6-phosphogluconate dehydrogenase: a target for drugs in African trypanosomes

New drugs are urgently required for Human African Trypanosomiasis (sleeping sickness), a disease which has re-emerged as a major health threat in Sub-Saharan Africa. The third enzyme of the pentose phosphate pathway, 6-phosphogluconate dehydrogenase, has been shown to be a good target for drugs. The enzyme is essential to the trypanosomes that causes sleeping sickness and structural differences when compared to its mammalian counterpart allow for selective inhibition. Three series of inhibitors have been designed, these include phosphorylated carbohydrate substrate and transition state analogues, non-carbohydrate substrate analogues and also triphenylmethane-based compounds. All have shown selective inhibition of the trypanosomal 6-phosphogluconate dehydrogenase and representatives of each have trypanocidal activity.     

360-feedback in health care management: a field study

In recent years, organizations representing all types of industries, including health care, have adopted the 360-feedback approach with the goal of strengthening leader performance. But while 360-feedback enjoys a high level of face validity, current research shows that it is not problem-free and often fails to achieve its goals without proper development and implementation. This research, conducted in a large public hospital, surveyed the top management team of 49 executives who participated in a 360-feedback project beginning in February 2001. The survey, designed to solicit opinions about the effectiveness of the 360-feedback project, resulted in several recommendations to improve the process: One, both mentors and participants (raters and those rated) should be formally trained to improve the feedback process. Two, participants--both raters and those rated--should be significantly involved in 360-feedback planning and development efforts. Three, the 360-feedback process should be linked to hospital objectives. Four, the 360-feedback process should focus not only on interpersonal issues but departmental and organizational goals as well. First and foremost, our findings show that regardless of how popular a management development program may be, no technique for improving management and organizational effectiveness, including 360-feedback, will work unless properly designed and implemented.     

Inhibition of leukotriene biosynthesis by quinolone alkaloids from the fruits of Evodia rutaecarpa

The n-hexane extract of the fruits of Evodia rutaecarpa showed a considerable inhibiting effect on leukotriene biosynthesis in human granulocytes. Bioassay-guided fractionation of the extract led to the isolation of the 5 quinolone alkaloids: 1-methyl-2-nonyl-4(1H)-quinolinone, 1-methyl-2-(6Z)-6-undecenyl-4(1H)-quinolinone, 1-methyl-2-(4Z,7Z)-4,7-tridecadienyl-4(1H)-quinolinone, evocarpine and 1-methyl-2-(6Z,9Z)-6,9-pentadecadienyl-4(1H)-quinolinone. The compounds exhibited inhibitory activity on leukotriene biosynthesis in a bioassay using human polymorphonuclear granulocytes, with IC50 values of 12.1, 10.0, 10.1, 14,6 and 12.3 microM, respectively. Structure elucidation of the compounds was achieved by 1D and 2D NMR experiments and comparison of spectral data with literature data.     

Negotiation as relationship-building in healthcare organizations: a case study exercise

A key skill needed by healthcare managers is an ability to simultaneously maintain and enhance relationships with multiple stakeholders, most notably clinical professionals, through the process of decision-making and negotiation. Additionally, healthcare managers need to be able to actively integrate various components of functional areas into their decision-making process. This article presents two exercises that serve the following purposes: (1) it can help raise students' awareness of the complexity involved in decision-making and negotiating, (2) it can create an understanding that decision-making and negotiations are embedded in a larger context involving multiple relationships between parties, and (3) it can be used as a means to measure the student's integrative ability within the traditional curriculum of an MHA program.     

Patterns of intra-cluster correlation from primary care research to inform study design and analysis

OBJECTIVE: To provide information concerning the magnitude of the intraclass correlation coefficient (ICC) for cluster-based studies set in primary care. STUDY DESIGN AND SETTING: Reanalysis of data from 31 cluster-based studies in primary care to estimate intraclass correlation coefficients from random effects models using maximum likelihood estimation. RESULTS: ICCs were estimated for 1,039 variables. The median ICC was 0.010 (interquartile range [IQR] 0 to 0.032, range 0 to 0.840). After adjusting for individual- and cluster-level characteristics, the median ICC was 0.005 (IQR 0 to 0.021). A given measure showed widely varying ICC estimates in different datasets. In six datasets, the ICCs for SF-36 physical functioning scale ranged from 0.001 to 0.055 and for SF-36 general health from 0 to 0.072. In four datasets, the ICC for systolic blood pressure ranged from 0 to 0.052 and for diastolic blood pressure from 0 to 0.108. CONCLUSION: The precise magnitude of between-cluster variation for a given measure can rarely be estimated in advance. Studies should be designed with reference to the overall distribution of ICCs and with attention to features that increase efficiency.     

Age-related variations in progression of cancer at diagnosis and completeness of cancer registry data

There is some evidence that stage and grade at diagnosis of cancer decreases with age and that the availability of data on stage and grade of cancer decreases with age. This may be because older people tend to receive less intensive investigation of cancer but this has not been confirmed. We investigated the relationship between age at diagnosis of cancer and both stage and grade at diagnosis, and the chances of data on stage or grade at diagnosis being unavailable, in people with colorectal cancer (n=12,419) and women with breast cancer (n=12,793) using 2 years of cancer registry data from the north of England. Stage and grade decreased with increasing age in colorectal cancer. Grade decreased but stage increased with increasing age in women with breast cancer. The chances of data on stage and grade at diagnosis being unavailable increased with age in all cases.     

Frequency and timing of symptoms in infants screened for sepsis: effectiveness of a sepsis-screening pathway

To determine the frequency and timing of symptoms and to evaluate the effectiveness of a sepsis-screening pathway in term and near-term infants, data were collected prospectively for a period of 1 year from December 1, 2000, to November 30, 2001. Results confirmed that a sepsis-screening pathway using a combination of at least 2 serial complete blood cell count and C-reactive protein measurements in both symptomatic and asymptomatic infants is a safe, simple strategy that prevents unnecessary treatment of infants with risk factors with antibiotics. However, most infants with presumed or suspected early-onset sepsis are symptomatic. Routine treatment of asymptomatic infants with risk factors or prior treatment with intrapartum antibiotics is unnecessary. A combined approach of screening in the presence of risk factors and /or symptoms of sepsis and adequate follow-up for infants discharged at less than 72 hours of age may help reduce unnecessary treatment of infants with antibiotics.     

Future challenges in analysis and treatment of human immune senescence

Immune functions decline with age; immunorestorative approaches have been explored in laboratory animals and humans with definite, but limited success. In the clinical setting, the age-associated immune deficiency (immunesenescence) is compounded by the presence of comorbidities that are associated with a functional decline in immunity. Thus, any successful immune reconstitution strategy for humans must involve treatment of the underlying diseases. Furthermore, general health measures such as nutrition and exercises may have powerful effects on restoring immunity, to the extent that malnutrition and a sedentary lifestyle have contributed to existing immune deficiency. More selective approaches, such as with specific cytokines or organ transplantation are of experimental interest but are quite distant from achieving clinical applicability as interventions to restore immunity in the frail elderly.     

Serial analysis of gene expression provides new insights into regulatory T cells

It is now possible to induce donor-specific transplantation tolerance in adult rodents using a number of therapeutic strategies. Such peripheral tolerance is maintained by regulatory CD4+ T cells, not only in transplantation models, but also in autoimmunity. Differential gene expression analyses have been used to identify potential new markers for regulatory T cells, aiming to reveal new insights into their mechanisms of action, and to find novel targets for therapeutic manipulation of the immune system.