Quantitative study of a proposed interstitial del (20p 12.2) in multiple endocrine neoplasia (MEN-II)

A quantitative measurement of the prophase Giemsa banding patterns in chromosome 20 of the peripheral blood samples obtained from seven patients with medullary carcinoma of the thyroid (MCT), three nonsymptomatic family members of MCT patients, and three normal controls has revealed no differences in the short arms of the two homologs. More specifically, measurements of band from 20p 12.1 to 20p 12.3 and statistical analysis of the mean ratio between these bands have given no indication of intersitial deletion in chromosome 20p of MCT patients.     

A practical approach to control of nonlinear discrete-time state-delay systems

The robust feedback stabilization of a class of nonlinear discrete-time systems with unknown constant state-delay and uncertain function of nonlinear perturbations is considered based on linear matrix inequality (LMI)-based analysis and design procedures. In both cases of nominal and resilient feedback designs, the trade-off between the size of the controller gains and the bounding factors is illuminated and incorporated into the design formalism. A dynamic output feedback controller is then designed for this class of systems. Seeking computational convenience, all the developed results are cast in the format of LMIs and several numerical examples are presented throughout the paper to demonstrate the advantages of the design methods. Copyright © 2007 John Wiley & Sons, Ltd.     

Pharmacokinetics of oral cyclosporine (Neoral) in heart transplant recipients during the immediate period after surgery

Neoral cyclosporine has better absorption characteristics than the original Sandimmun formulation. This has allowed Neoral to be administered orally in circumstances where Sandimmun had been ineffective, including the postoperative phase of liver transplantation. Sampling strategies, such as the measurement of drug concentration 2 h after oral administration, have been used in a variety of settings to estimate systemic exposure to Neoral (measured as the area under the blood concentration curve (AUC) of the drug) in blood. We conducted a pilot study to determine whether Neoral could be administered orally immediately after heart transplantation and to determine which pharmacokinetic parameters reflect systemic drug exposure in this setting. Eight male patients (mean age 50 years) undergoing a first heart transplant were studied. Neoral was administered orally before surgery and at 12-h intervals via a nasogastric tube after surgery. Twelve-hour pharmacokinetic profiles were obtained on postoperative days 1, 3 and 5. Cyclosporine concentrations were measured with the Dade Behring Emit assay, which is specific for the parent drug. Drug concentrations were dose-normalised and drug exposure was measured by the AUC. Drug exposure following administration (AUC(0-12)) was low on day 1 but increased by 99% between postoperative day 1 and day 5 ( P<0.05), indicating more complete absorption of cyclosporine; exposure in the first 4 h post-dose (AUC(0-4)) increased by 126% ( P<0.01), reflecting more rapid cyclosporine absorption, and the maximum blood concentration observed increased by 137% ( P<0.05) during the same period. The correlation between the cyclosporine trough concentration and AUC(0-12) was low on all days. Due to the changing pattern of cyclosporine absorption, concentration measurements at a single time point could not accurately predict 12-h exposure to the drug on all study days. However, the drug concentration at 2 h post-dose had a high correlation with drug exposure during the first 4 h (correlation of C(2) to AUC(0-4): r(2)>0.93 on all days). Absorption of Neoral was low immediately after heart transplantation but improved substantially during the first 5 days after surgery. No single timed measurement of drug concentration reflected cyclosporine exposure; however, the 2-h concentration did provide an accurate measure of the early phase of drug absorption (AUC(0-4)). Oral administration of Neoral may result in inadequate immunosuppression immediately after heart transplantation unless it is supplemented either by intravenous cyclosporine or by the use of an induction agent.     

Mental defeat in chronic pain: initial exploration of the concept

OBJECTIVES: "Mental defeat" has been found to be an important psychologic reaction to painful trauma. Chronic pain patients also report mental defeat in relation to their experience of pain episodes. A measure of mental defeat was devised and evaluated in terms of (1) psychometric properties and (2) specificity of scores in relation to disabling chronic pain. METHODS: A total of 304 participants completed the Pain Self Perception Scale, a questionnaire designed to measure mental defeat as a reaction to pain. Participants also completed the Short-Form McGill Pain Questionnaire and Hospital Anxiety and Depression Scale. Chronic pain patients from a tertiary hospital clinic (n=94) were compared with patients experiencing acute pain (n=38), pain-free controls (n=79), community volunteers suffering from chronic pain (n=32) or acute pain (n=30), and patients diagnosed with anxiety disorders (n=31). Test-retest reliability was assessed in subsamples of chronic pain patients and community volunteers. RESULTS: The mental defeat measure was both internally consistent and reliable. Chronic pain patients showed elevated levels of mental defeat relative to all other groups, including people with chronic pain of the same intensity of pain who were not seeking treatment. Pain-specific mental defeat may be linked to disability and the seeking of specialist treatment. CONCLUSIONS: Research on mental defeat may allow the development of new treatment strategies for chronic pain syndromes and a better understanding of the link between chronic pain, depression, and posttraumatic stress disorder.     

Are provider self-efficacy and attitudes related to cardiovascular prevention associated with better treatment outcomes?

Cardiovascular risk factor control is inadequate in many high-risk patients. Although many provider-directed educational interventions attempt to address this issue by enhancing provider self-efficacy, a link between greater self-efficacy and better patient outcomes has not been established. Primary care providers (PCPs) in outpatient clinics of a large Veteran's Administration (VA) facility were asked to complete 4 subscales assessing self-efficacy and attitudes related to cardiovascular prevention (CVP). Using a cross-sectional study design, responses were linked with process and CVP outcomes related to blood pressure (BP) and low-density lipoprotein-cholesterol (LDL-C) control and the Framingham Risk Score (FRS), a summary measure of risk factor control, in diabetic patients observed by participating PCPs between December 1, 2004 and December 31, 2005. Multivariable, multilevel models assessed associations between these patient outcomes and provider self-efficacy and CVP-related attitudes, after accounting for patient characteristics, including baseline risk factor control, provider characteristics, and patient clustering within provider practices. Fifty-nine PCPs (86%) providing care to 1495 patients with diabetes completed the survey. Mean scores for provider efficacy and CVP-related attitudes were moderate to high. Higher self-efficacy scores were associated with initiation of medications in previously untreated individuals with inadequate BP or lipid control at baseline. Despite adequate power, however, multilevel models demonstrated neither consistent nor substantive associations between providers' self-efficacy and CVP-related attitudes and patient outcome measures. These findings underscore the need for interventions to enhance cardiovascular risk factor control that look beyond educational strategies to address a broader range of factors with potential influence on patient outcomes and the delivery of preventive care.     

Genome analysis linking recent European and African influenza (H5N1) viruses

To better understand the ecology and epidemiology of the highly pathogenic avian influenza virus in its transcontinental spread, we sequenced and analyzed the complete genomes of 36 recent influenza A (H5N1) viruses collected from birds in Europe, northern Africa, and southeastern Asia. These sequences, among the first complete genomes of influenza (H5N1) viruses outside Asia, clearly depict the lineages now infecting wild and domestic birds in Europe and Africa and show the relationships among these isolates and other strains affecting both birds and humans. The isolates fall into 3 distinct lineages, 1 of which contains all known non-Asian isolates. This new Euro-African lineage, which was the cause of several recent (2006) fatal human infections in Egypt and Iraq, has been introduced at least 3 times into the European-African region and has split into 3 distinct, independently evolving sublineages. One isolate provides evidence that 2 of these sublineages have recently reassorted.     

Clinical and haemodynamic effects of sildenafil in pulmonary hypertension: acute and mid-term effects.

AIM: The treatment of patients with pulmonary arterial hypertension remains a challenge. We set out to investigate the use of sildenafil, a selective inhibitor of phosphodiesterase type 5, in patients with this disease. METHODS AND RESULTS: Ten patients (8 females, mean age 34.5+/-3.3 years) with pulmonary hypertension underwent right heart catheterisation with vasodilator testing using incremental doses of intravenous sildenafil without adverse events. All patients were subsequently commenced on oral sildenafil 50 mg t.d.s. Nine patients had repeat right heart catheterisation 3 months after the commencement of oral therapy. There was a significant reduction in mean pulmonary artery pressure (from 55.8+/-5.9 to 50.4+/-6.1 mmHg, p=0.038 ) and pulmonary vascular resistance (from 10.1+/-1.7 to 8.6+/-1.5 Wood units, p=0.009 ), and an increase in cardiac output (from 4.7+/-0.3 to 5.0+/-0.4 l/min, p=0.15 ). Furthermore, there was a significant increase in the 6-minute walk test, a mean of 112 m. In response to a quality-of-life questionnaire, patients indicated marked clinical improvement on sildenafil. Sildenafil was discontinued in 1 patient due to a transient visual disturbance. The only patient previously awaiting transplantation was removed from the active transplantation list. CONCLUSIONS: Sildenafil is well tolerated in its intravenous and oral forms and appears to improve both pulmonary haemodynamics and the clinical status of patients with pulmonary hypertension after 3 months of oral therapy.     

ET(A) and ET(B) receptors modulate the proliferation of human pulmonary artery smooth muscle cells

We determined the distribution of ET(A) and ET(B) receptors in pulmonary arteries from pulmonary hypertensive patients and control subjects, using in vitro autoradiography, and investigated their role in mediating the proliferative effects of endothelin-1 (ET-1) on distal human pulmonary artery smooth muscle cells (PASMCs). Distal arteries possessed more medial [(125)I]-ET-1 binding sites (105 +/- 10 versus 45 +/- 6 amol/mm(2); p < 0.001) and a greater proportion of ET(B) receptors than proximal arteries (36 +/- 3% versus 3 +/- 1%; p < 0.001). Receptor density in distal arteries and lung parenchyma was twofold greater (p < 0.05) in pulmonary hypertensive patients than in control subjects. ET-1 (10(-9)-10(-7) mol/L) stimulated DNA synthesis (147 +/- 10% of control subjects; p < 0.05) and attenuated the antiproliferative action of cicaprost and forskolin on PASMCs, these effects being mediated via ET(A) and ET(B) receptors. Serum-stimulated proliferation was attenuated by inhibiting either endogenous ET-1 release with phosphoramidon (10(-5) mol/L) or its action with PD145065 (10(-5) mol/L). Cicaprost (10(-10)-10(-7) mol/L) inhibited ET-1 release from PASMCs (49 +/- 16% of control after 24 h; p < 0.001) and increased intracellular cAMP levels, whereas ET(B) receptor stimulation selectively reduced cAMP levels. In conclusion, ET(A) and ET(B) receptors are differentially distributed in human pulmonary arteries. Both receptors promote the proliferation of PASMCs in vitro and may contribute to vascular remodeling in pulmonary hypertension.