Ca2+/calmodulin regulation of the Arabidopsis kinesin-like calmodulin-binding protein

This observational study explored the effects of demographics, sickness, and polypharmacy on the non-steady state population pharmacokinetics of intravenous phenytoin. One hundred fifteen patients were studied. Models were developed using the NONMEM program with hybrid first-order conditional estimation. A Michaelis-Menten model with delayed induction was preferred over a Michaelis-Menten model without induction, a Michaelis-Menten model with immediate induction, or a linear model with delayed induction. When the data were fit to a Michaelis-Menten model with delayed induction, the volume of distribution (Vd) was found to depend on weight and serum albumin. The Vd was estimated to be 0.95 l/kg, assuming an albumin level of 3 g/dl. The Michaelis-Menten constant (km) was estimated to be 7.9 mg/l. The baseline maximum metabolic rate was 580 mg/day for a 70-kg patient. The average time to onset of induction was 59.5 hours. If a fever developed after induction began, it increased the extent of induction. This model was evaluated retrospectively in 26 additional patients, yielding a mean prediction error of -0.4 mg/l (-3.0-2.2 mg/l) and a mean absolute prediction error of 4.7 mg/l (3.2-6.2 mg/l) based on two-level feedback. Given the large interindividual variances in maximum metabolic rate, phenytoin levels should be measured frequently.     

Opposing roles for dopamine D1 and D2 receptors in the regulation of hypothalamic tuberoinfundibular dopamine neurons

The purpose of the present study was to characterize pharmacologically dopamine D1 receptor-mediated inhibition of tuberoinfundibular dopamine neurons in males rats, and to determine if inhibitory dopamine D1 receptors oppose stimulatory dopamine D2 receptors and account for the inability of mixed dopamine receptor agonists to alter the activity of these neurons. Tuberoinfundibular dopamine neuronal activity was estimated by measuring the concentrations of the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the median eminence, the region of the hypothalamus containing terminals of these neurons. Administration of the dopamine D1 receptor agonist (+/-)-1 phenyl-2,3,4,5-tetrahydro-(1 H)-3-benzazepine-7,8-diol (SKF38393) decreased median eminence DOPAC and increased plasma prolactin concentrations, whereas administration of the dopamine D1 receptor antagonist ((-)-trans,6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5H -benzo[d]naphtho-[2,1 b]azepine (SCH39166) increased median eminence DOPAC concentrations but had not effect on plasma prolactin. The inhibitory effect of SKF38393 on median eminence DOPAC concentrations was blocked by SCH39166. These results demonstrate that acute activation of dopamine D1 receptors inhibits the activity of tuberoinfundibular dopamine neurons and thereby increases prolactin secretion, and that under basal conditions dopamine D1 receptor-mediated inhibition of tuberoinfundibular dopamine neurons is tonically active. Administration of the dopamine D2 receptor agonist (5aR-trans)-5,5a,6,7,8,9,9a,10-octahydro-6-propyl-pyridol[2, 3-g]quinazolin-2-amine (quinelorane) increased median eminence DOPAC concentrations, and SKF38393 caused a dose-dependent reversal of this effect. Administration of the mixed dopamine D1/D2 receptor agonist R(-)-10,11-dihydroxy-apomorphine (apomorphine) had no effect per se, but blocked quinelorane-induced increases in DOPAC concentrations in the median eminence. These results reveal that concurrent activation of dopamine D1 and D2 receptors nullifies the actions of each of these receptors on tuberoinfundibular dopamine neurons, which likely accounts for the lack of an acute effect of mixed dopamine D1/D2 receptor agonists on these hypothalamic dopamine neurons.     

Hailey-Hailey disease keratinocytes: normal assembly of cell-cell junctions in vitro

The blisters in the inherited disorder, Hailey-Hailey disease, may be caused by defective epidermal junctional complexes. We evaluated these structural complexes in vivo and in vitro. We induced a vesicular lesion in the apparently normal skin of a patient with Hailey-Hailey disease and studied a biopsy of this lesion by transmission electron microscopy. To determine whether acantholysis was related to a defect in the number or assembly of intercellular junctions, we cultured Hailey-Hailey disease keratinocytes in medium containing 0.1 mM Ca2+ and increased the [Ca2+] to 1.1 mM in order to induce assembly of cell-cell junctions. Keratinocytes were examined by double immunofluorescence with antibodies to the desmosome protein, desmoplakin, and the adherens junction protein, vinculin, at intervals after the increase in [Ca2+]. Characteristic Hailey-Hailey disease histopathology was observed by electron microscopy of the patient's skin after trauma, but we found no splitting of desmosomes. Based on the location, intensity, and rate of change of immunofluorescent staining, Hailey-Hailey and normal keratinocytes did not differ in their ability to assemble desmosomes and adherens junctions. Furthermore, we observed no significant morphologic differences between normal and Hailey-Hailey keratinocytes cultured in low and high [Ca2+]-containing media; Hailey-Hailey cells contained abundant normal-appearing desmosomes in 1.1 mM [Ca2+]. Since Hailey-Hailey disease keratinocytes can assemble normal-appearing adherens junctions and desmosomes in vitro, the functional defect may not lie in assembly of cell-cell adhering junctions, or additional perturbation may be required to expose the defect.     

Targeted therapy with a novel enediyene antibiotic calicheamicin theta(I)1 effectively suppresses growth and dissemination of liver metastases in a syngeneic model of murine neuroblastoma

The suppression of metastases in malignant diseases is one of the major goals in targeted chemotherapy. This was achieved with an antibody drug conjugate between a novel, rationally designed enediyene antibiotic calicheamicin theta(I)1 of exceptionally high cytotoxic potency and an antiganglioside GD2 monoclonal antibody 14G2a. Effective suppression of hepatic metastases was demonstrated in a novel syngeneic model of murine neuroblastoma that simulates the situation in patients in terms of antigen heterogeneity and presence of the target antigen on normal tissues. Here, we describe the first successful use of calicheamicin theta(I)1 for targeted chemotherapy in a clinically relevant syngeneic metastasis model.     

Infertility education in baccalaureate schools of nursing

The increasing number of couples who enter the current health care system for assistance with fertility needs warrants an examination of the ways nurse educators are preparing nurse generalists to meet those needs. A survey was conducted of baccalaureate nursing programs to determine what, if any, information was being presented on infertility. Analysis of data with a 50% return rate indicated most schools of nursing in this sample are in fact including some information on infertility in their curricula. What is interesting to note is only slightly more than half of respondents included information on the emotional and psychosocial issues of infertility, despite the fact that the greatest cost of infertility is the emotional one. One of the major concerns of infertile couples is health care providers, including nurses, do not seem to understand what they are experiencing. How do nurses obtain such understanding if they are not prepared in their educational program to do so?