In vitro studies with methylproamine: a potent new radioprotector

New analogues of the minor groove binding ligand Hoechst 33342 have been investigated in an attempt to improve radioprotective activity. The synthesis, DNA binding, and in vitro radioprotective properties of methylproamine, the most potent derivative, are reported. Experiments with V79 cells have shown that methylproamine is approximately 100-fold more potent than the classical aminothiol radioprotector WR1065. The crystal structures of methylproamine and proamine complexes with the dodecamer d(CGCGAATTCGCG)(2) confirm that the new analogues also are minor groove binders. It is proposed that the DNA-bound methylproamine ligand acts as a reducing agent by an electron transfer mechanism, repairing transient radiation-induced oxidizing species on DNA.     

The Texas Medication Algorithm Project antipsychotic algorithm for schizophrenia: 2003 update

BACKGROUND: The Texas Medication Algorithm Project (TMAP) has been a public-academic collaboration in which guidelines for medication treatment of schizophrenia, bipolar disorder, and major depressive disorder were used in selected public outpatient clinics in Texas. Subsequently, these algorithms were implemented throughout Texas and are being used in other states. Guidelines require updating when significant new evidence emerges; the antipsychotic algorithm for schizophrenia was last updated in 1999. This article reports the recommendations developed in 2002 and 2003 by a group of experts, clinicians, and administrators. METHOD: A conference in January 2002 began the update process. Before the conference, experts in the pharmacologic treatment of schizophrenia, clinicians, and administrators reviewed literature topics and prepared presentations. Topics included ziprasidone's inclusion in the algorithm, the number of antipsychotics tried before clozapine, and the role of first generation antipsychotics. Data were rated according to Agency for Healthcare Research and Quality criteria. After discussing the presentations, conference attendees arrived at consensus recommendations. Consideration of aripiprazole's inclusion was subsequently handled by electronic communications. RESULTS: The antipsychotic algorithm for schizophrenia was updated to include ziprasidone and aripiprazole among the first-line agents. Relative to the prior algorithm, the number of stages before clozapine was reduced. First generation antipsychotics were included but not as first-line choices. For patients refusing or not responding to clozapine and clozapine augmentation, preference was given to trying monotherapy with another antipsychotic before resorting to antipsychotic combinations. CONCLUSION: Consensus on algorithm revisions was achieved, but only further well-controlled research will answer many key questions about sequence and type of medication treatments of schizophrenia.     

Significance of intraoperative peritoneal culture of fungus in perforated peptic ulcer

BACKGROUND: The incidence of postoperative fungal infection is increasing and the gastrointestinal tract is the major source, but antifungal therapy in perforated peptic ulcer (PPU) is still controversial. The aim of this study was to determine the significance of intraoperative peritoneal fluid culture of fungus and establish the indications for treatment. METHODS: Between July 1997 and September 2001, all patients admitted with a PPU were studied. Clinical data and peritoneal fluid for culture were collected. Risk factors for a positive peritoneal fluid culture of fungus and outcome were evaluated, and related to the development of surgical site infection, duration of hospital stay and mortality rate. RESULTS: One hundred and forty-five patients with a PPU were included; 63 (43.4 per cent) had positive peritoneal fluid fungal culture. Age, preoperative organ failure, delay in operation, high Mannheim Peritonitis Index (MPI) and Acute Physiology And Chronic Health Evaluation (APACHE) II scores, and preoperative antibiotic therapy were risk factors for a positive fungal culture. Sex and an MPI score of 20 or more remained significant in multivariate analysis (P < 0.001). Patients with a positive fungal culture had a higher incidence of surgical site infection, a longer hospital stay and a significantly higher mortality rate, especially when this was combined with a high MPI score. CONCLUSION: Positive peritoneal fungal culture was common and was a significant risk factor for adverse outcome in patients with a PPU. A high MPI score could be used as an indicator for prophylactic antifungal therapy.     

Genetic alterations of lung adenocarcinoma in relation to smoking and ethnicity

Adenocarcinoma of the lung is now the most common histologic subtype of non-small-cell lung cancer (NSCLC) worldwide. In Chinese populations, the incidence of lung adenocarcinoma is amongst the highest worldwide and its development in non-smoking females is particularly striking. Information on the associated underlying genetic changes has been, however, minimal to date. The present study represents the first systematic analysis on the overall genetic changes in lung adenocarcinoma of Chinese female non-smokers. We undertook a genome-wide investigation into the abnormalities in lung adenocarcinomas of 18 life-long non-smoking Chinese females using the technique of comparative genomic hybridization (CGH). With a view to isolating the relative roles of gender, ethnicity and tobacco consumption, we recruited control groups of 10 Caucasian female non-smokers and 22 male Chinese smokers. Although gains on 1q, 5p, 7p and 8q, and regional losses on 8p, 17p, 13q and 18q were commonly seen, there were no significant differences between the Caucasian and Chinese non-smoking women. The observation suggests that lung adenocarcinomas, regardless of ethnic origin, adopt similar pathologic pathways during the accumulation of genetic events. Besides, genomic imbalances, particularly gains per tumor, were significantly more common among the tobacco-related tumors (P=0.006). In particular, regional over-representations of 13q21-q34 (P=0.044), 17q25 (P=0.015), 19q13.1 (P=0.044) and 22q (P=0.044) may have implications for the pathologic pathways associated with the tobacco-related lung adenocarcinoma.     

Cellular and subcellular morphological localization of normal prion protein in rodent cerebellum

Normal cellular prion protein, a necessary protagonist in fatal neurodegenerative prion diseases, was mapped in rodent cerebellum to establish its cellular and ultrastuctural localization. Existing morphological data about native prion protein distribution in brain tissues remain, indeed, contradictory and do not fit with biochemical and cell biological results. Using ultrastructural preembedding immunocytochemistry and a monoclonal anti-mouse prion protein antibody, this report shows that cellular prion protein is present in all cortico-cerebellar and deep nuclei neuronal cell types, as well as in all glial cell types. The heaviest expression appears on parallel fibres and astrocytic processes. The protein is exclusively located on the outer cell membrane and in Golgi and endosomal intracytoplasmic organelles, with no cytoplasmic or synaptic vesicle labelling. Most important, and in contrast with previous ultrastructural data, cellular prion protein is shown to be distributed on all portions of neurons, without any preferential synaptic targeting. The present morphological report shows, for the first time in vivo, that the cellular prion protein is present on the entire cell surface membrane of all neuronal and glial cell types of the rat cerebellum. This ubiquitous presence supports the notion that prion protein has a generalized cellular function in brain tissue rather than a specialized role restricted to synaptic transmission.     

Fear and stigma: the epidemic within the SARS outbreak

Because of their evolving nature and inherent scientific uncertainties, outbreaks of emerging infectious diseases can be associated with considerable fear in the general public or in specific communities, especially when illness and deaths are substantial. Mitigating fear and discrimination directed toward persons infected with, and affected by, infectious disease can be important in controlling transmission. Persons who are feared and stigmatized may delay seeking care and remain in the community undetected. This article outlines efforts to rapidly assess, monitor, and address fears associated with the 2003 severe acute respiratory syndrome (SARS) epidemic in the United States. Although fear, stigmatization, and discrimination were not widespread in the general public, Asian-American communities were particularly affected.