Bacterial Pneumonias during an Influenza Pandemic: How Will We Allocate Antibiotics?

We are currently in the midst of the 2009 H1N1 pandemic, and a second wave of flu in the fall and winter could lead to more hospitalizations for pneumonia. Recent pathologic and historic data from the 1918 influenza pandemic confirms that many, if not most, of the deaths in that pandemic were a result of secondary bacterial pneumonias. This means that a second wave of 2009 H1N1 pandemic influenza could result in a widespread shortage of antibiotics, making these medications a scarce resource. Recently, our University of Michigan Health System (UMHS) Scarce Resource Allocation Committee (SRAC) added antibiotics to a list of resources (including ventilators, antivirals, vaccines) that might become scarce during an influenza pandemic. In this article, we summarize the data on bacterial pneumonias during the 1918 influenza pandemic, discuss the possible impact of a pandemic on the University of Michigan Health System, and summarize our committee's guiding principles for allocating antibiotics during a pandemic.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78141/1/bsp.2009.0019.pd

FAN1 controls mismatch repair complex assembly via MLH1 retention to stabilize CAG repeat expansion in Huntington's disease.

CAG repeat expansion in the HTT gene drives Huntington's disease (HD) pathogenesis and is modulated by DNA damage repair pathways. In this context, the interaction between FAN1, a DNA-structure-specific nuclease, and MLH1, member of the DNA mismatch repair pathway (MMR), is not defined. Here, we identify a highly conserved SPYF motif at the N terminus of FAN1 that binds to MLH1. Our data support a model where FAN1 has two distinct functions to stabilize CAG repeats. On one hand, it binds MLH1 to restrict its recruitment by MSH3, thus inhibiting the assembly of a functional MMR complex that would otherwise promote CAG repeat expansion. On the other hand, it promotes accurate repair via its nuclease activity. These data highlight a potential avenue for HD therapeutics in attenuating somatic expansion

FAN1 modifies Huntington's disease progression by stabilising the expanded HTT CAG repeat

Huntington’s disease (HD) is an inherited neurodegenerative disease caused by an expanded CAG repeat in the HTT gene. CAG repeat length explains around half of the variation in age-at-onset, but genetic variation elsewhere in the genome accounts for a significant proportion of the remainder. Genome-wide association studies have identified a bidirectional signal on chromosome 15, likely underlain by FAN1 (FANCD2 and FANCI Associated Nuclease 1), a nuclease involved in DNA interstrand cross link repair. Here we show that increased FAN1 expression is significantly associated with delayed age-at-onset and slower progression of HD suggesting FAN1 is protective in the context of an expanded HTT CAG repeat. FAN1 overexpression in human cells reduces CAG repeat expansion in exogenously expressed mutant HTT exon 1, and in patient-derived stem cells and differentiated medium spiny neurons, FAN1 knockdown increases CAG repeat expansion. The stabilising effect is FAN1 concentration and CAG repeat length dependent. We show that FAN1 binds to the expanded HTT CAG repeat DNA and its nuclease activity is not required for protection against CAG repeat expansion. These data shed new mechanistic insights into how the genetic modifiers of HD act to alter disease progression, and show that FAN1 affects somatic expansion of the CAG repeat through a nuclease-independent mechanism. This provides new avenues for therapeutic interventions in HD and potentially other triplet repeat disorders

Evidence that 2 Nonoverlapping High-Affinity Calmodulin-Binding Sites are Present in the Head of Synapsin-1

Calmodulin is an important element in the regulation of nerve terminal exocytosis by Ca2+. Calmodulin has been shown to interact with the synaptic vesicle phosphoproteins synapsins Ia and Ib [Okabe, T. and Sobue, K. (1987) FEBS Lett. 213, 184-188; Hayes, N. V. L., Bennett, A. E and Baines, A. J. (1991) Biochem. J. 275, 93-97]. These proteins are thought to provide regulated linkages between synaptic vesicles and cytoskeletal elements. It is well established that calmodulin modulates synapsin I activities via calmodulin-dependent protein-kinase-LT-catalysed phosphorylation. The direct binding of calmodulin to synapsin I suggests a second mode of regulation in addition to phosphorylation. In this study, we present evidence indicating that two sites for calmodulin binding exist in the N-terminal head region of synapsins Ia and Ib. In unphosphorylated synapsin I, these sites had a K-d value of = 36+/-14 nM for binding to calmodulin labelled with acetyl-N'-(5-sulpho-1-naphthyl)ethylene diamine. The K-d values for synapsin I phosphorylated at various sites were as follows: site I 18+/-11 nM; sites II and III 35+/-14 nM; sites I-III 16+/-9 nM. The fluorescence data indicated a stoichiometry of not less than 2 mol calmodulin bound to 1 mol synapsin I at saturation in each case. Consistent with this stoichiometry, two chemically cross-linked species (96 kDa and 116 kDa) containing calmodulin and synapsin I were generated in vitro, corresponding to one and two calmodulin molecules bound/synapsin I. Defined fragments of synapsin I were generated with the reagent 2-nitro-5-thiocyanobenzoic acid, which cleaves at cysteine residues. Cysteine-specific cleavage of whole synapsin I after cross-linking to biotinylated calmodulin generated a pair of polypeptide complexes (approximately 46 kDa and 38 kDa), the masses of which indicated cross-linking of calmodulin to the N-terminal and middle regions of synapsin I. Purified N-terminal and middle fragments each showed a Ca2+-dependent interaction with calmodulin affinity columns. Two calmodulin-binding fragments (7.4 kDa and 6.5 kDa) were generated using Staphylococcus aureus V8 protease digestion of synapsin I. These fragments were isolated by calmodulin affinity chromatography and reverse-phase HPLC. N-terminal sequence analysis indicated that the fragments originated from two non-overlapping areas of the synapsin I head region, and that each was contained within one of the 2-nitro-5-thiocyanobenzoic-acid-derived calmodulin-binding fragments. The origins of these fragments are close to the putative sites of actin and tubulin interaction. Addition of calmodulin in the presence of Ca2+ to mixtures of F-actin and synapsin I reduced both the binding of synapsin I to F-actin and bundling of F-actin by synapsin I. Direct binding of calmodulin to synapsin I may represent a non-covalent. mode of regulation of synapsin I activity in addition to covalent regulation by phosphorylation

A Multimedia Intervention on Cardiopulmonary Resuscitation and Advance Directives

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74528/1/j.1525-1497.1999.11208.x.pd

Managing the tension between performance measurement and strategy : coping strategies

Purpose - The aim of this paper is to explore an important but relatively uncharted territory: the actual functioning of performance measurement systems (PMS) in their organisational context. The objective of the paper is to document the ways in which managers go about aligning operational measures with their organisation's strategy in practice. Design/methodology/approach - This research adopts an interpretive multiple-case approach in order to gather rich data on the strategies used in managing operational PMS. Data were collected from detailed interviews with managers and supervisors in four government agencies. Findings - The expectations were that the operations managers would adjust their performance measures to support the changes in strategy. This was not the case. All the interviewees employed one or more tactics to cope with the tensions between strategy and performance measures. The ten tactics identified are collected into three strategies; do-nothing strategy, pseudo-realigning strategy, and distracting strategy. Research limitations/implications - This paper casts some doubt on the practice, rather than the principle, of strategy-aligned performance management. More work needs to be carried out to ascertain how other, both for profit and public sector, organisations deal with these tensions in practice. Practical implications - From a practitioner point of view it raises the question as to whether senior managers are exerting sufficient control over the alignment issue or providing suitable tools, methods or indeed incentives to bring alignment about. Originality/value - The paper highlights a gap between theory and practice and suggests that the way to ensure implementation of "modern management methods," might be to deal firstly with the issues of relevance, timeliness, structure, integration, and symmetry