Inhibition of the epidermal growth factor receptor tyrosine kinase by PD153035 in human A431 tumors in athymic nude mice

Summary PD153035 is a potent (K_i=6 pm) and specific inhibitor of the epidermal growth factor (EOF) receptor tyrosine kinase that suppresses tyrosine phosphorylation of the EGF receptor in A431 cells at nanomolar concentrations in cell culture. We have examined the pharmacokinetics of this compound and its ability to rapidly suppress phosphorylation of the EGF receptor in A431 human epidermoid tumors grown as xenografts in immunodeficient nude mice. Following a single i.p. dose of 80 mg/kg, the drug levels in the plasma and tumor rose to 50 and 22 M within 15 minutes. While the plasma levels of PD153035 fell below 1 M by 3 hours, in the tumors it remained at micromolar concentrations for at least 12 hours. The tyrosine phosphorylation of the EGF receptor was rapidly suppressed by 80–90% in the tumors. However receptor phosphorylation returned to control levels after 3 hours despite the continued presence of the drug at concentrations which, based on previousin vitro results, were predicted to maintain inhibition. EGF-stimulated tyrosine kinase activity in tumor extracts was decreased and recovered in parallel with the effects of PD153035 on receptor phosphorylation though the activity had reached only about half of the control activity after three hours. These results demonstrate the potential for using small molecule inhibitors to inhibit the EGF receptor tyrosine kinasein vivo, though a fair evaluation of their potential anti-cancer activity will have to wait for solutions to problems with sustained delivery which may allow us to maintain suppression of EGF receptor phosphorylation.     

MRI of the Stener lesion

Objective. To assess the utility of MR in detecting surgically induced Stener lesions (displaced thumb ulnar collateral ligaments) in cadaveric models. Design. Six cadaver thumbs had ulnar collateral ligament (UCL) tears created surgically. MR examinations (2D STIR and 3D GRASS) were performed identically on all specimens both before displacement (non-Stener) and after displacement (Stener lesion) of the UCL. The MR images were then randomly numbered. Each image was evaluated separately in blinded fashion by four musculoskeletal radiologists for the presence or absence of a Stener lesion. Each radiologist reinterpreted the images after an interval of several days. The interpretation was based on previously published criteria for Stener lesion diagnosis by MR. Results. The sensitivity of GRASS ranged from 0.17 to 0.67 with the most experienced reader scoring the lowest. The specificity of GRASS ranged from 0.33 to 1.0 (most experienced reader 0.67, 0.83). STIR had a sensitivity of 0.00–0.17 and a specificity of 0.53–0.83. The values for inter- and intraobserver agreement were measured. The intraobserver for GRASS was 0.27–0.75 (most experienced reader 0.75). Conclusions. 2D imaging is probably inadequate for the evaluation of Stener lesions. The most likely reason is that the STIR slice thickness of 3 mm limits resolution of small UCLs. The poor sensitivity and specificity of GRASS as well as poor interobserver agreement suggest that MR may not be sufficiently accurate for Stener lesion evaluation.     

Laser Doppler velocimetry in retinal arteries of infants

The present study was conducted to assess the feasibility of laser Doppler velocimetry in young infants, as a prelude to ultimately undertaking such measurements in premature infants. A portable, unidirectional laser Doppler velocimeter was developed based on a Kowa RC-2 hand-held fundus camera. Six infants between 1 and 21 weeks of age were studied. Relative red blood cell velocity (f_max) at the centre of retinal arteries was measured over approximately 10 heart cycles. A pulsatility parameter (P=1–f_max.dia/f_max.sys), a summary index of vascular status, was determined from the average diastolic and systolic values of f_max. Velocity waveforms were obtained in four of the six infants. Arterial pulsatility for the group was 0.63±0.13. Precise non-invasive measurement of arterial red blood cell velocity waveforms in young infants was achieved. The high signal-to-noise ratio and temporal resolution of this data suggest that relative measurements of retinal blood flow may permit assessment of haemodynamic changes in premature infants.     

Utilization of services for mentally ill chemically abusing patients discharged from residential treatment

Little is known about outcomes of treatment for individuals with mental illness and chemical dependencies. This article compares services utilization preadmission and postdischarge in 534 patients discharged from a residential treatment program in Washington State. A number of services, including chemical dependency detoxification, mental health crisis, inpatient psychiatric, medical emergency, and general medical inpatient hospitalization, were used less frequently in the period after discharge. The total reimbursement for all Medicaid services decreased by 44% from $5 million in the year prior to discharge to $2.8 million in the year after discharge. Also, individuals (32%) who completed the program were less likely to use costly, acute care services. This study was limited by the absence of a control group and posttreatment alcohol and drug use data. In addition, other unmeasured factors could have explained the association between program completion and better outcomes.     

Effect of prolonged moderate and severe energy restriction and refeeding on plasma leptin concentrations in obese women.

BACKGROUND: Plasma leptin in humans is subject to both long- and short-term regulation; it correlates with indexes of body fat that can only change slowly. However, short-term fasting causes large and rapid decreases. OBJECTIVE: We tested the interactions between energy intake and fat loss on plasma leptin during prolonged moderate and severe energy restriction, with a view to understanding mechanisms of control. DESIGN: Postabsorptive leptin was measured with an enzyme-linked immunosorbent assay specific for the human peptide in 21 obese women aged 41 +/- 3 y (weight: 102 +/- 4 kg; 48 +/- 1% body fat) after 1 wk of a weight-maintaining diet and then weekly for 4 wk during a total fast (group 1); a 1.9-MJ/d all-protein, very-low-energy diet (VLED) (group 2); or a low-energy, balanced-deficit diet (BDD) providing 50% of maintenance energy (group 3). In groups 1 and 2, leptin was also measured after 1 wk of refeeding with a diet equivalent to the BDD. RESULTS: Mean leptin decreased markedly by up to 66% (P < 0.001) at week 1 of energy restriction and then gradually thereafter. The change in leptin per kilogram fat mass correlated with that in glucose concentrations [r = 0.538 (P = 0.012) at week 1 and r = 0.447 (P = 0.042) at week 4] but not with that in fat mass. During refeeding postfasting, leptin increased (P = 0.008), despite an ongoing loss of fat mass and correlated positively with changes in resting energy expenditure. At times with comparable cumulative energy restriction and fat loss between diets, the percentage change in leptin paralleled that in glucose. CONCLUSIONS: In obesity, changes in energy intake over days to weeks are a primary modulator of plasma leptin concentrations that are related to the change in glycemia and are able to override the regulatory influence of fat mass.     

The use of patient mix‐adjusted control charts to compare in‐hospital costs of care

We introduce a technique for patient mixadjusting charts and compared differences between unadjusted and patient mixadjusted results. Our data came from coronary artery bypass graft (CABG) surgery patients at Baptist Medical Center, Oklahoma City, Oklahoma. We first developed an unadjusted control chart to compare monthly changes in CABG surgery costs and then used a published model to patient mixadjust our control chart information. Before adjustment, the average log costs for three of ten months were outside the 90% control limit lines, and there was a trend toward increasing costs. After adjustment, two months had average costs outside the 90% lower control limit lines, and the trend toward increasing costs had been explained by differences in patient acuity.     

Differential chemokine induction by the mouse adenovirus type-1 in the central nervous system of susceptible and resistant strains of mice

Mouse adenovirus-type 1 (MAV-1) has recently been shown to cause a fatal hemorrhagic encephalopathy in certain strains of mice whereas other strains are resistant. Morbidity is associated with a productive infection of cerebrovascular endothelial cells, resulting in necrosis of the vasculature, infarction, hemorrhage and death within 4 - 6 days. Previous studies were not able to define a role for the innate or acquired immune response. In the current study we have addressed the effect of MAV-1 on chemokine and chemokine receptor expression in the central nervous system (CNS) and spleen of susceptible (C57BL/6) and resistant (BALB/c) strains of mice. Intra-peritoneal infection with MAV-1 in C57BL/6 animals resulted in early and prominent induction of IP-10/crg-2 in the spleen and CNS. Increased expression of MCP-1, MIP-1alpha, MIP-1beta and RANTES was also noted in the CNS of MAV-1-infected C57BL/6 animals commencing around 72 h post-infection. In contrast, chemokine expression in BALB/c animals was more restricted with prominent upregulation only of MIP-2 in the CNS. In situ hybridization identified the vascular endothelium and CNS glia as the principal site of IP-10/crg-2 production in the C57BL/6 animals. The chemokine receptors CCR1-5 were upregulated in the CNS of both strains of mice. These data show that productive infection of the CNS with MAV-1 leads to the upregulation of a characteristic pattern of chemokines and their receptors, which may point to a role for these factors in disease pathogenesis.     

Papillary fibroelastoma: increasing recognition of a surgical disease

Papillary fibroelastomas are uncommon benign tumors usually involving the heart valves, which historically have been diagnosed at autopsy. With the advent of echocardiography, however, the number of patients diagnosed in life has increased. Papillary fibroelastomas represent a surgically treatable cause of cerebrovascular and cardiovascular ischemia and infarction making their identification clinically important. We report three unusual cases of papillary fibroelastoma; two patients presenting with symptoms of cerebrovascular ischemia and one presenting with myocardial infarction. We also present a comprehensive review of the literature and provide a compilation of all case reports to date.