Persistence of advanced systemic pharmacological treatment of moderate-to-severe psoriasis among bio-naïve patients-A retrospective register-based cohort study in Finland and Sweden.

BACKGROUND: Plaque psoriasis (PsO) requires long-term treatment for symptom control and remission; thus, a long-term pharmacological intervention is necessary. Treatment persistence reflects long-term therapeutic effectiveness and tolerance. OBJECTIVES: This study investigates drug persistence and compares treatment discontinuation rates across biologic agents and apremilast used by PsO patients in Finland and Sweden. METHODS: This retrospective register-based cohort study included bio-naïve patients (≥18 years) with moderate-to-severe PsO, who initiated treatment with abatacept, adalimumab, brodalumab, certolizumab pegol, etanercept, golimumab, guselkumab, ixekizumab, risankizumab, secukinumab, tildrakizumab, ustekinumab or apremilast during 2008-2020 in Finland or Sweden. The main analysis evaluated persistence (based on duration of continuous treatment) and compared rates of treatment discontinuation using guselkumab as reference drug, during 2018-2020 in Finland. Treatment discontinuation was assessed by survival analysis of the time to first drug discontinuation, including switching to other study drugs. Due to limited sample size (n < 20), certain biologics (abatacept, brodalumab, certolizumab pegol, etanercept, golimumab, risankizumab and tildrakizumab) were excluded from the persistence analysis. RESULTS: In Finland, 709 patients fulfilled the inclusion criteria during 2018-2020 for the main analysis. The highest persistence was observed for guselkumab and ustekinumab with 90 and 85% of treated patients, respectively, continuing treatment for ≥1 year. Comparable results were observed in the expanded cohort analysis (index starting in 2008; 2745 bio-naïve patients in Finland and 10,970 in Sweden). Furthermore, patients treated with guselkumab in Finland showed lower treatment discontinuation rates compared to other study drugs. CONCLUSION: Guselkumab and ustekinumab demonstrated high persistence as measured by continued treatment for at least 1 year. Furthermore, these treatments demonstrated lower rates of discontinuation compared to other study drugs included in the analysis. Understanding the balance between efficacy and feasibility in treatment decisions is crucial, as feasibility may impact persistency outcomes and potentially increase persistency rates.

Extraoral vertical ramus osteotomy combined with internal fixation for the treatment of mandibular deformities.

Extraoral vertical ramus osteotomy (EVRO) is used in orthognathic surgery for the treatment of mandibular deformities. Originally, EVRO required postoperative intermaxillary fixation (IMF). EVRO has been developed using rigid fixation, omitting postoperative IMF. We examined retrospectively the long-term stability and postoperative complications for patients with mandibular deformities who underwent EVRO with internal rigid fixation. Patients who were treated with EVRO for a mandibular deformity in the period 2008-2017 at the Clinic of Oral and Maxillofacial Surgery, Mölndal, Sweden were included (N = 26). Overjet and overbite were calculated digitally and cephalometric analyses were performed preoperatively, and at three days, six months, and 18 months postoperatively. There was a general setback of the mandible, decreased gonial angle and reduced degree of skeletal opening. Excellent dental and vertical skeletal stabilities were seen up to 18 months postoperatively, although relapse was seen sagitally up to six months postoperatively. Since the overjet did not show any significant change over time, the sagittal skeletal changes have been attributed to dental compensation. There was no permanent damage to the facial nerve and 5.8% neurosensory damage to the inferior alveolar nerve was observed.

Malocclusion in children with speech sound disorders and motor speech involvement: a cross-sectional clinical study in Swedish children.

OBJECTIVES: The objectives of this study were to investigate the occurrence, types and severity of malocclusions in children with speech sound disorder (SSD) persisting after 6 years of age, and to compare these findings to a control group of children with typical speech development (TSD). METHODS: In total, 105 children were included: 61 with SSD and motor speech involvement (mean age 8:5 ± 2:8 years; range 6:0-16:7 years, 14 girls and 47 boys) and 44 children with TSD (mean age 8:8 ± 1:6; range 6:0-12:2 years, 19 girls and 25 boys). Extra-oral and intra-oral examinations were performed by an orthodontist. The severity of malocclusion was scored using the IOTN-DHC Index. RESULTS: There were differences between the SSD and TSD groups with regard to the prevalence, type, and severity of malocclusions; 61% of the children in the SSD group had a malocclusion, as compared to 29% in the TSD group. In addition, the malocclusions in the SSD group were rated as more severe. Functional posterior crossbite and habitual lateral and/or anterior shift appeared more frequently in the SSD group. Class III malocclusion, anterior open bite and scissors bite were found only in the SSD group. CONCLUSION: Children with SSD and motor speech involvement are more likely to have a higher prevalence of and more severe malocclusions than children with TSD.

Dietary supplement use patterns in men with prostate cancer: the Cancer Prostate Sweden study.

BACKGROUND: In a European setting, we know little about the use of dietary supplements among men with prostate cancer (PCa) and to what extent lifestyle, disease or other factors influence such use. PATIENTS AND METHODS: We evaluated supplement use in 1127 men with incident PCa and in 900 population controls in Sweden. Age-adjusted binary regression with an identity link was carried out to estimate prevalence differences and corresponding 95% confidence intervals (CIs). Modifying effects of lifestyle- and diet-related factors were explored by statistical assessment of additive interaction. RESULTS: Among men with PCa, 542 individuals (48%) had used supplements, which was a 10% (95% CI: 5.9%-15%) higher prevalence than among population controls. Among individuals with high intake of fatty fish, vegetables, and phytoestrogens, but low intake of saturated fat, supplement use was 29% (95% CI: 18%-41%) more common in men with PCa than in population controls. We found no evidence of heterogeneity by categories of education, smoking history, body mass index, fiber, fruit, or phytoestrogen intake, treatment, or disease stage. CONCLUSION: Supplement use is common in Swedish men with PCa, especially among those with a healthy dietary pattern.

In inflammatory reactive astrocytes co-cultured with brain endothelial cells nicotine-evoked Ca(2+) transients are attenuated due to interleukin-1beta release and rearrangement of actin filaments.

The aim of this study was to investigate whether nicotine acetylcholine receptors (nAChRs) are expressed in a more pronounced way in astrocytes co-cultured with microvascular endothelial cells from adult rat brain, compared with monocultured astrocytes, as a sign of a more developed signal transduction system. Also investigated was whether nicotine plays a role in the control of neuroinflammatory reactivity in astrocytes. Ca(2+) imaging experiments were performed using cells loaded with the Ca(2+) indicator Fura-2/AM. Co-cultured astrocytes responded to lower concentrations of nicotine than did monocultured astrocytes, indicating that they are more sensitive to nicotine. Co-cultured astrocytes also expressed a higher selectivity for alpha7nAChR and alpha4/beta2 subunits and evoked higher Ca(2+) transients compared with monocultured astrocytes. The Ca(2+) transients referred to are activators of Ca(2+)-induced Ca(2+) release from intracellular stores, both IP(3) and ryanodine, triggered by influx through receptor channels. The nicotine-induced Ca(2+) transients were attenuated after incubation with the inflammatory mediator lipopolysaccharide (LPS), but were not attenuated after incubation with the pain-transmitting peptides substance P and calcitonin-gene-related peptide, nor with the infection and inflammation stress mediator, leptin. Furthermore, LPS-induced release of interleukin-1beta (IL-1beta) measured by enzyme-linked immunosorbent assay (ELISA) was more pronounced in co-cultured versus monocultured astrocytes. Incubation with both LPS and IL-1beta further attenuated nicotine-induced Ca(2+) response. We also found that LPS and IL-1beta induced rearrangement of the F-actin filaments, as measured with an Alexa488-conjugated phalloidin probe. The rearrangements consisted of increases in ring formations and a more dispersed appearance of the filaments. These results indicate that there is a connection between a dysfunction of nicotine Ca(2+) signaling in inflammatory reactive astrocytes and upregulation of IL-1beta and the rearrangements of actin filaments in the cells.

mu-Opioid agonists inhibit the enhanced intracellular Ca(2+) responses in inflammatory activated astrocytes co-cultured with brain endothelial cells.

In order to imitate the in vivo situation with constituents from the blood-brain barrier, astrocytes from newborn rat cerebral cortex were co-cultured with adult rat brain microvascular endothelial cells. These astrocytes exhibited a morphologically differentiated appearance with long processes. 5-HT, synthetic mu-, delta- or kappa-opioid agonists, and the endogenous opioids endomorphin-1, beta-endorphin, and dynorphin induced higher Ca(2+) amplitudes and/or more Ca(2+) transients in these cells than in astrocytes in monoculture, as a sign of more developed signal transduction systems. Furthermore, stimulation of the co-cultured astrocytes with 5-HT generated a pronounced increase in intracellular Ca(2+) release in the presence of the inflammatory or pain mediating activators substance P, calcitonin gene-related peptide (CGRP), lipopolysaccharide (LPS), or leptin. These Ca(2+) responses were restored by opioids so that the delta- and kappa-opioid receptor agonists reduced the number of Ca(2+) transients elicited after incubation in substance P+CGRP or leptin, while the mu- and delta-opioid receptor agonists attenuated the Ca(2+) amplitudes elicited in the presence of LPS or leptin. In LPS treated co-cultured astrocytes the mu-opioid receptor antagonist naloxone attenuated not only the endomorphin-1, but also the 5-HT evoked Ca(2+) transients. These results suggest that opioids, especially mu-opioid agonists, play a role in the control of neuroinflammatory activity in astrocytes and that naloxone, in addition to its interaction with mu-opioid receptors, also may act through some binding site on astrocytes, other than the classical opioid receptor.

Antibody responses to deamidated gliadin peptide show high specificity and parallel antibodies to tissue transglutaminase in developing coeliac disease.

Coeliac disease (CD) is an enteropathy induced in genetically susceptible individuals by gluten components, gliadin, hordein and secalin, polypeptides present in cereals such as wheat, barley and rye, respectively. Although the disease starts as intolerance to gliadins, antibodies to tissue transglutaminase (tTG) in the gut epithelium are characteristic of the disease. Whereas serum autoantibodies against tTG (tTGA) are highly specific for CD, antibodies to gliadin are less informative as they can also be detected in other enteropathies, and even in healthy individuals. However, it was shown recently that antibodies to certain gliadin peptides occur with high specificity in CD patient sera. We developed a solid phase lanthanide-based immunofluorometric assay for simultaneous detection of serum IgA and IgG antibodies to a synthetic peptide derived from gamma gliadin of wheat comprising amino acids 86-103. Three glutamine residues of this native 18-mer peptide were replaced by glutamic acids and the peptide was biotinylated. Sera from 87 individuals who had undergone duodenal biopsy and were diagnosed with CD and from 81 healthy individuals were analysed for the presence of both IgA and IgG anti-gliadin peptide antibodies. The performance of the peptide AGA assay was excellent, showing a specificity and sensitivity of 90% and 92% for IgA, and 98% and 75% for IgG, respectively. The corresponding values for conventional anti-gliadin antibody (AGA) enzyme-linked immunosorbent assay (ELISA) tests were 72% specificity and 87% sensitivity for IgA, and 64% specificity and 78% sensitivity for IgG. In a prospective study, almost all the tTGA-positive sera drawn from children who later developed CD were also positive for gliadin peptide antibodies.

Insulin released from titanium discs with insulin coatings-Kinetics and biological activity.

Local administration of insulin from a titanium surface has been demonstrated to increase bone formation in non-diabetic rats. The authors hypothesized that insulin was released from the titanium surface and with preserved biological activity after the release. Thus, in the present in vitro study, human recombinant insulin was immobilized onto titanium discs, and the insulin release kinetics was evaluated using Electro-chemiluminescence immunoassay. Neutral Red uptake assay and mineralization assay were used to evaluate the biological effects of the released insulin on human osteoblast-like MG-63 cells. The results confirmed that insulin was released from titanium surfaces during a six-week period. Etching the disc prior to insulin coating, thickening of the insulin coating and incubation of the discs in serum-enriched cell culture medium increased the release. However, longer storage time decreased the release of insulin. Furthermore, the released insulin had retained its biological activity, as demonstrated by the significant increase in cell number and a stimulated mineralization process, upon exposure to released insulin. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1847-1854, 2017.

Ovarian cancer cell invasion is inhibited by paclitaxel.

Overproduction of matrix metalloproteinases (MMPs) and alterations in adhesive and migratory behavior are common characteristics of metastatic cancer cells. Ovarian cancer is a highly invasive type of malignancy. The effect of the antineoplastic drug paclitaxel on human ovarian cancer cell (Ovcar-3) invasion was studied using an in vitro invasion assay with reconstituted basement membrane. The effect of treatment with paclitaxel was also determined separately on certain invasion-associated events, such as the secretion of 72 kDa type IV collagenase (gelatinase A/MMP-2), the expression of the tissue inhibitor of metalloproteinase-2 (TIMP-2), cell attachment and migration. Ovcar-3 cell attachment, migration and in vitro invasion were significantly decreased after paclitaxel treatment (P = 0.02, P < 0.01 and P = 0.001, respectively) whereas no alteration in the secretion of latent MMP-2 was noted. However, the intracellular localization of the immunoreactive protein for MMP-2 was altered in response to paclitaxel treatment. Interestingly, paclitaxel increased the appearance of TIMP-2 protein in culture medium (P = 0.002) but did not change the expression of mRNA for TIMP-2 in Ovcar-3 cells. These data show that paclitaxel is an effective suppressor of Ovcar-3 cell invasion. It inhibits attachment and migratory activities of the cells but also causes a release of TIMP-2 protein into the tissue culture medium.

Regulation of 72-kd type IV collagenase-matrix metalloproteinase-2 by estradiol and gonadotropin-releasing hormone agonist in human granulosa-lutein cells.

OBJECTIVE: To examine the hormonal regulation of 72-kd type IV collagenase-gelatinase-matrix metalloproteinase-2 in human granulosa-lutein cells. DESIGN: The effect of E2 and GnRH agonist (GnRH-a) on matrix metalloproteinase-2 amount was examined on a long-term granulosa-lutein cell cultures. PATIENTS: The preovulatory follicles from women participating in our IVF program were aspirated through the vaginal wall. Follicular fluids were centrifuged and the granulosa cells were separated and pooled for culturing. MAIN OUTCOME MEASURES: Matrix metalloproteinase-2 enzyme activity was assayed with type IV collagen degradation assay and zymography. The matrix metalloproteinase-2 immunoreactive protein was studied by using specific antibodies. RESULTS: Matrix metalloproteinase-2 was the predominant form of gelatinase in cultured granulosa-lutein cells. The enzyme activity as well as the immunoreactive protein increased in the culture medium of the granulosa-lutein cells in the presence of E2. The effect of E2 was abolished by GnRH-a. CONCLUSIONS: Estradiol regulates the matrix metalloproteinase-2 enzyme amount in granulosa-lutein cells; the effect may be antagonized by GnRH-a.

Prediction of caries activity in children with today's low caries incidence.

One hundred 14-yr-old children were observed over 1 yr to find out if caries incidence and caries progression could be predicted in a low prevalence child population by means of well-known caries related factors. The mean caries incidence was low (0.45, SD 0.70) but, on the other hand, 32% of the children developed at least one new lesion during the test period. In only eight out of 35 children progressing lesions were demonstrated. Independent variables at baseline examination were caries prevalence, sucrose intake, fluoride exposure, oral hygiene, saliva secretion rate, and salivary concentrations of mutans streptococci and lactobacilli. A weak but statistically significant correlation was demonstrated between caries incidence and caries prevalence. No other significant correlations were shown. It was concluded that caries activity could not be predicted in this population. Low disease prevalence was a major reason for the weak correlations.

Do magnitude estimation and lexical decision tap similar processes?

Young adults (n = 54 for Exp. 1, n = 50 for Exp. 2) and elderly adults (the same n = 40 in each experiment) participated in studies that required nonspeeded magnitude estimation scaling in response to words that varied in frequency and number of meanings. Across both experiments and across both groups, subject and item analyses indicated significant word frequency effects (low-frequency words were judged more difficult to process than high-frequency words) and significant word meaning effects (unambiguous words were judged to be more difficult to process than ambiguous words). Mean magnitude estimate values were significantly and positively correlated with mean lexical-decision task values obtained from the same subjects on the same stimuli based on data from a previous experiment. Results suggest that processes required for magnitude estimation are similar to those measured with the lexical decision task in word-recognition studies involving young and elderly adults.

A new concept affecting restoration of inflammation-reactive astrocytes.

Long-lasting pain may partly be a consequence of ongoing neuroinflammation, in which astrocytes play a significant role. Following noxious stimuli, increased inflammatory receptor activity, influences in Na(+)/K(+)-ATPase activity and actin filament organization occur within the central nervous system. In astrocytes, the Ca(2+) signaling system, Na(+) transporters, cytoskeleton, and release of pro-inflammatory cytokines change during inflammation. The aim of this study was to restore these cell parameters in inflammation-reactive astrocytes. We found that the combination of (1) endomorphin-1, an opioid agonist that stimulates the Gi/o protein of the µ-opioid receptor; (2) naloxone, an opioid antagonist that inhibits the Gs protein of the µ-opioid receptor at ultralow concentrations; and (3) levetiracetam, an anti-epileptic agent that counteracts the release of IL-1ß, managed to activate the Gi/o protein and Na(+)/K(+)-ATPase activity, inhibit the Gs protein, and decrease the release of IL-1ß. The cell functions of astrocytes in an inflammatory state were virtually restored to their normal non-inflammatory state and it could be of clinical significance and may be useful for the treatment of long-term pain.

Effects of locally administered insulin on bone formation in non-diabetic rats.

The possibility to control bone formation would be favorable in many areas of medicine, where bone defects is still a major challenge. Insulin has been suggested to exert both systemic and local anabolic effects in bone tissues. This raised the question whether locally administrated insulin could provide new therapeutic strategies for patients with local bone defects and impaired bone healing. The aim of this study was to evaluate bone formation in non-diabetic rats when local insulin is administered. This study differs from previous reports in two aspects: the use of non-diabetic animals and locally administered insulin. Twenty-four implants were inserted into 12 rats-one insulin-coated and one control-in each tibia for four weeks. Interferometry and histomorphometry were used to evaluate the surface topography and bone formation, respectively. Results demonstrated no significant changes in surface topography after insulin immobilization. Histomorphometry revealed significantly more bone around the insulin-coated implants (BA) (p = 0.005) and a similar amount of bone at the implant surface (BIC) (p = 0.117) compared with the controls. It was concluded that locally administered insulin from a titanium implant surface has the potential to increase bone formation not only in diabetic subjects but also in non-diabetic subjects.

Naloxone in ultralow concentration restores endomorphin-1-evoked Ca²âº signaling in lipopolysaccharide pretreated astrocytes.

Long-term pain is a disabling condition that affects thousands of people. Pain may be sustained for a long time even after the physiological trigger has resolved. Possible mechanisms for this phenomenon include low-grade inflammation in the CNS. Astrocytes respond to inflammatory stimuli and may play an important role as modulators of the inflammatory response in the nervous system. This study aimed first to assess how astrocytes in a primary culture behave when exposed to the endogenous µ-opioid receptor agonist endomorphin-1 (EM-1), in a concentration-dependent manner, concerning intracellular Ca²âº responses. EM-1 stimulated the µ-opioid receptor from 10⁻¹5 M up to 10⁻4 M with increasing intensity, usually reflected as one peak at low concentrations and two peaks at higher concentrations. Naloxone, pertussis toxin (PTX), or the µ-opioid receptor antagonists CTOP did not totally block the EM-1-evoked Ca²âº responses. However, a combination of ultralow concentration naloxone (10⁻¹² M) and PTX (100 ng/ml) totally blocked the EM-1-evoked Ca²âº responses. This suggests that ultralow (picomolar) concentrations of naloxone should block the µ-opioid receptor coupled G(s) protein, and that PTX should block the µ-opioid receptor coupled G(i/o) protein. The second aim was to investigate exposure of astrocytes with the inflammatory agent lipopolysaccharide (LPS). After 4 h of LPS incubation, the EM-1-evoked Ca²âº transients were attenuated, and after 24 h of LPS incubation, the EM-1-evoked Ca²âº transients were oscillated. To restore the EM-1-evoked Ca²âº transients, naloxone was assessed as a proposed anti-inflammatory substance. In ultralow picomolar concentration, naloxone demonstrated the ability to restore the Ca²âº transients.

Harmonisation of food categorisation systems for dietary exposure assessments among European children.

Within the European project called EXPOCHI (Individual Food Consumption Data and Exposure Assessment Studies for Children), 14 different European individual food consumption databases of children were used to conduct harmonised dietary exposure assessments for lead, chromium, selenium and food colours. For this, two food categorisation systems were developed to classify the food consumption data in such a way that these could be linked to occurrence data of the considered compounds. One system served for the exposure calculations of lead, chromium and selenium. The second system was developed for the exposure assessment of food colours. The food categories defined for the lead, chromium and selenium exposure calculations were used as a basis for the food colour categorisation, with adaptations to optimise the linkage with the food colour occurrence data. With this work, an initial impetus was given to make user-friendly food categorisation systems for contaminants and food colours applicable on a pan-European level. However, a set of difficulties were encountered in creating a common food categorisation system for 14 individual food consumption databases that differ in the type and number of foods coded and in level of detail provided about the consumed foods. The work done and the problems encountered in this project can be of interest for future projects in which food consumption data will be collected on a pan-European level and used for common exposure assessments.