Personalising docetaxel and G-CSF schedules in cancer patients by a clinically validated computational model.

BACKGROUND: This study was aimed to develop a new method for personalising chemotherapeutic and granulocyte colony-stimulating factor (G-CSF) combined schedules, and use it for suggesting efficacious chemotherapy with reduced neutropenia. METHODS: Clinical data from 38 docetaxel (Doc)-treated metastatic breast cancer patients were employed for validating a new pharmacokinetic/pharmacodynamics model for Doc, combined with a mathematical model for granulopoiesis. An optimisation procedure was constructed and used for selecting improved treatment schedules. RESULTS: The combined model accurately predicted observed nadir timing (r=0.99), grade 3 or 4 neutropenia (86% success) and neutrophil counts over time in individual patients (r=0.63), and showed robustness to CYP3A-induced variability in Doc clearance. For average patients, the predicted optimal support for the standard chemotherapy regimen, Doc 100 µg m(-2) tri-weekly, is G-CSF, 300 µg, Q1D × 3, starting day 7 post-Doc. This regimen largely moderates chemotherapy-induced neutrophil nadir and neutropenia duration. The more intensive Doc dose, 150 mg m(-2), is optimally supported by the slightly less cost-effective G-CSF 300 µg, Q1D × 4, 5 days post-Doc. The latter regimen is optimal for borderline patients (2000 neutrophils per µl) under Doc, 100-150 mg m(-2) tri-weekly. CONCLUSIONS: The new computational method can serve for tailoring efficacious cytotoxic and supportive treatments, minimising side effects to individual patients. Prospective clinical validation is warranted.

Angiogenic peptides improve blood flow and promote capillary growth in a diabetic and ischaemic mouse model.

OBJECTIVES: It is a common clinical observation that collateral vessel development is impaired in diabetic patients with ischaemic vascular diseases. Consequently, alternative revascularisation strategies in diabetic patients are needed. This study presents the effect and mechanism of new peptide therapeutic angiogenesis in an ischaemic and diabetic mouse model. DESIGN: Streptozocin-injected mice that had undergone hind-limb ischaemia were treated with angiogenic peptides. Blood flow restoration was calculated by laser Doppler imager and corroborated by histological section. For the mechanism study, endothelial cells were exposed to hypoxia and high glucose concentrations to study the effect of the peptides on proliferation and anti-apoptosis. RESULTS: The peptides significantly restored blood perfusion 21 days after surgery in the diabetic mice (p < 0.01) by neo-vascularisation, corroborated by an increase in capillary density. In addition, the peptides induced the proliferation of hypoxic endothelial cells (p < 0.01) and protected the cells from apoptosis in high glucose cultures. CONCLUSIONS: This is the first approach for treatment of ischaemic vascular disease with peptides in a diabetic mouse model.

Treatment of ovalbumin-induced experimental allergic bronchitis in rats by inhaled inhibitor of secretory phospholipase A(2).

BACKGROUND: The pathophysiology of asthma involves the action of inflammatory/allergic lipid mediators formed following membrane phospholipid hydrolysis by phospholipase A(2) (PLA(2)). Cysteinyl leukotrienes are considered potent inducers of bronchoconstriction and airway remodelling. Ovalbumin (OVA) induced bronchoconstriction in rats is associated with increased secretory PLA(2) (sPLA(2)) activation and cysteinyl leukotriene production, together with suppression of cytosolic PLA(2) and prostaglandin E(2). These processes are reversed when the animals are pretreated systemically with an extracellular cell impermeable sPLA(2) inhibitor which also suppresses the early allergic reaction to OVA challenge. In this study we examine the capacity of the sPLA(2) inhibitor to ameliorate inflammatory and allergic manifestations (early and late bronchoconstriction) of OVA induced allergic bronchitis in rats when the inhibitor was administered by inhalation to confine it to the airways. METHODS: Rats sensitised with OVA were treated with the sPLA(2) inhibitor hyaluronic acid-linked phosphatidyl ethanolamine (HyPE). The rats were divided into four groups (n = 10 per group): (1) naïve controls (no sensitisation/no treatment); (2) positive controls (sensitisation + challenge with OVA inhalation and subcutaneous injection of 1 ml saline before each challenge; (3) sensitisation + challenge with OVA and HyPE inhalation before every challenge; and (4) sensitisation + challenge with OVA and treatment with subcutaneous dexamethasone (300 mug) before each challenge as a conventional reference. Another group received no treatment with HyPE during the sensitisation process but only before or after challenge of already sensitised rats. Pulmonary function was assessed and changes in the histology of the airways, levels of cysteinyl leukotrienes in BAL fluid, and the production of nitric oxide (No) and tumour necrosis factor alpha (TNFalpha) by BAL macrophages were determined. RESULTS: Inhalation of HyPE markedly suppressed OVA induced early and late asthmatic reactions as expressed by bronchoconstriction, airway remodelling (histology), cysteinyl leukotriene level in BAL fluid, and production of TNFalpha and NO by BAL macrophages. OVA induced bronchoconstriction in sensitised non-pretreated rats was also inhibited by inhalation of HyPE either before or after the challenge. CONCLUSIONS: These findings confirm the pivotal role of sPLA(2) in the pathophysiology of both the immediate allergic response and the inflammatory asthmatic process. Control of airway sPLA(2) may be a new therapeutic approach to the treatment of asthma.

[Biological value of Silybum marianum oil]. / Biologicheskaia tsennost' masla rastoropshi.

We are introduced the dates on an elemental compositional and physiochemical parameters of oil Silybum Marianum. In this assay we compare oil Silybum Varianum with the most widespread food oils. Presented perspectives of usage oil Silymum Marianym as the food and medical oil.

LaCrosse viral encephalitis mimics herpes simplex viral encephalitis.

Temporal lobe abnormalities, findings commonly associated with herpes simplex virus encephalitis, were observed in a male 10 years of age found to have LaCrosse virus encephalitis. Diagnostic features included magnetic resonance imaging revealing abnormal signal intensity in the bilateral frontotemporal regions, and left-sided periodic lateralizing epileptiform discharges. LaCrosse virus encephalitis should be included in the differential diagnosis of viral encephalitis associated with structural and electrographic temporal lobe lesions, represented by periodic lateralizing epileptiform discharges. The recently developed LaCrosse RNA polymerase chain reaction for cerebrospinal fluid may enable rapid diagnosis, prevent the need for treatment with acyclovir, and give parents an encouraging prognosis.

[Implantation with natursil as a method for repair of dental defects and normalization of oral homeostasis]. / Implantatsiia s ispol'zovaniem natursila kak sposob vosstanovleniia defektov zubnykh riadov i normalizatsii narushenii gomeostaza polosti rta.

Parameters of homeostasis in the oral liquid during adentia, after implantation of titanium implants gated in generally accepted way and also with usage of natursilum from Silybum marianum were studied. Application of natursilum in surgery and in postoperative period promoted optimization of an implant osteointegration and normalized physicochemical and metabolic parameters of the oral liquid.

[Effect of biologically active components of natursil on the course of reparative processes in the gastrointestinal mucosa in experiments and in patients with stomach and duodenal ulcers]. / Vliianie biologicheski aktivnykh komponentov natursila na techenie reparativnykh protsessov v slizistoi obolochke zheludochno-kishechnogo trakta v éksperimente i u bol'nykh iazvennoi bolezn'iu zheludka i dvenadtsatiperstnoi.

The outcomes, obtained in experiment, testify about high reparative ability of a natursilum. Natursilum has growth efficiency of conventional treatment of an ulcer of a stomach and duodenal intestine patients both on end results, and on terms of an adhesion increases. Is rotined, that natursilum has more expressed antiulcerous effect, than oil of hippopheae. The transendoscopy spraying of an ulcerative defect has not advantages before application of a drug inside. The specificity of a natursilum structure determines character of effect on exchange processes.

Maternal and infant use of erythromycin and other macrolide antibiotics as risk factors for infantile hypertrophic pyloric stenosis.

OBJECTIVES: To evaluate the risk for infantile hypertrophic pyloric stenosis (IHPS) among infants prescribed systemic erythromycin, infants prescribed a course of erythromycin ophthalmic ointment, and infants whose mothers were prescribed a macrolide antibiotic during pregnancy. STUDY DESIGN: Retrospective cohort study of infants born at an urban hospital from June 1993 through December 1999. RESULTS: Of 14,876 eligible infants, 43 (0.29%) developed IHPS. Infants prescribed systemic erythromycin had increased risk of IHPS, with the highest risk in the first 2 weeks of age (relative risk = 10.51 for erythromycin in first 2 weeks, 95% CI 4.48, 24.66). Erythromycin ophthalmic ointment for conjunctivitis was not associated with increased risk of IHPS. Maternal macrolide antibiotics within 10 weeks of delivery may have been associated with higher risk of IHPS but the data were not conclusive. CONCLUSIONS: This study confirms an association between systemic erythromycin in infants and subsequent IHPS, with the highest risk in the first 2 weeks of age. No association was found with erythromycin ophthalmic ointment. A possible association with maternal macrolide therapy in late pregnancy requires further study. Systemic erythromycin should be used with prudence in early infancy.

[The role of hyperlactatedehydrogenasemia in induction of metabolic disorders in the body]. / Rol' giperlaktatdegidrogenazemii v induktsii metabolicheskikh narushenii v organizme.

The effect of intravenous administration of lactate dehydrogenase (5000 E/kg) on some metabolic parameters was investigated. The hyperenzymemia was accompanied by changes of metabolite content (glutamate, 2-oxoglutarate, lactate, dihydroxyacetone phosphate) and enzyme activities (aldolase, lactate dehydrogenase, transaminase) in heart, liver and skeletal muscles. Intravenously administered tritiated lactate dehydrogenase was preferentially found in skeletal muscles, liver, kidneys and some other organs.

Scattering of electromagnetic radiation by multilayered spheroidal particles: recursive procedure.

A formalism is developed for the calculation of the electromagnetic field scattered by a multilayered spheroidal particle. The suggested formalism utilizes the recursive approach with respect to passing from one layer to the next; thus it does not require an increase in the size of the equation matrices involved as the number of layers increases. The equations operate with matrices of the same size as for a homogeneous spheroid. The special cases of extremely prolate and weakly prolate spheroids are considered in more detail. It is shown that in such cases one can avoid the matrix calculations by instead using the iterative scalar calculations.

The False Claims Act. An interview with Mark Kleiman.

JONA's Healthcare Law, Ethics, and Regulation interviewed Attorney Mark Allen Kleiman regarding the False Claims Act. Mr. Kleiman has had much experience with this Act in both prosecution and consulting. In this interview, he provides great insight into the details and interpretations of the Act, as well as implications for healthcare providers.

Cross-reactivity in Histoplasma capsulatum variety capsulatum antigen assays of urine samples from patients with endemic mycoses.

We evaluated cross-reactivity in the antigen assay used for the diagnosis of histoplasmosis by testing urine samples from patients with disseminated fungal infections. The mycoses chosen for this study were selected on the basis of the observation that during clinical testing, cross-reactions may occur between Histoplasma capsulatum var. capsulatum, Paracoccidioides brasiliensis, Blastomyces dermatitidis, Coccidioides immitis, and Penicillium marneffei. We detected antigen in 12 of 19 patients with blastomycosis, 8 of 9 with paracoccidioidomycois, in 17 of 18 with P. marneffei infection, and in one with disseminated H. capsulatum var. duboisii infection. Cross-reactions were not observed in the assays for six patients with disseminated coccidioidomycosis. Cross-reactivity between the agents of other endemic mycoses should be considered in interpreting a positive H. capsulatum var. capsulatum antigen assay. Antigen detection may provide a rapid, provisional diagnosis for patients with serious infections caused by one of these organisms.

Dosimetric characteristics of a new high-intensity 192Ir source for remote afterloading.

A new high-intensity 192Ir source has recently become commercially available for remote afterloading brachytherapy treatment. The dosimetric characteristics (dose rate constant, radial dose function, and anisotropy function) of this source were experimentally determined through the application of AAPM Task Group 43 recommendations. Complete dosimetric data are presented in this manuscript.

Preparing for capitated hospital services.

Although HMOs have been reluctant to capitate hospital services, capitated payments allow hospitals greater control over their strategic and economic position. Healthcare financial managers have a role to play in demonstrating to HMOs that capitating hospital services can create a win/win situation.

Provider integration: PO (physician organization) versus PHO (physician hospital organization).

The PO model, in which a PO and hospitals "peacefully coexist" without some level of integration, may not be sustainable in the long term, as managed care and healthcare reform initiatives pressure providers to integrate delivery and align their economic incentives (either on a fee-for-service or capitated basis). Therefore, while integrating physicians and hospitals within a PHO may not be attractive to physicians initially, opting for an approach that does not integrate physician and hospital services and align their economic incentives can eventually invite a significant level of competition between the two.