Epidermal growth factor receptor - but not histamine receptor - is upregulated in seasonal allergic rhinitis

BACKGROUND: We were interested in exploring the molecular mechanisms underlying the observed difference in histamine (H) responsiveness between seasonal allergic rhinitic (SAR) and nonrhinitic (NR) subjects. We hypothesized that SAR subjects express higher nasal mucosal histamine receptor 1 (H1R) and 2 (H2R) levels than do NR subjects. In addition, we examined expression of genes involved in regulating the glandular response, including epidermal growth factor (EGF), EGF receptor (EGFR), and mucins (Muc5Ac and Muc5B). METHODS: Fourteen subjects, seven SAR and seven NR, were provoked during pollen season with doubling doses of H (0.125-8.0 mg/ml). Nasal airway resistance (NAR) was measured by active posterior rhinomanometry. Provocation was halted when NAR exceeded 150% of baseline. Prior to provocation, nasal scrapings were obtained and mRNA quantified using two-step real-time PCR. RESULTS: The mean PD50 (concentration of H producing a 50% increase in NAR) was significantly lower in the SAR than NR group (0.36 vs 1.32 mg/ml; P < 0.05). The ratio of relative gene copy numbers between the SAR and NR groups were as follows: H1R, 0.85 (P = 0.52); H2R, 0.67 (P = 0.35); EGF, 1.02 (P = 0.93), and EGFR, 103.5 (P < 0.05). CONCLUSIONS: There were no significant differences in H1R or H2R mRNA levels between SAR and NR subjects in-season, despite observed differences in H reactivity. SAR subjects, however, did show a significant elevation in EGFR expression, consistent with the observation of mucus hypersecretion in allergic rhinitis.     

Absence of multiple local minima effects in intensity modulated optimization with dose-volume constraints

This paper reports on the analysis of intensity modulated radiation treatment optimization problems in the presence of non-convex feasible parameter spaces caused by the specification of dose-volume constraints for the organs-at-risk (OARs). The main aim was to determine whether the presence of those non-convex spaces affects the optimization of clinical cases in any significant way. This was done in two phases: (1) Using a carefully designed two-dimensional mathematical phantom that exhibits two controllable minima and with randomly initialized beamlet weights, we developed a methodology for exploring the nature of the convergence characteristics of quadratic cost function optimizations (deterministic or stochastic). The methodology is based on observing the statistical behaviour of the residual cost at the end of optimizations in which the stopping criterion is progressively more demanding and carrying out those optimizations to very small error changes per iteration. (2) Seven clinical cases were then analysed with dose-volume constraints that are stronger than originally used in the clinic. The clinical cases are two prostate cases differently posed, a meningioma case, two head-and-neck cases, a spleen case and a spine case. Of the 14 different sets of optimizations (with and without the specification of maximum doses allowed for the OARs), 12 fail to show any effect due to the existence of non-convex feasible spaces. The remaining two sets of optimizations show evidence of multiple minima in the solutions, but those minima are very close to each other in cost and the resulting treatment plans are practically identical, as measured by the quality of the dose-volume histograms (DVHs). We discuss the differences between fluence maps resulting from those similar treatment plans. We provide a possible reason for the observed results and conclude that, although the study is necessarily limited, the annealing characteristics of a simulated annealing method may not be justified in clinical optimization in the presence of dose-volume constraints. The results of optimizations by the Newton gradient (NG) method with a quadratic cost function are reported in detail. An adaptive simulated annealing method, optimizing the same function, and the dynamically penalized likelihood method, optimizing a log likelihood function, have also been used in the study. The results of the latter two methods have only been discussed briefly, as they yielded the same conclusions as the NG method.     

Variation in diabetes care by age: opportunities for customization of care

Background  

The quality of diabetes care provided to older adults has usually been judged to be poor, but few data provide direct comparison to other age groups. In this study, we hypothesized that adults age 65 and over receive lower quality diabetes care than adults age 45–64 years old.     

Procalcitonin does not influence the surface expression of inflammatory receptors on whole blood leukocytes

The plasma levels of procalcitonin (PCT) are increased in patients with severe bacterial infections. Its cellular origin and potential pathophysiological function in sepsis is, however, unclear. White blood cells have recently been described to express both PCT mRNA and protein. The aim of this study was to determine whether PCT has any influence on the surface expression of receptors, relevant in inflammation, on human whole blood leukocytes under normal and septic conditions. Venous blood from healthy donors was incubated with PCT (40 ng/ml or 1200 ng/ml) alone or in combination with lipopolysaccharide (LPS, 10 ng/ml) or peptidoglycan (PepG, 10 micrograms/ml) for 6 h. The surface expression of CD14, CD54, CD64, CD80, CD86 and HLA-DR was determined by flow cytometry. We could not detect any influence of PCT on the expression of these receptors. Further studies on potential effects on other cell types during infection seem warranted.     

Patient satisfaction and discussion of smoking cessation during clinical visits

OBJECTIVE: To learn whether patients who smoke and who receive smoking cessation information during medical office visits were less likely to be satisfied with the smoking cessation help they received than patients who smoke but who did not receive such information. PATIENTS AND METHODS: A total of 3703 current cigarette smokers were identified by a mailing in November 1998 to 163,596 members of 2 Minnesota health plans, and 2714 (77.3%) responses to a 44-item questionnaire were available for analysis. Using hierarchical analysis to control confounding variables, we assessed the relationship between patient-reported smoking cessation support actions at the last physician visit and satisfaction "with the help received from your doctor about quitting smoking." RESULTS: Smokers were very satisfied (12.0%), satisfied (25.3%), neutral (48.6%), and dissatisfied or very dissatisfied (13.5%) with physician help. After controlling for other characteristics, the 1898 patients who reported that they had been asked about tobacco use or advised to quit during the latest visit had 10 percentage point greater satisfaction ratings and 5 percentage point less dissatisfaction than those not reporting such discussions (P<.001). Smokers reporting no interest in quitting at the time of the latest visit also demonstrated greater satisfaction in association with these actions. CONCLUSION: Smoking cessation interventions during physician visits were associated with increased patient satisfaction with their care among those who smoke. This information should reduce concerns of physicians or nurses about providing tobacco cessation assistance to patients during office visits.     

Paradoxical hormonal and behavioral responses to hypothyroid and hyperthyroid states in the Wistar-Kyoto rat.

Wistar-Kyoto (WKY) rats show endogenous depressive behavior that can be reversed by antidepressants. Given that WKYs exhibit decreased sensitivity to some antidepressants and treatment-resistant depressed patients often show hypothalamic-pituitary-thyroid (HPT) dysregulation, we examined the behavioral and HPT hormonal responses of WKYs to altered thyroid status. "Euthyroid" WKYs had elevated basal plasma TSH and T(3) levels as compared to Wistars. Hypothyroidism increased TSH levels more in WKYs than in Wistars and increased response latency in the open field test (OFT) of WKYs only. Administration of T(4) and T(3) suppressed plasma TSH equally in both strains. Wistars responded to increased T(3) levels with decreased response latency and increased activity in the OFT, but increased immobility in the forced swim test. In contrast, WKYs responded only to the high T(3) levels with decreased response latency in the OFT. These results suggest the existence of a decreased central nervous system sensitivity to thyroid hormones in WKYs that could be related to their depressive behavior.     

Novel animal models of affective disorders

Is there an appropriate animal model for human affective disorders? The traditional difficulties in accepting animal models for psychopathology stem from the argument that there is no evidence for concluding that what occurs in the brain of the animal is equivalent to what occurs in the brain of a human. However, if one models any or some core aspects of affective disorder, this model can become an invaluable tool in the analysis of the multitude of causes, genetic, environmental, or pharmacological, that can bring about symptoms homologous to those of patients with affective disorders. Animal models can also allow the study of the mechanisms of specific behaviors, their pathophysiology, and can aid in developing and predicting therapeutic responses to pharmacologic agents. Although animals exhibit complex and varied social and emotional behaviors for which well-validated and standardized measures exist, an understanding that a precise replica of human affective disorders cannot be expected in a single animal model is crucial. Instead, a good animal model of a human disorder should fulfill as many of the four main criteria as possible: (1) strong behavioral similarities, (2) common cause, (3) similar pathophysiology, and (4) common treatment. An animal model fulfilling any or most of these criteria can be used to elucidate the mechanisms of the specific aspect of the model that is homologous to the human disorder. A wide range of animal models of affective disorders, primarily depression, has been developed to date. They include models in which "depressive behavior" is the result of genetic selection or manipulation, environmental stressors during development or in adulthood, or pharmacologic treatments. The assessment of these animal models is based either on behavioral tests measuring traits that are homologous to symptoms of the human disorder they model, or behavioral tests responsive to appropriate pharmacologic treatments. The goal of this review is to focus on relatively recent developments of selected models, to aid in understanding their strengths and weaknesses, and to help those choosing the difficult task of developing novel animal models of affective disorders. The ideal animal model of affective disorders of the future would be an endogenous, genetic model that reiterates the essential, core aspects of the human disease and responds to the standard regimens of therapy. Because complex diseases have been approached from the genetic startpoint by using rodent models, a genetic model of affective disorder would open up possibilities for genetic analysis of polygenic traits that seem to underlie these disorders.     

First radiotherapy of human metastatic brain tumors delivered by a computerized tomography scanner (CTRx)

Purpose: This Phase I study was designed to evaluate the computed tomography (CT) scanner as a device for radiation therapy of human brain tumors (CTRx). This first use in humans of a modified CT for treatment was founded on extensive research experience with canine tumors. An additional objective was to increase the therapeutic radiation dose to tumors compared to normal tissue by concentration of infused contrast material in tumors, an effect available at diagnostic x-ray energies but not at megavoltage energies.

Methods and Materials: A small metastatic brain tumor in each of eight patients received 3–5-weekly fractions of 5 Gy equivalent per fraction from a CT scanner modified to deliver radiation therapy. In each patient, one additional tumor, lying completely outside the volume treated by CTRx, served as a control. The tumor receiving CTRx was treated after infusion of iodinated x-ray contrast media (CM) for dose enhancement. Many of these patients also received conventional 40 Gy whole brain radiation, before, during, or after CTRx treatment.

Results: None of the patients showed adverse reactions to the CM or necrosis of the normal brain from the CTRx boost radiation. Monte Carlo calculations of the radiation dose distributions in a model tumor showed that the CTRx irradiation of tumors carrying 10 mg or more of iodine per gram of tumor was as good or better than the dose distribution from conventional 10-MV X-rays. The treated tumor in two of the patients vanished after four treatments, whereas a control tumor in one patient remained constant and grew 4-fold in another patient.

Conclusion: The CTRx concept effectively combines a modified CT scanner as a diagnostic device, as a simulator dedicated to radiotherapy, and as a treatment machine. Thus, CTRx could be very useful for radiation oncologists in controlling CM-enhanced and other small brain tumors.