Denmark, Finland, Norway and Sweden). This initiative gathered Nordic dermatologists and ophthalmologists to identify consensus in this area using a modified Delphi process. The initiative was led by a Nordic expert panel who developed a questionnaire that was circulated to a wider group. The results informed an agenda consisting of 24 statements to be voted on using a 5-point Likert scale at a meeting in Copenhagen on 24 April 2019. A facilitator moderated discussion and revised statements according to expert feedback for a second vote when required to reach consensus. Consensus was reached for 23 statements regarding the diagnosis, treatment and referral of these patients, which we hope will improve patient management in the Nordic region.

Follow-up of six patients with neurofibromatosis 1-related osteoporosis treated with alendronate for 23 months.

This is the first prospective follow-up study to describe the effects of oral alendronate medication on neurofibromatosis 1 (NF1)-related osteoporosis. NF1 is a neurocutaneous skeletal syndrome associated with increased fracture risk and high frequency of osteopenia and osteoporosis. Alendronate is a bisphosphonate drug which inhibits the function of bone-resorbing osteoclasts, ultimately leading to an increase in bone mineral density (BMD) and reduction in fracture risk. However, in vitro studies have shown that NF1 osteoclasts display insensitivity to apoptotic signals caused by bisphosphonates. Our aim was to monitor the effects of alendronate medication in patients with NF1. Five men and one woman, aged 28-76 years, with NF1-related osteoporosis were enrolled to the study. Study participants did not have other conditions and were not taking any medication known to affect bone. The medication included a weekly dose of 70 mg alendronate and a daily 20 µg vitamin D supplementation. After 23 months of follow-up, BMD was increased in five out of six patients, but the increase was not statistically significant. Serum levels of the bone turnover markers CTX and PINP were reduced, suggesting slower bone remodeling, as expected. An unexpected result was that serum levels of the osteoclast activity marker TRAP5b did not change during the follow-up. One new stress fracture of the tibia was documented during the alendronate therapy. Even though the study group was small, the findings of the current study (one new fracture and one patient with decreased BMD) call for a larger study to assess the efficacy of bisphosphonates in NF1-related osteoporosis.

Neurofibromatosis 1-related osteopenia often progresses to osteoporosis in 12 years.

The current study is based on our earlier investigation carried out in 1999, where bone mineral density (BMD) of 35 neurofibromatosis type 1 (NF1) patients was measured and osteoporosis was shown to be common in NF1. The findings have been confirmed by a number of later publications. The purpose of the current longitudinal study was to assess the bone health of these 35 NF1 patients 12 years after the initial study. A total of 28 patients were reached, and BMD of 19 patients was subsequently remeasured. Fracture history of 28/35 NF1 patients who were reached was verified from the medical records. Six NF1 patients had osteoporosis in 1999, and three of them had an osteoporotic fracture between 1999 and 2011, showing an increased fracture risk compared to NF1 patients without osteoporosis. BMD of 19 patients was remeasured in 2011, and four patients who had osteopenia in 1999 had osteoporosis in 2011. The decrease in BMD was not explained by changes in smoking habits, physical activity, sunlight exposure, body mass index, or laboratory parameters, even though secondary hyperparathyroidism was common. Osteoporosis was found in 2011 in patients aged 37 years or older, both men and women. The results showed that NF1-related osteopenia often progresses to osteoporosis since BMD decreases with aging even in young patients. Even though our sample size was 19 patients, we recommend follow-up of NF1 patients with osteopenia and consideration of prophylactic measures to prevent osteoporosis and associated fracture risk.

Impaired gap junction formation and intercellular calcium signaling in urinary bladder cancer cells can be improved by Gö6976.

PURPOSE: Calcium wave propagation and connexin 26, 32 and 43 expression were studied in normal and malignant urothelial cells. MATERIALS AND METHODS: Human urothelial cell cultures were established from tissue biopsies obtained from three healthy control persons and compared to human transitional cell carcinoma (TCC) cell line 5637. Fluo-3 was used to study intercellular calcium signaling in urothelial cells. The cells were stimulated mechanically in the presence of inhibitors of gap-junctional or ATP-mediated communication to determine which pathways are operative in intercellular calcium signaling. In addition, Gö6976 was used to determine the effects of PKC alpha and betaI inhibition on intercellular calcium signaling. RESULTS: In normal urothelial cells, the primary pathway for intercellular calcium mediated cell signaling was gap junctional intercellular communication (GJIC), but the paracrine ATP-mediated signaling was also operative. In 5637 TCC cells, GJIC and ATP-mediated signaling routes were altered when compared to normal urothelial cells. More specifically, inhibition of GJIC resulted in a complete block of intercellular calcium signaling, while inhibition of ATP-mediated signaling decreased signal transduction in 5637 TCC cells. The results of the present study also demonstrated that connexin 26 was the most abundant gap junction plaque protein in cultured normal human urothelial cells and that it did not form gap junction plaques in 5637 TCC cell culture. Treatment with Gö6976 induced gap junction plaque formation by connexin 26 in 5637 TCC cells. In addition, the exposure to Gö6976 enhanced intercellular calcium mediated signaling in 5637 TCC cells, but not in normal cells. CONCLUSIONS: The results of the present study suggest that gap junctions play a major role in intercellular calcium signaling in urothelial cells. In addition, intercellular calcium signaling is altered in urinary bladder carcinoma cells, and it can be improved by PKC alpha and betaI inhibition. (Supplementary materials are available for this article. Go to the publisher's online edition of Cell Communication and Adhesion for the following free supplemental resources; Movie files of Fig. 2normal Gö6976-, normal Gö6976+, TCC Gö6976-, TCC Gö6976+ and image of Supplementary Figure 1).

Sex hormone-binding globulin and insulin-like growth factor-binding protein-1 as indicators of metabolic syndrome, cardiovascular risk, and mortality in elderly men.

Two binding proteins, SHBG and IGF-binding protein-1 (IGFBP-1), are both down-regulated by insulin and therefore could serve as potential indicators of the metabolic syndrome and hyperinsulinemia-related cardiovascular risk. We compared serum SHBG and IGFBP-1 as potential markers of abnormal glucose tolerance, the metabolic syndrome, diabetes mellitus, cardiovascular risk factors, and total, cardiovascular, and coronary heart disease mortality in elderly men. Of the original cohort of 1711 men, 524 were alive on January 1, 1989, and 413 participated in the 30-yr examination, of whom 335 men, aged 70-89 yr, formed the study group for the present analysis. Low SHBG and IGFBP-1 were both associated with an increased prevalence of abnormal glucose tolerance and the metabolic syndrome, but only SHBG was associated with diabetes mellitus. SHBG was less influenced by body mass index than IGFBP-1. Low SHBG indicated increased cardiovascular and coronary disease mortality; the association remained after adjustment for abnormal glucose tolerance, but not after adjustment for prevalent cardiovascular disease. IGFBP-1 had no association with mortality. It is concluded that low SHBG is a better indicator of increased cardiovascular mortality than low or high IGFBP-1.

The effect of extracellular calcium concentration on calcium-mediated cell signaling in NF1 tumor suppressor-deficient keratinocytes.

Capacitative calcium entry and calcium wave propagation were studied in keratinocytes from healthy volunteers and patients with type 1 neurofibromatosis (NF1) in calcium-depleted and in low calcium culture medium. In previous studies, we found evidence that mutations of the NF1 tumor suppressor gene can lead to altered calcium-mediated cell signaling in keratinocytes cultured in the presence of a high extracellular calcium concentration. The present study demonstrated that the differences between normal and NF1 keratinocytes were dependent on extracellular calcium concentration. Specifically, when keratinocytes were exposed to thapsigargin under calcium-depleted culture conditions the subsequent increase in free intracellular calcium concentration was moderate in NF1 keratinocytes compared to controls. The finding indicates lowered endoplasmic calcium stores in NF1 which may also in part explain the reduced activation signal for capacitative calcium influx and the wound-induced intracellular Ca2+ transient observed in NF1 keratinocytes maintained in culture medium containing 0.05 mM calcium. The differences between control and NF1 keratinocytes were most pronounced when the cells were cultured in the presence of a high (1.8 mM) calcium concentration. Since elevated extracellular calcium levels induce keratinocytes to form cellular contacts and lead to terminal differentiation, markedly aberrant responses of NF1 keratinocytes in the presence of a high calcium concentration may help to explain previous findings on impaired formation of cellular junctions and differentiation in NF1 deficient cells.

Endothelium-derived nitric oxide metabolites and soluble intercellular adhesion molecule-1 in diabetic and normal pregnancies.

OBJECTIVE: Endothelial dysfunction has been demonstrated in adult subjects with diabetes. We studied if maternal diabetes is associated with altered endothelial function in the fetus, as this might shed light on mechanisms by which adult diseases are programmed in utero. STUDY DESIGN: Total nitrate/nitrite (NOx) concentration was measured spectrophotometrically with the Griess reagent method. Soluble intercellular adhesion molecule-1 (sICAM-1) concentration was measured by enzyme-linked immunoassay. RESULTS: Venous cord serum NOx concentration at birth was highest in pregnancies complicated by type 1 diabetes (29.5+/-1.8 micromol/l, n=63) (P<0.0001 versus controls) and lowest in normal pregnancies (19.0+/-1.0 micromol/l, n=56). The concentration was intermediate in pregnancies complicated by gestational diabetes (23.9+/-2.7 micromol/l, n=24), but not significantly higher than in normal pregnancies (P=0.172). Venous cord serum sICAM-1 concentration did not differ between the three groups (P=0.191). Maternal serum NOx concentration in the third trimester was higher in pregnancies complicated by type 1 diabetes (22.9+/-3.4 micromol/l, n=22) than in normal pregnancies (15.4+/-1.4 micromol/l, n=21) (P=0.049). CONCLUSIONS: : Increased cord serum NOx but unaltered sICAM-1 concentration in diabetic pregnancies indicates that maternal diabetes does not cause a general alteration in fetal endothelial function. The increase in cord serum and maternal serum NOx concentration in diabetic pregnancies may be due to abnormalities in insulin-induced nitric oxide release or to a diminished reactivity of the vasculature to the effects of nitric oxide.

Reduced IGFBP-1 is associated with thickening of the carotid wall in type 2 diabetes.

OBJECTIVE: The aim of the present study was to assess the role of the insulin-like growth factor (IGF) system and lipids in predicting the carotid intima-media thickness (IMT) in type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 239 type 2 diabetic participants in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study (76 women) aged 50-75 years were examined before fenofibrate intervention. Patients underwent carotid ultrasonography for determination of IMT. IGF-I, IGF binding protein 1 (IGFBP-1), IGFBP-3, cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, apolipoprotein B (apoB), lipoprotein(a) (Lp(a)), glucose, HbA(1c), and C-peptide were measured in fasting samples. Patients were divided in groups without (n = 168) and with (n = 71) clinical cardiovascular disease (CVD). RESULTS: Partial correlations adjusted for age, sex, BMI, and diabetes duration showed an inverse association of IGFBP-1 with C-peptide (r = -0. 24, P = 0.018) and with maximal IMT (r = -0.42, P < 0.001), whereas IGF I and IGFBP-3 correlated positively with several risk-promoting lipid parameters. In linear regression analysis controlling for age, sex, BMI, diabetes duration, and presence or absence of oral antihyperglycemic or insulin medication, determinants of IMT were age, IGFBP-1, pulse pressure, Lp(a), diabetes duration, and insulin treatment. IGFBP-1 persisted in the model for subjects with CVD. CONCLUSIONS: In summary, a decrease in IGFBP-1 is a marker of carotid IMT thickening in patients with type 2 diabetes.

Postpartum bone mineral density in women treated for thromboprophylaxis with unfractionated heparin or LMW heparin.

Venous thromboembolism remains an important cause of maternal mortality. In a randomised open study, 44 pregnant women with confirmed previous or current thromboembolism were randomised to receive either low-molecular-weight heparin, dalteparin (N = 21) once daily subcutaneously or unfractionated sodium heparin (UF heparin, N = 23) twice daily subcutaneously for thromboprophylaxis during pregnancy and puerperium. Bone mineral density (BMD) in the lumbosacral spine was measured with dual X-ray absorptiometry (DEXA) 1, 6, 16, 52 weeks and, if possible, 3 years after delivery. BMD values were also compared with those of healthy, delivered women (N = 19). Mean BMD of the lumbar spine was significantly lower in the unfractionated heparin group compared with the dalteparin and with the control groups (repeated measures ANOVA p = 0.02). BMD in the dalteparin group did not differ from BMD of healthy delivered women. Multiple logistic regression analysis revealed that therapy was the only independent factor influencing BMD at weeks 16 and 52. Therefore we recommend use of dalteparin instead of UF heparin for long-term thromboprophylaxis during and after pregnancy.

Diabetic pregnancy associated with increased epidermal growth factor in cord serum at term.

OBJECTIVE: Epidermal growth factor is a ubiquitous mitogen that also possesses insulin-like properties. Fetal mal-growth is associated with altered epidermal growth factor levels. Maternal diabetes is frequently complicated by macrosomia, but the effect of maternal diabetes on fetal epidermal growth factor levels is not known. We studied cord serum epidermal growth factor concentrations in pregnancies complicated by diabetes and in normal pregnancies. METHODS: Cord serum epidermal growth factor concentrations were measured at birth by a sandwich-type time-resolved immunofluorometric assay in 63 pregnancies complicated by insulin-dependent diabetes mellitus, in 25 pregnancies complicated by insulin-treated gestational diabetes, and in 56 normal pregnancies. RESULTS: Cord serum epidermal growth factor correlated positively with the duration of pregnancy in diabetic and normal pregnancies. In a subgroup of women at similar gestational ages (38-39 weeks), cord serum epidermal growth factor concentrations were higher in pregnancies complicated by insulin-dependent diabetes mellitus (962 +/- 211 ng/L, P =.047; n = 9) and in pregnancies complicated by gestational diabetes (1133 +/- 115 ng/L, P =.001; n = 9) than in controls (564 +/- 75 ng/L; n = 22). In multiple regression analysis, only umbilical artery hemoglobin in diabetic pregnancies and vaginal delivery in normal pregnancies were associated with cord serum epidermal growth factor. CONCLUSION: Epidermal growth factor concentrations are higher than normal in fetuses of diabetic mothers at term. Pregnancy complications, such as hypertensive disorders, fetal hypoxia and fetal malgrowth, may not explain the rise in epidermal growth factor levels. We hypothesize that the rise in epidermal growth factor levels is a metabolic response of the fetoplacental unit to diabetes-related hyperglycemia. LEVEL OF EVIDENCE: III

Reevaluation of the normal epidermal calcium gradient, and analysis of calcium levels and ATP receptors in Hailey-Hailey and Darier epidermis.

Electron probe microanalysis was used to analyze elemental content of human epidermis. The results revealed that the calcium content of the basal keratinocyte layer was higher than that of the lowest spinous cell layer in normal epidermis. This was surprising, as it is generally accepted that the calcium level increases with cellular differentiation from the proliferative basal layer to the stratum corneum. Hailey-Hailey disease (HHD) and Darier disease (DD) are caused by mutations in Ca(2+)-ATPases with the end result of desmosomal disruption and suprabasal acantholysis. The results demonstrated three major aberrations in HHD and DD lesions. First, in HHD and DD lesions the calcium content in the basal layer was lower than in the normal skin. Second, adenosine triphosphate (ATP) receptor P2Y2 was not localized to plasma membrane in acantholytic cells, whereas P2X7 appeared in the plasma membrane, potentially mediating apoptosis. Third, transition of keratin 14 to keratin 10 was abnormal as demonstrated by the presence of keratinocytes expressing both cytokeratins, which are usually exclusive in normal epidermis. Our results provide to our knowledge previously unreported elements for understanding how the disturbed calcium gradient is linked to the alterations in ATP receptors and keratin expression, leading to the clinical findings in HHD and DD.

Tight junctions in Hailey-Hailey and Darier's diseases.

Hailey-Hailey disease (HHD) and Darier's disease (DD) are caused by mutations in Ca(2+)-ATPases with the end result of desmosomal disruption and suprabasal acantholysis. Tight junctions (TJ) are located in the granular cell layer in normal skin and contribute to the epidermal barrier. Aberrations in the epidermal differentiation, such as in psoriasis, have been shown to lead to changes in the expression of TJ components. Our aim was to elucidate the expression and dynamics of the TJ proteins during the disruption of desmosomes in HHD and DD lesions. Indirect immunofluorescence and avidin-biotin labeling for TJ, desmosomal and adherens junction proteins, and subsequent analyses with the confocal laser scanning microscope were carried out on 14 HHD and 14 DD skin samples. Transepidermal water loss (TEWL) was measured in normal and lesional epidermis of nine HHD and eight DD patients to evaluate the function of the epidermal barrier in HHD and DD skin. The localization of TJ proteins claudin-1, claudin-4, ZO-1, and occludin in perilesional HHD and DD epidermis was similar to that previously described in normal skin. In HHD lesions the tissue distribution of ZO-1 expanded to the acantholytic spinous cells. In agreement with previous findings, desmoplakin was localized intracellularly. In contrast claudin-1 and ZO-1 persisted in the cell-cell contact sites of acantholytic cells. TEWL was increased in the lesional skin. The current results suggest that TJ components follow different dynamics in acantholysis of HHD and DD compared to desmosomal and adherens junction proteins.

Concentration of cord serum placenta growth factor in normal and diabetic pregnancies.

OBJECTIVE: To investigate whether maternal diabetes or diabetes-related complications, such as macrosomia and chronic fetal hypoxia, are associated with altered placenta growth factor (PlGF) levels in cord serum. DESIGN: Case-control study. SETTING: Helsinki University Central Hospital, Helsinki, Finland. POPULATION: Sixty-two normal pregnancies, 67 pregnancies complicated by type 1 diabetes and 28 pregnancies complicated by insulin-treated gestational diabetes. METHODS: Cord serum PlGF concentration was measured by an enzyme-linked immunosorbent assay. Amniotic fluid erythropoietin concentration was measured by a chemiluminescent immunologic method. Umbilical artery gas variables were analysed with standard blood gas and pH electrodes. MAIN OUTCOME MEASURE: PlGF concentration in cord serum at birth. RESULTS: Cord serum PlGF concentration was similar in normal pregnancies [13.4 (1.0) ng/L], in pregnancies complicated by type 1 diabetes [15.1 (1.8) ng/L, P= 0.583 vs controls] and in pregnancies complicated by insulin-treated gestational diabetes [13.6 (0.9) ng/L, P= 0.991 vs controls]. Cord serum PlGF did not correlate with relative birthweight. In diabetic pregnancies, cord serum PlGF correlated negatively with amniotic fluid erythropoietin (r=-0.449, P < 0.0001) and positively with umbilical artery Po(2) (r= 0.333, P= 0.001). There was a trend toward lower cord serum PlGF levels in diabetic pregnancies with pre-eclampsia compared with those without any hypertensive disorders. CONCLUSIONS: Maternal diabetes per se is not associated with altered PlGF levels in cord serum. The correlation between PlGF and indices of fetal hypoxia in diabetic pregnancies may be related to the role of PlGF in potentiating the angiogenic response to vascular endothelial growth factor in ischaemia.

Cord serum glycodelin concentrations in normal pregnancies and pregnancies complicated by diabetes.

OBJECTIVE: Glycodelin is a glycoprotein released by secretory/decidualized endometrial glands. Its synthesis increases during pregnancy. Hormonal factors whose levels have been shown to change in diabetes (vascular endothelial growth factor, relaxin) may mediate the actions or regulate the synthesis of glycodelin. Cord serum glycodelin levels have not been studied in pregnancies complicated by diabetes. METHODS: Cord serum glycodelin concentrations were measured at birth by an immunofluorometric assay in 62 normal pregnancies, in 67 pregnancies complicated by type 1 diabetes, and in 28 pregnancies complicated by insulin-treated gestational diabetes. RESULTS: The mean glycodelin concentration in cord serum was 2.7 ng/ml (standard error of the mean 0.6) in normal pregnancies. The concentration was not altered in pregnancies complicated by diabetes. Cord serum glycodelin concentrations were also unaltered in diabetic pregnancies with hypertensive disorders (chronic hypertension, pregnancy-induced hypertension or pre-eclampsia) or fetal macrosomia. There was a negative borderline correlation between cord serum glycodelin concentrations and the birth weight in pregnancies complicated by diabetes (r=-0.21, p=0.049). CONCLUSIONS: Decidual function, as assessed by cord serum glycodelin levels, is not markedly altered in diabetic pregnancies. The negative correlation between cord serum glycodelin and the birth weight of the newborns in diabetic pregnancies may be due to the decline in glycodelin levels with advancing pregnancy in the third trimester.

Fetal hypoxia is associated with elevated cord serum C-reactive protein levels in diabetic pregnancies.

Maternal diabetes increases the risk of intrauterine hypoxia. Inflammation may play a role in the pathogenesis of hypoxia-related neonatal complications. We studied correlations between levels of cord serum C-reactive protein (CRP), measured by a highly sensitive immunofluorometric assay, and indices of fetal hypoxia in diabetic pregnancies. Cord serum CRP correlated positively with amniotic fluid erythropoietin and umbilical artery pCO2. A negative correlation existed between cord serum CRP and umbilical artery pH and pO2. Amniotic fluid erythropoietin showed an independent effect on cord serum CRP in multiple regression analysis. These data suggest that the fetus responds to hypoxia by an inflammatory reaction.

Serum insulin-like growth factor-I and insulin-like growth factor binding protein-3 in premature rupture of membranes.

BACKGROUND: The aim of the study was to evaluate whether the circulating levels of insulin-like growth factor-I (IGF-I) and its major circulating binding protein, IGFBP-3, are affected in premature rupture of membranes (PROM) and preterm delivery. METHODS: The levels of IGF-I and IGFBP-3 were measured in 32 pregnant women with PROM and in 27 healthy gestational age-matched pregnant women. Statistical analyzes were performed by analysis of variance. RESULTS: All the patients with PROM had preterm delivery, at a gestational age of 31.9 +/- 0.4 weeks (mean +/- SEM). In the control subjects, pregnancy proceeded to term. In the PROM patients, the serum IGF-I and IGFBP-3 levels (289 +/- 21 ng/ml and 8248 +/- 407 ng/ml, respectively) were not statistically different from those in the control subjects (275 +/- 22 ng/ml and 7579 +/- 488 ng/ml). Seventeen patients with PROM showed a rise in serum C-reactive protein, indicating subclinical intrauterine infection. Also in this subgroup of patients the levels of serum IGF-I (281 +/- 27 ng/ml) and IGFBP-3 (9010 +/- 633 ng/ml) were not different from those in the control subjects. Before delivery, serial serum samples were available from 22 patients with PROM. No consistent changes in IGF-I or IGFBP-3 concentrations were seen during the mean follow-up period of 9 days. CONCLUSIONS: IGF-I and IGFBP-3 do not appear to play any significant role in the maintenance of pregnancy in PROM patients with preterm delivery, whether or not associated with emerging intrauterine infection.