The dynamics of gene expression of interleukin-19 and interleukin-20 and their receptors in psoriasis.

Background: Interleukin (IL)-20 and IL-19 are recently discovered members of the IL-10 family of cytokines. The skin of transgenic mice overexpressing IL-20 shows histological changes resembling some of those seen in psoriasis, i.e.

Generalized cellular hypertrophy is induced by a dual-acting PPAR agonist in rat urinary bladder urothelium in vivo.

Some developmental dual-acting PPARalpha/gamma agonists, such as ragaglitazar, have shown carcinogenic effects in the rodent urinary bladder urothelium after months-years of dosing. We examined early (precancerous) changes in the bladder urothelium of rats orally dosed with ragaglitazar, using a newly developed flow cytometric method. Following 3 weeks of oral ragaglitazar dosing, increases in physical size occurred in a generalized fashion in rat bladder urothelial cells, determined by flow cytometry.

Age and colorectal cancer with focus on the elderly: trends in relative survival and initial treatment from a Danish population-based study.

Purpose: Elderly patients with colorectal cancer undergo surgery with curative intent less frequently than younger patients, and survival declines with increasing age. We compared relative survival of colorectal cancer among patients older than 75 years with that of younger patients in Denmark during the period 1977 to 1999. We also examined trends in choice of initial treatment.

Inverse regulation of the nuclear factor-kappaB binding to the p53 and interleukin-8 kappaB response elements in lesional psoriatic skin.

Nuclear factor-kappaB (NF-kappaB) is an inducible nuclear transcription factor regulating a range of cellular processes. An imbalance of the DNA binding activity of NF-kappaB may, therefore, be part of the pathophysiological mechanisms in psoriasis. The purpose of this study was to determine the NF-kappaB DNA binding activity in psoriatic skin using three different kappaB sites and to determine how DNA binding activity was modulated by the anti-psoriatic drug calcipotriol.

Long term effects of hysterectomy on mortality: nested cohort study.

Objectives: To investigate the long term risk (mean > 20 years) of death from all causes, cardiovascular disease, and cancer in women who had or had not had a hysterectomy.

Design: Nested cohort study.

Setting: Royal College of General Practitioners' oral contraception study.

Population-based study of short- and long-term survival from colorectal cancer in Denmark, 1977-1999.

Background: Survival rates for patients with colorectal cancer have been lower in Denmark than in other European countries. The aim of this study was to examine temporal trends in relative survival from colorectal cancer between 1977 and 1999.

Methods: All patients diagnosed with colorectal cancer between 1977 and 1999 were identified using the nationwide population-based Danish Cancer Registry.

Lysophosphatidylcholine induces keratinocyte differentiation and upregulation of AP-1- and NF-kappaB DNA-binding activity.

Lysophosphatidylcholine (lysoPC) is generated by the action of phospholipase A2 on membrane phosphatidylcholine, the most abundant cellular phospholipid. In vitro, lysoPC has pro-inflammatory properties, as it upregulates the expression of adhesion molecules and is a chemoattractant to monocytes and T lymphocytes. It upregulates the expression of a variety of genes including genes encoding growth factors and cyclooxygenase-2 and modulates other cellular responses like proliferation and differentiation.

Signal transduction pathways in human epidermis.

Cytokines, hormones and other signaling molecules regulate a number of diverse biological processes in the skin including the control of cell growth, differentiation, homeostasis, and various immune functions. This review describes the fundamental concepts of signaling in the cell and we discuss more thoroughly selected signaling pathways important in the skin. Fundamentally cellular signaling can be mediated through two different signaling mechanisms: 1) through binding to a receptor at the outer surface of the cellular-membrane and a subsequent activation of a signal transduction cascade.

Long-term effects of exposure to cannabis.

The long-term use of cannabis, particularly at high intake levels, is associated with several adverse psychosocial features, including lower educational achievement and, in some instances, psychiatric illness. There is little evidence, however, that long-term cannabis use causes permanent cognitive impairment, nor is there is any clear cause and effect relationship to explain the psychosocial associations. There are some physical health risks, particularly the possibility of damage to the airways in cannabis smokers.

Relation between diagnoses on severity, sick leave and loss of job among patients with occupational hand eczema.

Background: Epidemiological studies indicate that occupational hand eczema (OHE) often is associated with persistent dermatitis and prolonged sick leave, which may lead to unemployment. Previous studies suggest that OHE caused by allergic contact dermatitis and atopic dermatitis (AD) carries the worst prognosis.

Objectives: To evaluate and compare the severity and consequences of recognized OHE in different diagnostic and subdiagnostic groups.

The mitogen-activated protein kinases p38 and ERK1/2 are increased in lesional psoriatic skin.

Background: Alterations in specific signal transduction pathways may explain the hyperproliferation and abnormal differentiation of the keratinocytes as well as the increased expression of inflammatory cytokines seen in psoriasis. Major signalling pathways used by eukaryotic cells to transduce extracellular signals into cellular responses impinge on the mitogen-activated protein kinases (MAPKs).

Objectives: To investigate the expression of the MAPK p38, extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) in psoriatic skin.

Tumor necrosis factor-alpha-induced CTACK/CCL27 (cutaneous T-cell-attracting chemokine) production in keratinocytes is controlled by nuclear factor kappaB.

CTACK/CCL27 is pivotal in mediating the migration of lymphocytes into the skin, through the binding to the chemokine receptor CCR10. CCL27 is continuously expressed by keratinocytes, but highly upregulated in inflammatory skin diseases such as atopic dermatitis and psoriasis. CCL27 can be induced in cultured keratinocytes by tumor necrosis factor (TNF)-alpha, which is also known to induce activity of the transcription factor NF-kappaB.

A survey of occupational hand eczema in Denmark.

Occupational hand eczema (OHE) is the most frequently recognized work-related disease in Denmark and the annual cost to society is high. Understanding of the epidemiology of OHE is essential to be able to give appropriate recommendations for its prevention. The study comprised 758 persons, 490 females and 268 males with recognized OHE in the period October 2001 to November 2002.

GABA pharmacology--what prospects for the future?

Following the recognition of GABA as an inhibitory neurotransmitter, the discovery of high affinity GABA uptake, and the characterisation of GABA receptors great progress has been made in developing GABA pharmacology. Tiagabide, the first marketed GABA uptake inhibitor may be followed by new and more selective uptake inhibitors. Knowledge of the molecular pharmacology of GABA-A receptors, both synaptic and non-synaptic, may lead to improved anti-anxiety/anticonvulsant agents devoid of the sedative and dependence liabilities of earlier compounds and new hypnotics.

Activator protein 1 DNA binding activity is decreased in lesional psoriatic skin compared with nonlesional psoriatic skin.

Background: Psoriasis is a common benign skin disease characterized by hyperproliferation and abnormal differentiation of keratinocytes. The transcription factor activator protein 1 (AP-1) is known to play an important role in cell proliferation and differentiation.

Objectives: To investigate AP-1 DNA binding activity in psoriatic skin.

1alpha,25(OH)(2)D(3) regulates NF-kappaB DNA binding activity in cultured normal human keratinocytes through an increase in IkappaBalpha expression.

NF-kappaB is a dimeric transcription factor which regulates transcription of a number of different genes including IL-8 and p53. In resting cells NF-kappaB is usually retained in an inactive state in the cytoplasm through binding to a member of the inhibitory kappaB (IkappaB) protein family. The purpose of this study was to determine the effect of 1alpha,25(OH)(2)D(3) on NF-kappaB activation in both unstimulated and stimulated (IL-1alpha) cultured normal human keratinocytes.

Water-molecule network and active-site flexibility of apo protein tyrosine phosphatase 1B.

Protein tyrosine phosphatase 1B (PTP1B) plays a key role as a negative regulator of insulin and leptin signalling and is therefore considered to be an important molecular target for the treatment of type 2 diabetes and obesity. Detailed structural information about the structure of PTP1B, including the conformation and flexibility of active-site residues as well as the water-molecule network, is a key issue in understanding ligand binding and enzyme kinetics and in structure-based drug design. A 1.

Cynical hostility, socioeconomic position, health behaviors, and symptom load: a cross-sectional analysis in a Danish population-based study.

Objective: To analyze the cross-sectional association between cynical hostility and high symptom load in a Danish population-based study. Furthermore, the aim was to investigate to what extent health risk behaviors mediated this association.

Methods: Data were based on a postal questionnaire in a Danish random sample of 3426 men and 3699 women aged 40 or 50 years.

Residue 259 in protein-tyrosine phosphatase PTP1B and PTPalpha determines the flexibility of glutamine 262.

To study the flexibility of the substrate-binding site and in particular of Gln262, we have performed adiabatic conformational search and molecular dynamics simulations on the crystal structure of the catalytic domain of wild-type protein-tyrosine phosphatase (PTP) 1B, a mutant PTP1B(R47V,D48N,M258C,G259Q), and a model of the catalytically active form of PTPalpha. For each molecule two cases were modeled: the Michaelis-Menten complex with the substrate analogue p-nitrophenyl phosphate (p-PNPP) bound to the active site and the cysteine-phosphor complex, each corresponding to the first and second step of the phosphate hydrolysis. Analyses of the trajectories revealed that in the cysteine-phosphor complex of PTP1B, Gln262 oscillates freely between the bound phosphate group and Gly259 frequently forming, as observed in the crystal structure, a hydrogen bond with the backbone oxygen of Gly259.

Identification, synthesis, and characterization of new glycogen phosphorylase inhibitors binding to the allosteric AMP site.

Inhibition of glycogen phosphorylase (GP) has attracted considerable attention during the last five to 10 years as a means of treating the elevated hepatic glucose production seen in patients with type 2 diabetes. Several different GP inhibitors binding to various binding sites of the GP enzyme have been reported in the literature. In this paper we report on a novel class of compounds that have been identified as potent GP inhibitors.