Sulfonylpiperazine compounds prevent Plasmodium falciparum invasion of red blood cells through interference with actin-1/profilin dynamics.

With emerging resistance to frontline treatments, it is vital that new antimalarial drugs are identified to target Plasmodium falciparum. We have recently described a compound, MMV020291, as a specific inhibitor of red blood cell (RBC) invasion, and have generated analogues with improved potency. Here, we generated resistance to MMV020291 and performed whole genome sequencing of 3 MMV020291-resistant populations.

A function of profilin in force generation during malaria parasite motility that is independent of actin binding.

During transmission of malaria-causing parasites from mosquito to mammal, sporozoites migrate at high speed within the skin to access the bloodstream and infect the liver. This unusual gliding motility is based on retrograde flow of membrane proteins and highly dynamic actin filaments that provide short tracks for a myosin motor. Using laser tweezers and parasite mutants, we previously suggested that actin filaments form macromolecular complexes with plasma membrane-spanning adhesins to generate force during migration.

Apicomplexan actin polymerization depends on nucleation.

Filamentous actin is critical for apicomplexan motility and host cell invasion. Yet, parasite actin filaments are short and unstable. Their kinetic characterization has been hampered by the lack of robust quantitative methods.

A unique profilin-actin interface is important for malaria parasite motility.

Profilin is an actin monomer binding protein that provides ATP-actin for incorporation into actin filaments. In contrast to higher eukaryotic cells with their large filamentous actin structures, apicomplexan parasites typically contain only short and highly dynamic microfilaments. In apicomplexans, profilin appears to be the main monomer-sequestering protein.

Calcium modulates calmodulin/α-actinin 1 interaction with and agonist-dependent internalization of the adenosine A receptor.

Adenosine receptors are G protein-coupled receptors that sense extracellular adenosine to transmit intracellular signals. One of the four adenosine receptor subtypes, the adenosine A receptor (AR), has an exceptionally long intracellular C terminus (AR-ct) that mediates interactions with a large array of proteins, including calmodulin and α-actinin. Here, we aimed to ascertain the α-actinin 1/calmodulin interplay whilst binding to AR and the role of Ca in this process.

H(N), N, C(α), C(β) and C' assignments of the intrinsically disordered C-terminus of human adenosine A2A receptor.

The C-terminus of the human adenosine A2A receptor differs from the other human adenosine receptors by its exceptional length and lack of a canonical cysteine residue. We have previously structurally characterized this C-terminal domain and its interaction with calmodulin. It was shown to be structurally disordered and flexible, and to bind calmodulin with high affinity in a calcium-dependent manner.

Human adenosine A2A receptor binds calmodulin with high affinity in a calcium-dependent manner.

Understanding how ligands bind to G-protein-coupled receptors and how binding changes receptor structure to affect signaling is critical for developing a complete picture of the signal transduction process. The adenosine A2A receptor (A2AR) is a particularly interesting example, as it has an exceptionally long intracellular carboxyl terminus, which is predicted to be mainly disordered. Experimental data on the structure of the A2AR C-terminus is lacking, because published structures of A2AR do not include the C-terminus.

Bridge over troubled proline: assignment of intrinsically disordered proteins using (HCA)CON(CAN)H and (HCA)N(CA)CO(N)H experiments concomitantly with HNCO and i(HCA)CO(CA)NH.

NMR spectroscopy is by far the most versatile and information rich technique to study intrinsically disordered proteins (IDPs). While NMR is able to offer residue level information on structure and dynamics, assignment of chemical shift resonances in IDPs is not a straightforward process. Consequently, numerous pulse sequences and assignment protocols have been developed during past several years, targeted especially for the assignment of IDPs, including experiments that employ H(N), H(α) or (13)C detection combined with two to six indirectly detected dimensions.

Structural features of adenosine receptors: from crystal to function.

The important role that extracellular adenosine plays in many physiological processes is mediated by the adenosine class of G protein-coupled receptors, a class of receptors that also responds to the antagonist caffeine, the most widely used pharmacological agent in the world. The crystallographic model of the human adenosine A(2A) receptor was recently solved to 2.6Å in complex with the antagonist ZM241385, which is also referred to as "super-caffeine" because of its strong antagonistic effect on adenosine receptors.

Causes of death in patients with rheumatoid arthritis autopsied during a 40-year period.

We studied causes of death (CoDs) between 1952 and 1991 assessed by a clinician before autopsy and then determined at autopsy by a pathologist in 369 subjects with rheumatoid arthritis (RA) and 370 subjects without RA (non-RA). We analysed clinical data for RA subjects between 1973 and 1991. In RA subjects, leading autopsy-based CoDs were RA, cardiovascular diseases and infections.

Infectious causes of death in patients with rheumatoid arthritis: an autopsy study.

Objective: To study mortality from infections and accuracy of pre-mortem diagnoses in patients with rheumatoid arthritis (RA) autopsied during a 40-year period.

Methods: We investigated infectious causes of death, findings at autopsy, and clinicians' estimation of cause of death in 369 consecutively autopsied RA and 371 autopsied non-RA patients with same sex, age at death, and year of autopsy. We also compiled clinical features of RA patients from medical records available and examined the association between these and infectious causes of death.

Patient satisfaction with occupational health physicians, development of a questionnaire.

Aims: To develop a questionnaire that measures specific aspects of patient satisfaction with occupational health physicians.

Methods: General patient satisfaction questionnaires, a literature survey, and interviews with patients were used. An initial questionnaire was distributed among sick listed patients (n = 432) of occupational physicians (n = 90) from different occupational health services.

Predictors of productivity loss in early rheumatoid arthritis: a 5 year follow up study.

Objective: To explore baseline risk factors for productivity loss and work disability over 5 years in patients with early, active RA.

Patients And Methods: In the FIN-RACo trial, 195 patients with recent onset RA were randomised to receive either a combination of DMARDs with prednisolone or a single DMARD for 2 years. At baseline, 162 patients were working or available for work.

Organizational climate, perceived work-related symptoms and sickness absence: a population-based survey.

Very few reports have been published on organizational climate, health, and sickness absence in a representative sample of the entire workforce. The aim of this study was to determine how the perceived organizational climate of a workplace is related with work-related symptoms and sickness absence and how these factors vary according to sociodemographic and work-related characteristics. Data were collected in computer-assisted telephone interviews of a random sample of 4209 currently employed Finns drawn from the population register.

Focal sialadenitis in patients with ankylosing spondylitis and spondyloarthropathy: a comparison with patients with rheumatoid arthritis or mixed connective tissue disease.

Objectives: To investigate the occurrence of and risk factors for focal sialadenitis in patients with rheumatoid arthritis (RA), mixed connective tissue disease (MCTD), ankylosing spondylitis (AS), and spondyloarthropathy (SpA).

Methods: A total of 85 patients (25 with RA, 19 with MCTD, 19 with AS, 22 with SpA) participated in the study. Each patient filled out a questionnaire for eye and oral symptoms and for the use of medication, and was interviewed; other tests included Schirmer's test, laboratory tests, collection of unstimulated and stimulated whole saliva, and minor salivary gland biopsy.

Consumer satisfaction with occupational health services: should it be measured?

Objectives: To find answers in the literature to the questions if, why, and how consumer satisfaction with occupational health services (OHSs) should be measured.

Methods: Publications about the concept of consumer satisfaction with health care and surveys of consumer satisfaction with occupational health care were reviewed.

Results: For care providers, surveys of consumer satisfaction can be useful to improve quality or as indicators of non-compliant behaviour among patients.

Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial. FIN-RACo trial group.

Background: The treatment of rheumatoid arthritis should aim at clinical remission. This multicentre, randomised trial with 2-year follow-up sought evidence on the efficacy and tolerability of combination therapy (sulphasalazine, methotrexate, hydroxychloroquine, and prednisolone) compared with treatment with a single disease-modifying antirheumatic drug, with or without prednisolone, in the treatment of early rheumatoid arthritis.

Methods: 199 patients were randomly assigned to two treatment groups.

Roles of acid/base nature and molecular weight in drug release from matrices of gelfoam and monoisopropyl ester of poly(vinyl methyl ether-maleic anhydride).

Ophthalmic drug inserts are usually placed in the conjunctival sac. Being in contact with the conjunctiva, they may provide means to deliver large and hydrophilic molecules, such as peptides and oligonucleotides into the eye. We evaluated Gelfoam and monoisopropyl ester of poly(vinyl methyl ether/maleic anhydride) (PVM/MA) as potential polymers for ocular inserts.

Is continuous intranasal salmon calcitonin effective in treating axial bone loss in patients with active rheumatoid arthritis receiving low dose glucocorticoid therapy?

Objective: To investigate the efficacy of intranasal salmon calcitonin (sCT) in treating axial bone loss in patients with rheumatoid arthritis (RA) taking low dose glucocorticoids.

Methods: In this open, multicenter study 32 women with RA were treated one year with sCT 100 IU/day and calcium (Ca) 500 mg/day; 31 women were treated with Ca alone. Bone mineral density (BMD) was measured at the lumbar spine and proximal femur (femoral neck, Ward's triangle, trochanter) before sCT therapy and again after 6 and 12 months.

Gliadin immune reactivity in patients with rheumatoid arthritis.

Objective: To investigate whether patients with rheumatoid arthritis (RA) have immunological or clinical evidence of gluten hypersensitivity.

Methods: Antigliadin antibodies (AGA) and antireticulin antibodies (ARA) were determined in two groups of RA patients and in a control group of patients with spondylarthropathies. In the first group of 42 patients with recent-onset RA, AGA and ARA were studied longitudinally during a one-year follow up period.

Non-invasive monitoring of finger arterial pressure in patients with Raynaud's phenomenon: effects of exposure to cold.

We studied the effects of exposure to cold on finger arterial pressure (FAP) measured by a finger arterial pressure monitor in 15 patients with Raynaud's phenomenon and in 15 healthy volunteers. The cold exposure induced vasoconstriction of the peripheral vascular bed as judged by the plethysmograph of a pulse oximeter and had marked effects on FAP values compared with upper arm arterial pressure. Immediately after the cold exposure, FAP decreased significantly (P less than or equal to 0.

Patients with arthritis and anti-U1-RNP antibodies: a 10-year follow-up.

Five hundred and forty patients attending a rheumatology ward were screened for antinuclear antibodies (ANA) by indirect immunofluorescence (IFL). Seventy had a significant titre of ANA. Twenty-three had U1-ribonucleoprotein antibodies (U1-RNP-ab).

Clinical and serological follow-up of patients with polyarthritis, Raynaud's phenomenon, and circulating RNP antibodies.

Fourteen patients with polyarthritis, Raynaud's phenomenon/sclerodactyly, and circulating (U1)RNP antibodies were followed up for 10 years. All patients could be classified as having the mixed connective tissue disease at the end of the follow-up. The immunoblotting analysis revealed marked heterogeneity in the ribonucleoprotein antibody profiles.

Signs and symptoms in the masticatory system in ten patients with mixed connective tissue disease.

Ten patients with mixed connective tissue disease (MCTD) were examined for signs and symptoms in the masticatory system. The study included clinical, radiological, histological and immunohistochemical examinations. The status of the teeth and periodontium did not seem to differ from that found in the general Finnish population.