Dynamic allosteric communication pathway directing differential activation of the glucocorticoid receptor.

Allosteric communication within proteins is a hallmark of biochemical signaling, but the dynamic transmission pathways remain poorly characterized. We combined NMR spectroscopy and surface plasmon resonance to reveal these pathways and quantify their energetics in the glucocorticoid receptor, a transcriptional regulator controlling development, metabolism, and immune response. Our results delineate a dynamic communication network of residues linking the ligand-binding pocket to the activation function-2 interface, where helix 12, a switch for transcriptional activation, exhibits ligand- and coregulator-dependent dynamics coupled to graded activation. The allosteric free energy responds to variations in ligand structure: subtle changes gradually tune allostery while preserving the transmission pathway, whereas substitution of the entire pharmacophore leads to divergent allosteric control by apparently rewiring the communication network. Our results provide key insights that should aid in the design of mechanistically differentiated ligands.

Prostate cancer evolution from multilineage primary to single lineage metastases with implications for liquid biopsy.

The evolutionary progression from primary to metastatic prostate cancer is largely uncharted, and the implications for liquid biopsy are unexplored. We infer detailed reconstructions of tumor phylogenies in ten prostate cancer patients with fatal disease, and investigate them in conjunction with histopathology and tumor DNA extracted from blood and cerebrospinal fluid. Substantial evolution occurs within the prostate, resulting in branching into multiple spatially intermixed lineages. One dominant lineage emerges that initiates and drives systemic metastasis, where polyclonal seeding between sites is common. Routes to metastasis differ between patients, and likely genetic drivers of metastasis distinguish the metastatic lineage from the lineage that remains confined to the prostate within each patient. Body fluids capture features of the dominant lineage, and subclonal expansions that occur in the metastatic phase are non-uniformly represented. Cerebrospinal fluid analysis reveals lineages not detected in blood-borne DNA, suggesting possible clinical utility.

Somatic mutations in clonally expanded cytotoxic T lymphocytes in patients with newly diagnosed rheumatoid arthritis.

Somatic mutations contribute to tumorigenesis. Although these mutations occur in all proliferating cells, their accumulation under non-malignant conditions, such as in autoimmune disorders, has not been investigated. Here, we show that patients with newly diagnosed rheumatoid arthritis have expanded CD8+ T-cell clones; in 20% (5/25) of patients CD8+ T cells, but not CD4+ T cells, harbour somatic mutations. In healthy controls (n=20), only one mutation is identified in the CD8+ T-cell pool. Mutations exist exclusively in the expanded CD8+ effector-memory subset, persist during follow-up, and are predicted to change protein functions. Some of the mutated genes (SLAMF6, IRF1) have previously been associated with autoimmunity. RNA sequencing of mutation-harbouring cells shows signatures corresponding to cell proliferation. Our data provide evidence of accumulation of somatic mutations in expanded CD8+ T cells, which may have pathogenic significance for RA and other autoimmune diseases.

Prevention of pressure ulcers in acute and long-term care facilities in Finland: results of a survey.

The purpose of this study was to identify those healthcare organizations that have a high incidence of pressure ulcers, and to determine what their staffs do to prevent pressure ulcer formation. The sample was formed from 11 hospitals in one large city on a certain day in Finland in 1998. The researchers sent questionnaires to 154 hospital units and achieved a 94% response rate. Psychiatric; gynecologic; obstetric; and eye, ear, nose, and throat units were not included. The data were collected using two questionnaires: The first gathered data about the organization and the second about the patients. Fifty-seven percent of the units surveyed reported having patients with pressure ulcers. Of these units, 45% were acute and 55% were long-term care. Thirty-nine percent of all units had a pressure ulcer team. Units with pressure ulcer patients had a staffing level of 0.6 registered nurses and practical nurses per bed, compared with 0.7 registered nurses and practical nurses per bed for those units without pressure ulcer patients. The average length of stay on the unit was less for those without pressure ulcers compared to those with ulcers (P < 0.001) and only 18% of the units without pressure ulcers had a pressure ulcer team. According to the results, those units with pressure ulcer patients identified the need for more preventive measures more frequently than the units without ulcer patients. In conclusion, pressure ulcers seem to predominate in long-term care settings, and the educational level of healthcare staffing seems to impact the occurrence of pressure ulcers. Common preventive measures are used by the staff in both acute and long-term care settings.

Patients' needs in hospital: nurses' and patients' views.

This study set out to identify the most important needs of hospital patients on surgical and medical wards and to assess the ability of nurses to identify these needs. The population consisted of 92 Finnish patients and 69 Finnish nurses. The study was carried out using a questionnaire designed on the basis of the need theory presented by Yura and Walsh. The results of the statistical analyses were presented in the form of frequencies, cross-tabulations and chi-square tests. The patients' most common needs were related to vital functions (44%), followed by those related to functional health status (38%) and environmental needs (36%). The last item on the list of expressed needs concerned reactions to functional health status (31%). Over 70% of the surgical patients suffered from problems related to sleep and rest. Less than 60% of them suffered from acute pain. Medical patients, in turn, had more frequent needs related to vital functions than did surgical patients. Three out of four medical patients suffered from acute pain. Sleep and rest disturbances, stress, bad mood and listlessness were also common problems. The nurses underestimated all patient needs, apart from environmental needs, which they regarded as the main concern of patients. There was a statistically significant difference between patients' and nurses' assessments for 38% of all needs. Moreover, there were differences in assessments between the surgical and medical wards included in the study.

Reliability of a vibration test in screening for predisposition to tenosynovitis.

The reliability of a vibration test has been studied in terms of its feasibility for screening for predisposition to tenosynovitis in an occupational health setting. In a worker population with a high prevalence of tenosynovitis the specificity and sensitivity of the method in the best cases were 68% and 50%, respectively. In an apparently healthy population there were significant interindividual differences; but in successive trials the same individual could have index values indicating both a predisposition and a lack of predisposition for tenosynovitis. The index value seems to be dependent on the temperature of the test room. It was concluded, in contrast to earlier results, that the vibration test is, of no value in screening for a predisposition to tenosynovitis in an occupational health setting.

Patients with pressure ulcers in Finnish hospitals.

The purpose of this descriptive study was to produce knowledge of the degree of pressure ulcers, pressure ulcer patients' physical and psychological well-being and the association of these factors with pressure ulcers' severity. These patients were treated in Finland's capital area hospitals. The pressure ulcer patients' sampling was gathered during 1 day with two questionnaires, which was completed by nurses. The response rate was 94%, and data analysis was based on percentage distributions. Statistical association was tested with the chi2 test. The measurement identified 164 patients with a total of 257 pressure ulcers. Prevalence was 6.4%. Most of the ulcers (40%) were grade II ulcers. Fifty-six per cent of patients suffered poor general health, 63% of the patients were immobile, but psychological well-being was better with 29% of pressure ulcer patients being adequately motivated to follow treatment for their pressure ulcers. It is essential to identify high-risk patients in order to provide optimal care.

Determination of the degree of derivatization of acryloylated polysaccharides by Fourier transform proton NMR spectroscopy.

Dextran, glycogen, hydroxyethyl starch, and maltodextrin were derivatized with acrylic acid glycidyl ester at alkaline pH. The degree of derivatization was determined by water-elimination Fourier transform nuclear magnetic resonance (NMR) and compared with a bromination method. The signals from the anomeric protons of the glucose residues were used as an internal standard and the degree of derivatization was obtained from the relation between the integrated signals from the acrylic and anomeric protons. The NMR technique is shown to be more precise and convenient for the determination of acryloyl groups than the bromination method used.

Nocturnal body movements and hypoxemia in middle-aged females after lower abdominal surgery under general anesthesia: a study with the static-charge-sensitive bed (SCSB).

OBJECTIVE: The aim of this study was to evaluate the feasibility of the static-charge-sensitive-bed (SCSB) combined with pulse oximetry (SpO2) for postoperative monitoring and to determine variables which could be used for evaluating the quality of postoperative sleep and breathing. METHODS: The frequency of body movements and the perioperative breathing abnormalities were assessed using the SCSB and pulse oximeter in 15 female ASA-class I-II patients undergoing elective lower abdominal surgery under general anesthesia. Anesthesia and control of postoperative pain followed standard practice. The patients were monitored during one preoperative and three consecutive postoperative nights. Movements were analyzed according to their duration and time interval. The effect of opioids was evaluated by measuring arterial oxyhemoglobin saturation (SpO2) with pulse oximetry for one hour before and two hours after administration of standard doses of oxycodone. RESULTS: The total movement time per hour increased during the first postoperative night (p = 0.003). Conversely, periodic movement activity decreased significantly during the three postoperative nights (p = 0.05, p < 0.001, p = 0.007). The mean SpO2 decreased during the first postoperative night (95.5% vs. 94.2%, p = 0.002), but returned to the preoperative level during the following nights. No episodes of apnea with significant oxygen desaturation (a decrease in SpO2 > 5%) were observed. Opioid administration was associated with decreased mean SpO2 (94.8% vs. 93.6%, p = 0.02), but did not lead to clinically significant hypoxemia (lowest observed SpO2 89.8%). CONCLUSIONS: Postoperative periodic movement activity was suppressed, but sleep remained fragmented with frequent body movements. In our middle-aged non-obese females (ASA I-II), no severe postoperative hypoxemia was observed during the three-nights postoperative survey. Perioperative movement monitoring with the SCSB was a valuable tool in rejecting movement artefacts of SpO2 and in evaluating general sleep quality.