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1.  Total Knee Arthroplasty in the Elderly: Does Age Affect Pain, Function or Complications? 
TKA is one of the most commonly performed procedures in the elderly, yet whether age influences postoperative pain, function, and complication rates is not fully understood for this group. This is because the current literature has limited followup, small sample sizes, and no comparator group.
We therefore asked if increasing age adversely affects postoperative pain, Knee Society Scores©, and complication rates.
We retrospectively reviewed all 438 patients 80 years or older who underwent primary TKA between 1995 and 2005. We established a comparator group of 2754 patients younger than 80 years. We assessed pain, the Knee Society Score© (KSS), and the Knee Society Function Score© (KSFS). The number and type of complications were recorded and those graded 2 or more using the classification of Dindo et al. were analyzed. Minimum followup was 5 years (mean, 6 years; range, 5–15.5 years).
We found no difference in pain scores at 3, 5, and 10 years between the two groups. The KSS was comparable between groups at Year 5, but the KSFS was lower in the octogenarians. Major complications rates were higher in the octogenarian group (19% versus 15%).
When compared with younger patients, octogenarians can expect comparable pain relief and KSS but lower function and more complications.
Level of Evidence
Level III, therapeutic study. See Instructions for Authors for a complete description of levels of evidence.
PMCID: PMC3706666  PMID: 23354464
2.  Lipid Phase Separation and Protein-Ganglioside Clustering in Supported Bilayers Are Induced by Photorelease of Ceramide† 
Soft matter  2013;9(19):4890-4899.
Photolysis of 6-bromo-7-hydroxycoumarinyl-caged ceramide was used to generate ceramide with spatial and temporal control in supported lipid bilayers prepared from mixtures of caged ceramide and phospholipids. The caged ceramide molecules are randomly distributed in fluid 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayers, and upon photolysis with long wavelength UV light small ordered ceramide domains are formed that phase separate from the bulk fluid membrane. Irradiation of a spatially restricted area leads to the transient formation of ceramide-enriched gel phase domains that equilibrate via lipid diffusion with the surrounding unirradiated membrane. Photorelease of C16-ceramide in supported bilayers prepared from POPC, caged ceramide and the ganglioside GM1 (90:10:1 molar ratio) results in partitioning of a ganglioside-protein complex into the ceramide-enriched domains, modeling some aspects of ceramide’s behavior in cells. The photo-uncaging strategy used here for delivery of ceramide in bilayers provides a novel and useful alternative to the enzymatic generation of ceramide in sphingomyelin-containing membranes. The ability to control membrane phase separation behavior and the clustering of membrane-anchored proteins illustrates the potential of photo-uncaging for studying the compartmentalization of ceramide in cellular membranes.
PMCID: PMC3649770  PMID: 23667384
3.  Photo-uncaging of Ceramides Promotes Reorganization of Liquid-Ordered Domains in Supported Lipid Bilayers 
6-Bromo-7-hydroxycoumarin (Bhc)-caged ceramide (Cer) analogs were incorporated into supported lipid bilayers containing a mixture of coexisting liquid-ordered (Lo) and liquid-disordered (Ld) phases. The release of N-palmitoyl and N-butanoyl-D-erythro-sphingosine (C16- and C4-Cer) by photolysis of the caged Cers using long wavelength UV light was studied using a combination of atomic force microscopy and fluorescence microscopy. This approach demonstrated the ability to generate Cer with spatial and temporal control, providing an alternative method to the enzymatic generation of Cer. The generation of C16-Cer from Bhc-C16-Cer disrupted the Lo domains, with the incorporation of small fluid phase regions and the disappearance of some smaller domains. Cer-rich gel-phase domains were not observed, in contrast to results reported by either direct Cer incorporation or enzymatic Cer generation. Photorelease of C4-Cer from Bhc-C4-Cer resulted in qualitatively similar changes in bilayer morphology, with disappearance of some Lo domains and no evidence for Cer-rich gel domains, but with a smaller height difference between the ordered and disordered phases.
PMCID: PMC3607952  PMID: 23402522
4.  Force Spectroscopy Measurements Show That Cortical Neurons Exposed to Excitotoxic Agonists Stiffen before Showing Evidence of Bleb Damage 
PLoS ONE  2013;8(8):e73499.
In ischemic and traumatic brain injury, hyperactivated glutamate (N-methyl-D-aspartic acid, NMDA) and sodium (Nav) channels trigger excitotoxic neuron death. Na+, Ca++ and H2O influx into affected neurons elicits swelling (increased cell volume) and pathological blebbing (disassociation of the plasma membrane’s bilayer from its spectrin-actomyosin matrix). Though usually conflated in injured tissue, cell swelling and blebbing are distinct processes. Around an injury core, salvageable neurons could be mildly swollen without yet having suffered the bleb-type membrane damage that, by rendering channels leaky and pumps dysfunctional, exacerbates the excitotoxic positive feedback spiral. Recognizing when neuronal inflation signifies non-lethal osmotic swelling versus blebbing should further efforts to salvage injury-penumbra neurons. To assess whether the mechanical properties of osmotically-swollen versus excitotoxically-blebbing neurons might be cytomechanically distinguishable, we measured cortical neuron elasticity (gauged via atomic force microscopy (AFM)-based force spectroscopy) upon brief exposure to hypotonicity or to excitotoxic agonists (glutamate and Nav channel activators, NMDA and veratridine). Though unperturbed by solution exchange per se, elasticity increased abruptly with hypotonicity, with NMDA and with veratridine. Neurons then invariably softened towards or below the pre-treatment level, sometimes starting before the washout. The initial channel-mediated stiffening bespeaks an abrupt elevation of hydrostatic pressure linked to NMDA or Nav channel-mediated ion/H2O fluxes, together with increased [Ca++]int-mediated submembrane actomyosin contractility. The subsequent softening to below-control levels is consistent with the onset of a lethal level of bleb damage. These findings indicate that dissection/identification of molecular events during the excitotoxic transition from stiff/swollen to soft/blebbing is warranted and should be feasible.
PMCID: PMC3758302  PMID: 24023686
5.  Cholesterol Tuning of BK Ethanol Response Is Enantioselective, and Is a Function of Accompanying Lipids 
PLoS ONE  2011;6(11):e27572.
In the search to uncover ethanol's molecular mechanisms, the calcium and voltage activated, large conductance potassium channel (BK) has emerged as an important molecule. We examine how cholesterol content in bilayers of 1,2-dioleoyl-3-phosphatidylethanolamine (DOPE)/sphingomyelin (SPM) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylethanolamine (POPE)/1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylserine (POPS) affect the function and ethanol sensitivity of BK. In addition, we examine how manipulation of cholesterol in biological membranes modulates ethanol's actions on BK. We report that cholesterol levels regulate the change in BK channel open probability elicited by 50 mM ethanol. Low levels of cholesterol (<20%, molar ratio) supports ethanol activation, while high levels of cholesterol leads to ethanol inhibition of BK. To determine if cholesterol affects BK and its sensitivity to ethanol through a direct cholesterol-protein interaction or via an indirect action on the lipid bilayer, we used the synthetic enantiomer of cholesterol (ent-CHS). We found that 20% and 40% ent-CHS had little effect on the ethanol sensitivity of BK, when compared with the same concentration of nat-CHS. We accessed the effects of ent-CHS and nat-CHS on the molecular organization of DOPE/SPM monolayers at the air/water interface. The isotherm data showed that ent-CHS condensed DOPE/SPM monolayer equivalently to nat-CHS at a 20% concentration, but slightly less at a 40% concentration. Atomic force microscopy (AFM) images of DOPE/SPM membranes in the presence of ent-CHS or nat-CHS prepared with LB technique or vesicle deposition showed no significant difference in topographies, supporting the interpretation that the differences in actions of nat-CHS and ent-CHS on BK channel are not likely from a generalized action on bilayers. We conclude that membrane cholesterol influences ethanol's modulation of BK in a complex manner, including an interaction with the channel protein. Finally, our results suggest that an understanding of membrane protein function and modulation is impossible unless protein and surrounding lipid are considered as a functional unit.
PMCID: PMC3226590  PMID: 22140451
6.  AFM Investigations of Phase Separation in Supported Membranes of Binary Mixtures of POPC and an Eicosanyl-based Bisphosphocholine Bolalipid 
Supported membranes prepared from binary mixtures of DOPC and the bolalipid C20BAS have been examined by atomic force microscopy (AFM). The supported membranes are phase separated to give a thicker DOPC-rich phase and a thinner bolalipid-rich phase for a range of lipid compositions. These results confirm an earlier prediction from mean field theory that phase separation is the thermodynamically stable state for membranes containing approximately equimolar C20BAS and double chain monopolar lipids with chain lengths exceeding fifteen carbons. Hydrophobic mismatch between the monopolar lipid hydrocarbon chains and the membrane spanning bolalipid chains was suggested to provide the driving force for phase separation. The AFM results also show that the morphology of the mixed POPC:C20BAS supported membranes varies significantly with the conditions used to prepare the vesicles and supported membrane samples. The complex membrane morphologies observed are attributed to the interplay of several factors, including a compositionally heterogeneous vesicle population, exchange of lipid between the vesicle solution and solid substrate during formation of the supported membrane, and slow equilibration of domains due to pinning of the lipids to the solid support.
PMCID: PMC2876224  PMID: 20099816
8.  Nurses' perceived barriers to the implementation of a Fall Prevention Clinical Practice Guideline in Singapore hospitals 
Theories of behavior change indicate that an analysis of barriers to change is helpful when trying to influence professional practice. The aim of this study was to assess the perceived barriers to practice change by eliciting nurses' opinions with regard to barriers to, and facilitators of, implementation of a Fall Prevention clinical practice guideline in five acute care hospitals in Singapore.
Nurses were surveyed to identify their perceptions regarding barriers to implementation of clinical practice guidelines in their practice setting. The validated questionnaire, 'Barriers and facilitators assessment instrument', was administered to nurses (n = 1830) working in the medical, surgical, geriatric units, at five acute care hospitals in Singapore.
An 80.2% response rate was achieved. The greatest barriers to implementation of clinical practice guidelines reported included: knowledge and motivation, availability of support staff, access to facilities, health status of patients, and, education of staff and patients.
Numerous barriers to the use of the Fall Prevention Clinical Practice Guideline have been identified. This study has laid the foundation for further research into implementation of clinical practice guidelines in Singapore by identifying barriers to change in acute care settings.
PMCID: PMC2422837  PMID: 18485235

Results 1-8 (8)