The key event in force-induced unfolding of Titin's immunoglobulin domains.
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Steered molecular dynamics simulation of force-induced titin immunoglobulin domain I27 unfolding led to the discovery of a significant potential energy barrier at an extension of approximately 14 A on the unfolding pathway that protects the domain against stretching. Previous simulations showed that this barrier is due to the concurrent breaking of six interstrand hydrogen bonds (H-bonds) between beta-strands A' and G that is preceded by the breaking of two to three hydrogen bonds between strands A and B, the latter leading to an unfolding intermediate. The simulation results are supported by Angstrom-resolution atomic force microscopy data. Here we perform a structural and energetic analysis of the H-bonds breaking. It is confirmed that H-bonds between strands A and B break rapidly. However, the breaking of the H-bond between strands A' and G needs to be assisted by fluctuations of water molecules. In nanosecond simulations, water molecules are found to repeatedly interact with the protein backbone atoms, weakening individual interstrand H-bonds until all six A'-G H-bonds break simultaneously under the influence of external stretching forces. Only when those bonds are broken can the generic unfolding take place, which involves hydrophobic interactions of the protein core and exerts weaker resistance against stretching than the key event. (+info)
Plasma bikunin as a favorable prognostic factor in ovarian cancer.
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PURPOSE: Bikunin is a multifunctional glycoprotein, which mediates suppression of tumor cell invasion and metastasis. The measurement of bikunin levels in the tissue of patients with malignant diseases has been introduced as a new and simple diagnostic tool for the evaluation of prognosis. The high bikunin expression in ovarian cancer tissue would enable the use of soluble bikunin protein present in the circulation of ovarian cancer patients as a biomarker of disease. PATIENTS AND METHODS: We developed a double-antibody immunoassay for bikunin and detected its presence in normal human circulation. We quantified, by enzyme-linked immunosorbent assay and/or immunoblot assay bikunin in sera from 200 healthy women (controls), 200 patients with benign gynecologic diseases, and 327 patients with ovarian cancer before surgical removal of the tumor. RESULTS: When the values of bikunin corresponding to the median were used as the cutoff value (11.5 microg/mL), low plasma bikunin was strongly associated with late-stage, suboptimal debulking with large residual tumor (> 2 cm) and low response to chemotherapy. The median survival time of the patients with a high bikunin level was more than 60 months as compared with 26 months among those with low bikunin level (P = .002). This difference corresponded to a 2.2-fold increased risk of dying for the lower plasma bikunin patients (hazard ratio, 0.45; P = .023) and remained significant in multivariate analysis (hazard ratio, 0.63; P = .041). CONCLUSION: Preoperative plasma bikunin concentration is a strong and independent favorable prognostic marker for ovarian cancer. (+info)
The efficacies of clozapine and haloperidol in refractory schizophrenia are related to DTNBP1 variation.
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Galantamine-ER for the treatment of mild-to-moderate Alzheimer's disease.
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An extended release form of the cholinesterase inhibitor (ChEI) drug galantamine (galantamine-ER) was developed, chiefly to increase adherence to medication regimes in patients with mild-to-moderate Alzheimer's disease (AD). Except for predicted differences in (C(max)) and t(max), comparable doses of once daily galantamine-ER and regular, immediate release galantamine, (galantamine-IR), are pharmacologically equivalent. A 24-week randomized, double-blind, placebo-and active-controlled, multicenter phase III trial, which compared galantamine-IR, galantamine-ER and placebo in subjects with mild to moderate AD (mini-mental state examination [MMSE] score range, 10 to 24) showed that both formulations of galantamine were significantly better than placebo in terms of cognition, although not with regard to global change. There was no difference in drug-related adverse events between galantamine-ER and galantamine-IR. Since its release onto the market galantamine-ER has enjoyed wide popularity and a recent surveillance study suggests that it has the highest 1-year persistence rate of all the ChEIs. (+info)
Access to leave benefits for primary caregivers of children with special health care needs: a double bind.
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Semantic barriers to family and professional collaboration.
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Mental health professionals have begun to show interest in working collaboratively with families of mentally ill people in the interest of the patient's well-being. Many professionals are aware, however, that considerable alienation exists. One source of difficulty may be the language used to describe families. Drawing from the field of general semantics, the author examines recent writings for examples of language that may appear confusing or offensive to families. It was found that difficulties result from professionals' tendencies to confuse fact with inference, to stereotype families by placing them in either/or categories, to use judgmental language, and to use language of control that contradicts their goals of collaboration or partnership. (+info)
Ethical problems in feeding patients with advanced dementia.
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Aged patients with dementia if not stricken by an acute disease sooner or later approach a terminal phase that is distinguished by a failure of spoon feeding. This condition induces great anxiety in the workers who care for these patients. The interaction between patient and care-worker during spoon-feeding failure is described by the psychological model of double-binding. Two serious consequences of double-binding are the distancing of the care-workers from the patient and scapegoating among the care-workers. It is essential that the pressure of double-bindings in the wards should be reduced. (+info)
Boundary issues. What do they mean for family physicians?
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Clear boundaries between physicians and patients help prevent abusive behaviour. Enforced boundaries help physicians fulfil their legal, ethical, and professional tasks. We review common elements in boundary violations: role reversal, secrecy, double binds, and indulgence of professional privilege. We also outline the legal and licensing issues of boundary violations and offer examples of nine boundaries. (+info)