Biologic aspects of thrombopoietins and the development of therapeutic agents

Thrombopoiesis is a multistage process beginning with pluripotent hematopoietic stem cells, progressing through proliferating cells committed to megakaryocytopoiesis, to megakaryocytes, and eventually ending with the shedding of platelets from megakaryocytes. Many growth factors stimulate thrombopoiesis; this review addresses those that act through binding to the thrombopoietin receptor. The cloning of thrombopoietin in 1994 greatly accelerated progress in understanding the biology of thrombopoiesis and of hematopoiesis in general. Detailed structural and functional studies of the thrombopoietin receptor, coupled with novel molecular pharmacology approaches, have led to new classes of thrombopoietic mimetics. Initial clinical trials with recombinant thrombopoietins faltered as they encountered significant neutralizing antibodies or difficulty finding a significant clinical niche in support of chemotherapy. Ongoing studies with the new thrombopoietic agents have invigorated the field, with positive results now reported in idiopathic thrombocytopenic purpura.     

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.     

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.     

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.     

Patient medical group continuity and healthcare utilization

Objectives: To measure continuity among medical groups of insured patients over a 5-year period and to test whether group continuity of care is associated with healthcare utilization and costs. Study Design: Retrospective observational study. Methods: We studied natural patient behavior by using insurance claims data in the absence of any medical group or health plan incentives for continuity. We conducted the study through a retrospective analysis of administrative data of 121,780 patients enrolled from 2005 to 2009 in HealthPartners, a large nonprofit Minnesota health plan. Each year, patients were attributed to the medical group where they received the greatest number of primary care visits. Multilevel multiple regression models were used to estimate the association of annualized medical cost and utilization with attribution and continuity categories. Results: Although patients with high medical group continuity were older and had more comorbidities than patients with medium or low continuity of care, they had a consistently lower probability of any inpatient expenditure or any emergency department (ED) utilization and lower total medical costs. Conclusions: Although a small proportion, health plan members who visited a primary care provider but had low or medium continuity among medical groups had higher inpatient and ED use than those with high continuity. Improved coordination and integration has potential to lower utilization and costs in this group.     

Chemical composition of fine particles (PM<Subscript>2.5</Subscript>): water-soluble organic fraction and trace metals

The chemical composition of the atmosphere changes rapidly due to the amount of air pollutants released every day. The aim of this research was to make an exploratory study on the chemical composition (metals and water-soluble organic fraction) of fine particulate matter (PM_2.5) in a region with tropical climate. Multiple sites, with and without the influence of the construction works for the World Cup and Olympic Games, were selected in Rio de Janeiro State, RJ, Brazil. PM_2.5 samples were collected every 6 days from January to December 2011. This is the first PM_2.5 data generated by RJ’s monitoring network. The PM_2.5 annual average concentrations in Rio de Janeiro ranged from 9 to 32 μg m^?3. Metals originated from industrial (Cu, Cd, Pb) and traffic (Cr, Mn, Ni, V, and Zn) emissions, as well as those from natural emissions (Na, K, Ca, Ti, Al, Mg, Fe), were quantified. The concentrations of the metals analyzed ranged from 0.4 to 13,000 ng m^?3. The highest concentrations found were related to metals present in the crust, such as Al (1.6 to 6.7 μg m^?3). In the places where there was the presence of railroad minerals, Ca and Mg appeared in higher concentrations than in the other sites. Fe and PM_2.5 annual and daily average were higher in areas under construction for urban mobility improvements or the Olympic arenas. Even though, the results for Ni, Pb, and Cu were 50% below WHO guidelines. Water-soluble organic carbon (WSOC) concentrations ranged from 0.8 to 4.9 μg m^?3. The highest concentrations (2.4 to 4.9 μg m^?3) were observed in urban areas with intense light vehicle fleet traffic as well as in areas of large industrial influence near highways with intense circulation of heavy vehicles. This is due to the fact that WSOC is mainly formed by the emissions from combustion processes. Studies are needed in order to assess to which extent the WSOC can increase the bioavailability of these and other metals.     

Urban Indians' smoking patterns and interest in quitting.

Little is known about smoking patterns of urban American Indians and their interest in quitting. Most published research has focused upon American Indians who live on rural reservations. In this study, personal interviews were conducted with a convenience sample of patients at Urban Indian Health Clinics in four geographically diverse sites: Milwaukee, WI, Minneapolis, MN, and Seattle and Spokane, WA. A total of 419 current smokers and 173 ex-smokers completed interviews. Current smokers reported a median cigarette consumption of 11 per day. Smokers indicated both a moderate desire to quit (mean 5.97, on a scale 0-10) and moderate confidence in their ability to do so (mean 5.56, on a scale 0-10). More than 70 percent of current smokers indicated having previously tried to quit. The most common reasons cited for relapse included craving, social situations, stress, and nervousness. The most common reasons for quitting given by ex-smokers included being "sick" of smoking, health concerns, respiratory problems, and pregnancy. The estimated quit-ratio (former smokers divided by current+former smokers) was 29.7 percent. This quit-ratio, although substantial, is lower than the 45 percent quit-ratio reported for the general U.S. population. Perhaps the most striking findings are the similarities between American Indians and the overall population in both interest in quitting and reasons for doing so. Smoking cessation previously has been viewed as a low priority for this population. The current results suggest the viability of systematic efforts to encourage urban American Indians to quit smoking.     

Is consistent primary care within a patient-centered medical home related to utilization patterns and costs?

The patient-centered medical home (PCMH) is seen as an important vehicle for providing consistent primary care and achieving cost savings through care coordination. We used health plan administrative data to evaluate utilization and cost among enrollees who attended a PCMH compared with those who fragmented their care. Controlling for demographic differences, PCMH attendees made significantly fewer primary care and specialist visits than other groups, and associated professional fees were significantly lower than for enrollees receiving less consistent primary care.