Replication in hydroxyurea: it's a matter of time

Hydroxyurea (HU) is a DNA replication inhibitor that negatively affects both the elongation and initiation phases of replication and triggers the "intra-S phase checkpoint." Previous work with budding yeast has shown that, during a short exposure to HU, MEC1/RAD53 prevent initiation at some late S phase origins. In this study, we have performed microarray experiments to follow the fate of all origins over an extended exposure to HU. We show that the genome-wide progression of DNA synthesis, including origin activation, follows the same pattern in the presence of HU as in its absence, although the time frames are very different. We find no evidence for a specific effect that excludes initiation from late origins. Rather, HU causes S phase to proceed in slow motion; all temporal classes of origins are affected, but the order in which they become active is maintained. We propose a revised model for the checkpoint response to HU that accounts for the continued but slowed pace of the temporal program of origin activation.     

Changes in career plans during medical training and practice: it's time to look ahead and act.

Major changes in physician-resource policies and in the structuring of medical licensure requirements in the past decade have resulted in a less flexible system with respect to both choosing and changing a career path in medicine. The survey results reported by Drs. Susan Shaw, Gordon Goplen and Donald S. Houston in this issue (see pages 1035 to 1038) indicate that a high percentage of physicians now practising in Saskatchewan changed their career plans after graduation. The author argues that this finding points to the need to reexamine the transition from undergraduate to postgraduate medical education. The present system needs to be made more flexible so that medical students can gain sufficient clinical experience before deciding on an area of practice and to give practising physicians who want to change specialties the option of retraining.     

Worms take to the slo lane: a perspective on the mode of action of emodepside

The cyclo-octapdepsipeptide anthelmintic emodepside exerts a profound paralysis on parasitic and free-living nematodes. The neuromuscular junction is a significant determinant of this effect. Pharmacological and electrophysiological analyses in the parasitic nematode Ascaris suum have resolved that emodepside elicits a hyperpolarisation of body wall muscle, which is dependent on extracellular calcium and the efflux of potassium ions. The molecular basis for emodepside's action has been investigated in forward genetic screens in the free-living nematode Caenorhabditis elegans. Two screens for emodepside resistance, totalling 20,000 genomes, identified several mutants of slo-1, which encodes a calcium-activated potassium channel homologous to mammalian BK channels. Slo-1 null mutants are more than 1000-fold less sensitive to emodepside than wild-type C. elegans and tissue-specific expression studies show emodepside acts on SLO-1 in neurons regulating feeding and motility as well as acting on SLO-1 in body wall muscle. These genetic data, combined with physiological measurements in C. elegans and the earlier physiological analyses on A. suum, define a pivotal role for SLO-1 in the mode of action of emodepside. Additional signalling pathways have emerged as determinants of emodepside's mode of action through biochemical and hypothesis-driven approaches. Mutant analyses of these pathways suggest a modulatory role for each of them in emodepside's mode of action; however, they impart much more modest changes in the sensitivity to emodepside than mutations in slo-1. Taken together these studies identify SLO-1 as the major determinant of emodepside's anthelmintic activity. Structural information on the BK channels has advanced significantly in the last 2?years. Therefore, we rationalise this possibility by suggesting a model that speculates on the nature of the emodepside pharmacophore within the calcium-activated potassium channels.     

HIV vaccine: it may take two to tango, but no party time yet

In a recent summary of integrase sequences, primary integrase inhibitor mutations were rare. In a review of integrase inhibitor-naïve Australian HIV-1 sequences, primary mutations were not identified, although the accessory mutation G140S was detected. A link with previous antiretroviral therapy, intra-subtype B divergence across the integrase gene and transmission of integrase polymorphisms were also noted. Based on these findings, we would recommend ongoing surveillance of integrase mutations, and integrase region sequencing for patients prior to commencement of integrase inhibitors.     

Why it's time for a national health program in the United States.

The United States lacks a coherent national health program. Current programs leave major gaps in coverage and recently have become more restrictive. Influential policies that have failed to correct crucial problems of the health-care system include competitive strategies, corporate intervention, and public-sector cutbacks with bureaucratic expansion. A national health program that combines elements of national health insurance and a national health service is a policy that would help solve current health-care problems. Previous proposals for national health insurance contained weaknesses that would need correction under a national program. Based on the experiences of other economically advanced countries, a national health program could provide universal entitlement to health care while controlling costs and improving the health-care system through structural reorganization. Current proposals for a national health program contain several basic principles dealing with the scope of services, copayments, financing, cost controls, physician and professional associations, personnel and distribution, prevention, and participation in policy making. Support for a national health program is growing rapidly. Such a program would help protect all people who live in this country from unnecessary illness, suffering, and early death.