Best evidence in critical care medicine Selective digestive decontamination decreases mortality and morbidity in the intensive care

SDD reduces ICU and in-hospital mortality, the length-of-stay in the ICU, the frequency of colonization with resistant GNB, and the total costs of antibiotic treatment. This supports the use of SDD in all patients expected to be on mechanical ventilation for at least two days in ICUs that have low prevalence of VRE and MRSA.     

Paraimmunoblastic variant of small lymphocytic lymphoma/leukemia

We report 16 cases of a distinctive, biologically aggressive variant of small lymphocytic lymphoma/leukemia (SLL/L) that is characterized by the diffuse proliferation of cells normally comprising the pseudoproliferation centers (so-called paraimmunoblasts). Demographically, the patients differed in no significant regard from patients with SLL/L of usual type. Rapidly progressive, generalized lymphadenopathy was the dominant clinical finding in 15 of the 16 patients; one patient presented with symptoms related to lymphomatous involvement of the stomach and regional lymph nodes. Splenomegaly was observed in five patients. Seven patients, two of whom had a history of indolent-phase chronic lymphocytic leukemia, had an absolute lymphocytosis at diagnosis. In most patients, bone marrow involvement was noted at diagnosis. It consisted predominantly of small lymphocytic infiltrates indistinguishable from those observed in SLL/L of usual type; significant paraimmunoblastic infiltration was infrequent and generally occurred late in the disease course. Immunohistochemical and cytogenetic study further substantiated the hypothesized relationship of these cases to SLL/L. Findings included (a) coexpression of sIg and Leu-1 antigen in the majority of cases and (b) the presence of a t(11;14) (q13;q32) chromosome translocation in two of three cases with analyzable metaphases. Although treatment protocols were not uniform, follow-up data indicated an accelerated clinical course. Eleven patients have died of their disease between 3 and 39 months after diagnosis; the median survival was 28 months.     

Studies on the molecular pharmacology of GR63178A. A novel pentacyclic pyrolloquinone anticancer drug.

GR63178A (NSC D611615) is the second pentacyclic pyrolloquinone to be evaluated clinically as an anticancer drug. Its mechanism of action is unknown but may be related either to its quinone group or planar ring system. In this report we have investigated the ability of GR63178A to bind non-covalently to DNA, inhibit topoisomerase II and undergo reduction to reactive free radical species. Using two DNA duplexes, a 12-mer oligonucleotide which is a preferred sequence for minor groove binders and a hexamer which is a preferred sequence for intercalators, no evidence of significant binding with GR63178A was found. Neither GR63178A nor GR54374X (its 9-hydroxy metabolite) inhibited purified human topoisomerase II in a decatenation assay. Free radical chemistry was studied by both pulse radiolysis and ESR spectroscopy as well as by in vitro drug incubations with NADPH-fortified rat liver microsomes and purified cytochrome P450 reductase. The one-electron reduction potential of GR63178A was -207 mV +/- 10 which is much more positive than other quinone-containing anticancer drugs such as doxorubicin, mitomycin C and mitozantrone. GR63178A underwent enzyme-catalysed quinone reduction more readily than doxorubicin but produced significantly fewer reactive oxygen species. No evidence was detected of drug-induced, radical-mediated DNA damage in vitro using pBR322 plasmid DNA. Disproportionation of the GR63178A semi-quinone free radical proceeded with a rate constant of 1 x 10(9) M-1 sec-1 under anaerobic conditions, one order of magnitude faster than doxorubicin. The preferential disproportionation of the semi-quinone may explain our inability to detect a free radical signal by ESR. The hydroquinone of GR63178A was stable and exhibited strong visible absorption with a bathochromic shift of 120 nm over the parent drug. These unusual properties may be due to the hydroquinone undergoing a form of keto-enol tautomerization. Thus, GR63178A free radical formation does not appear to result in significant drug activation. In conclusion, GR63178A is unlikely to mediate its antitumour activity by DNA binding, topoisomerase II inhibition or free radical formation in direct contrast to similar anthracycline- and anthraquinone-based anticancer drugs.     

The evolution of the dorsal thalamus of jawed vertebrates, including mammals: Cladistic analysis and a new hypothesis

The evolution of the dorsal thalamus in various vertebrate lineages of jawed vertebrates has been an enigma, partly due to two prevalent misconceptions: the belief that the multitude of nuclei in the dorsal thalamus of mammals could be meaningfully compared neither with the relatively few nuclei in the dorsal thalamus of anamniotes nor with the intermediate number of dorsal thalamic nuclei of other amniotes and a definition of the dorsal thalamus that too narrowly focused on the features of the dorsal thalamus of mammals. The cladistic analysis carried out here allows us to recognize which features are plesiomorphic and which apomorphic for the dorsal thalamus of jawed vertebrates and to then reconstruct the major changes that have occurred in the dorsal thalamus over evolution. Embryological data examined in the context of Von Baerian theory (embryos of later-descendant species resemble the embryos of earlier-descendant species to the point of their divergence) supports a new ‘Dual Elaboration Hypothesis’ of dorsal thalamic evolution generated from this cladistic analysis. From the morphotype for an early stage in the embryological development of the dorsal thalamus of jawed vertebrates, the divergent, sequential stages of the development of the dorsal thalamus are derived for each major radiation and compared. The new hypothesis holds that the dorsal thalamus comprises two basic divisions—the collothalamus and the lemnothalamus—that receive their predominant input from the midbrain roof and (plesiomorphically) from lemniscal pathways, including the optic tract, respectively. Where present, the collothalamic, midbrain-sensory relay nuclei are homologous to each other in all vertebrate radiations as discrete nuclei. Within the lemnothalamus, the dorsal lateral geniculate nucleus of mammals and the dorsal lateral optic nucleus of non-synapsid amniotes (diapsid reptiles, birds and turtles) are homologous as discrete nuclei; most or all of the ventral nuclear group of mammals is homologous as a field to the lemniscal somatosensory relay and motor feedback nuclei of non-synapsid amniotes; the anterior, intralaminar and medial nuclear groups of mammals are collectively homologous as a field to both the dorsomedial and dorsolateral (including perirotundal) nuclei of non-synapsid amniotes; the anterior, intralaminar, medial and ventral nuclear groups and the dorsal lateral geniculate nucleus of mammals are collectively homologous as a field to the nucleus anterior of anamniotes, as are their homologues in non-synapsid amniotes. In the captorhinomorph ancestors of extant land vertebrates, both divisions of the dorsal thalamus were elaborated to some extent due to an increase in proliferation and lateral migration of neurons during development. Mammals are unique in the degree to which their synapsid ancestors further elaborated the lemnothalamus, so that the identity of and previous experience with objects in their environment has become their most salient priority.