New Conversions and Functionalization Possibilities in Pyrimido[4,5-e][1,2,4]triazine-6,8-diones

Pharmaceutical Chemistry Journal -     

How to use a nasopharyngeal prong in Pierre Robin sequence

Pierre Robin sequence (PRS) describes a small mandible with retrognathia, an elevated and posteriorly positioned tongue, and an associated U-shaped cleft palate. The retracted tongue may obstruct the airway leading to respiratory failure, with failure to thrive and adverse neurodevelopmental outcomes if not addressed. If the airway obstruction cannot be overcome with conservative measures, there are non-surgical and surgical options. A nasopharyngeal prong (NPP) is a non-surgical, temporary treatment that avoids the complications inherent in an operation, especially given the natural history of mandibular growth and improved airway obstruction in PRS. Although the use of a prong requires training, support, and follow up, it effectively bypasses the obstruction in the majority of children with PRS, and allows the child to outgrow the airway obstruction until the prong is no longer required. On average, the prong can be removed between 6 and 12 months of age.     

Demoralization in Mental Health Organizations: Leadership and Social Support Help

Demoralization is a commonly observed feeling state that is characterized by a sense of loss of or threat to one??s personal values or goals and a perceived inability to overcome obstacles toward achieving these goals. Demoralization has features in common with burnout and may precede or accompany it. Psychiatrists working in many mental health care organizational settings, be they in the public or private sectors, may be at particular risk for demoralization. This is due partly to stressors that threaten their own professional values because of factors such as programmatic cut backs, budgetary reductions and changing social emphases on the value of mental health treatments. They also may be at risk for demoralization because of the effects on them of the governance styles of the agencies in which they are employed. The leadership or governance style in large organizational settings often is authoritarian, hierarchical and bureaucratic, approaches that are antithetical to the more participative leadership styles favored by many mental health professionals in their clinical activities. Clinical leaders in mental health organizations must exhibit various competencies to successfully address demoralization in clinical staff and to provide a counterbalance to the effects of the governance style of many agencies in which they are employed. Appropriate leadership skills, sometimes too simplistically termed ??social support??, have been found to reduce burnout in various populations and are likely to lessen demoralization as well. This paper reviews these important leadership issues and the relationship of social support to recognized leadership competencies.     

Electrocardiographic and hemodynamic changes in experimental right ventricular infarction

To investigate the electrocardiographic and hemodynamic changes in isolated right ventricular infarction, 0.25 ml or 0.5 ml of metallic mercury was injected into the right coronary artery of 14 closed-chest dogs. At autopsy, at least 60% of the right ventricle was necrotic in every dog. Hemodynamic observations were made in 11 and electrocardiographic mapping was performed in all 14 dogs. Right atrial pressure rose in 10 and left atrial pressure in nine of the 11 dogs; early right atrial pressure did not exceed left atrial pressure, but late right atrial pressure was greater in four dogs. Although cardiac output and blood pressure fell significantly, circulation was maintained. Twelve of 14 dogs had transient ST-segment elevation in the right precordial leads, and 12 developed right bundle branch block. Abnormal Q waves or R waves of 1 mm or less appeared in the right precordial leads in 13 of the 14 dogs. Since right bundle branch block and abnormal Q waves in the right precordial leads have not been recognized as useful signs in human right ventricular infarction, further investigations are warranted to determine their value in clinical applications.     

Differential CD26-mediated activation of the CD3 and CD2 pathways after CD6-depleted allogeneic bone marrow transplantation

Patients who have undergone allogeneic bone marrow transplantation (allo-BMT) are susceptible to a variety of opportunistic infectious complications in the months to years after engraftment. Impaired in vitro T-cell functions have been documented in these patients, and these T-cell dysfunctions contribute to the prolonged immune deficiency after allo-BMT. In the present study, we examined the expression of CD26 as well as the reconstitution of CD26-mediated T-cell costimulation via the CD3 and CD2 pathways at various times in patients aged greater than 18 years after CD6-positive, T-cell depleted allo- BMT. We found that the percentage of CD26- and CD3-positive cells, as well as the levels of expression of both antigens, was lower than in normal controls during the first 4 months after CD6-depleted allo-BMT. Subsequently, the amount of lymphocytes expressing CD3 and CD26 and the quantitative surface expression of CD3 and CD26 were not significantly different in patients and normal controls. Functional studies showed that CD26-mediated T-cell proliferation via the CD3 pathway was considerably improved and almost reached normal levels by 1 year, whereas recovery of CD26-mediated T-cell proliferation via the CD2 pathway was delayed for at least 2 years after CD6-depleted allo-BMT. As CD26 involvement in the regulation of human thymocyte activation is restricted preferentially to the CD3 pathway--unlike its involvement with both CD3 and CD2 pathways of peripheral T cells--our results suggest that the different effects of CD26-mediated costimulation via the CD3 and CD2 pathways after CD6-depleted allo-BMT may be a reflection of peripheral T-cell immaturity in those individuals, similar to that seen in mature medullary thymocytes or cord T lymphocytes.     

Fc gamma receptor II (CD32) on malignant B cells influences modulation induced by anti-CD19 monoclonal antibody

Antigenic modulation is one of many factors determining the effectiveness of monoclonal antibody (MoAb)-mediated therapy. To select the isotype of a CD19 MoAb most suitable for radioimmunotherapy of patients with B-cell malignancies, we studied the influence of MoAb isotype on modulation, after binding of the MoAb to different cell-line cells. The CD19-IgG1 MoAb was found to induce modulation of CD19 antigens on Daudi cell line cells more rapidly than did its IgG2a switch variant. We provide evidence that this difference in modulation rate is caused by the expression of Fc gamma receptor II (Fc gamma RII) on these cells. Experiments aimed at elucidating the mechanism of Fc gamma RII involvement in modulation induction by CD19-IgG1 showed that Fc gamma RII did not comodulate with CD19 MoAbs. However, cocrosslinking of CD19 and Fc gamma RII with CD19-IgG1 MoAb resulted in enhanced calcium mobilization in Daudi cells. This increased signal induction accompanies the enhanced capping and subsequent modulation of CD19 antigens. Because Fc gamma RII is expressed in varying densities on malignant B cells in all differentiation stages, our results have implications for the MoAb isotype most suitable for use in MoAb-based therapy of patients with B-cell malignancies.