Operational models of infrastructure resilience.

We propose a definition of infrastructure resilience that is tied to the operation (or function) of an infrastructure as a system of interacting components and that can be objectively evaluated using quantitative models. Specifically, for any particular system, we use quantitative models of system operation to represent the decisions of an infrastructure operator who guides the behavior of the system as a whole, even in the presence of disruptions. Modeling infrastructure operation in this way makes it possible to systematically evaluate the consequences associated with the loss of infrastructure components, and leads to a precise notion of "operational resilience" that facilitates model verification, validation, and reproducible results. Using a simple example of a notional infrastructure, we demonstrate how to use these models for (1) assessing the operational resilience of an infrastructure system, (2) identifying critical vulnerabilities that threaten its continued function, and (3) advising policymakers on investments to improve resilience.

Localization of changes in beta-actin expression in remodeled canine myocardium.

Beta-actin is a cytoskeletal protein that has been implicated as a potentially important mediator of the growth, signaling, migration, and remodeling of cells. Beta-actin is upregulated in remodeling myocardium in response to either pressure or volume overload. The cellular localization of this response has, however, not been determined and is a necessary first step to begin to clarify the role of beta-actin in myocardial remodeling. Here we demonstrate that beta -actin protein was confined primarily to the cardiac interstitium using immunofluorescent and immunohistochemical staining. Furthermore, both staining and immunoblotting showed markedly increased beta-actin protein in myocardium within 24 h of either regional left ventricular damage or chronic volume overload. More importantly, this increase persisted up to 90 days in both models. Double staining showed co-localization of beta-actin protein and von Willebrand factor, a specific endothelial cell marker. These results suggest that increased beta-actin expression predominantly localized in cardiac interstitial cells, including endothelial cells. The increased beta-actin could be due to either proliferation of the interstitial cells or upregulation of the beta-actin gene.

The efficacy and economic benefits of Paracox, a live attenuated anticoccidial vaccine, in commercial trials with standard broiler chickens in the United Kingdom.

The first large-scale broiler trials under modern commercial conditions of Paracox, a live attenuated anticoccidial vaccine administered in the drinking-water, are reported from the United Kingdom. The vaccine, comprising all seven of the species of Eimeria that parasitise the domesticated fowl, was compared with anticoccidial drug shuttles (halofuginone then salinomycin, or nicarbazin then monensin) in nine trials comprising over 936000 chickens, all of which also received the digestive enhancer virginiamycin. No clinical diseases were diagnosed in vaccinated birds in any of the trials. Necrotic enteritis occurred in the medicated controls (anticoccidial drug shuttles) of 2/9 trials and coccidiosis occurred concurrently with one of these outbreaks. Using additional criteria that particularly reflected economic benefits, the vaccine performed overall at least as well as the drug shuttles. The crucial results for vaccinated and medicated birds were: feeding costs (pence per kg liveweight of birds that were processed), 33.9 pence (vaccinated) and 33.7 pence (medicated) (P=0.549); feed conversion ratios, 2.01 (vaccinated) and 1.96 (medicated) (P=0.025); coefficient of variation in mean bird weight before processing, 9.3% (vaccinated) and 9.0% (medicated) (P=0.300); birds found dead, 3.0% (vaccinated) and 3.8% (medicated) (P<0.001); culled birds 4.0% (vaccinated) and 3.8% (medicated) (P=0.483); birds rejected during processing, 1.1% (vaccinated) and 1.2% (medicated) (P=0.271). In addition, the mean total water consumptions per chick were 7.82 L (vaccinated) and 7.76 L (medicated) (P=0.611), whilst the mean percentages of dry matter in the litter were 76.2% (vaccinated) and 75.2% (medicated) (P=0.195). Accumulation of oocysts in the litter of chicks vaccinated at 5 days of age peaked at 21 and 35 days, compared with medicated controls which showed a single higher peak at 35 days. Hence, the use of Paracox vaccine may control clinical coccidiosis in broilers and also achieve performances at least equal to anticoccidial drugs, particularly where drug resistance might result in failure to control disease.

Myocardial creatine kinase kinetics in hearts with postinfarction left ventricular remodeling.

This study examined whether alterations in myocardial creatine kinase (CK) kinetics and high-energy phosphate (HEP) levels occur in postinfarction left ventricular remodeling (LVR). Myocardial HEP and CK kinetics were examined in 19 pigs 6 wk after myocardial infarction was produced by left circumflex coronary artery ligation, and the results were compared with those from 9 normal pigs. Blood flow (microspheres), oxygen consumption (MVO2), HEP levels [31P magnetic resonance spectroscopy (MRS)], and CK kinetics (31P MRS) were measured in myocardium remote from the infarct under basal conditions and during dobutamine infusion (20 micrograms. kg-1. min-1 iv). Six of the pigs with LVR had overt congestive heart failure (CHF) at the time of study. Under basal conditions, creatine phosphate (CrP)-to-ATP ratios were lower in all transmural layers of hearts with CHF and in the subendocardium of LVR hearts than in normal hearts (P < 0.05). Myocardial ATP (biopsy) was significantly decreased in hearts with CHF. The CK forward rate constant was lower (P < 0.05) in the CHF group (0.21 +/- 0.03 s-1) than in LVR (0.38 +/- 0.04 s-1) or normal groups (0.41 +/- 0.03 s-1); CK forward flux rates in CHF, LVR, and normal groups were 6.4 +/- 2.3, 14.3 +/- 2.1, and 20.3 +/- 2.4 micromol. g-1. s-1, respectively (P < 0.05, CHF vs. LVR and LVR vs. normal). Dobutamine caused doubling of the rate-pressure product in the LVR and normal groups, whereas CHF hearts failed to respond to dobutamine. CK flux rates did not change during dobutamine in any group. The ratios of CK flux to ATP synthesis (from MVO2) under baseline conditions were 10.9 +/- 1.2, 8. 03 +/- 0.9, and 3.86 +/- 0.5 for normal, LVR, and CHF hearts, respectively (each P < 0.05); during dobutamine, this ratio decreased to 3.73 +/- 0.5, 2.58 +/- 0.4, and 2.78 +/- 0.5, respectively (P = not significant among groups). These data demonstrate that CK flux rates are decreased in hearts with postinfarction LVR, but this change does not limit the response to dobutamine. In hearts with end-stage CHF, the changes in HEP and CK flux are more marked. These changes could contribute to the decreased responsiveness of these hearts to dobutamine.

Delayed reperfusion alters matrix metalloproteinase activity and fibronectin mRNA expression in the infarct zone of the ligated rat heart.

Delayed reperfusion has a beneficial effect on prognosis, independent of infarct size. One potential mechanism to explain this observation may be an effect on infarct healing. In this study, the impact of delayed reperfusion on two aspects of the healing process was examined, the activity of matrix metalloproteinase (MMP) enzymes and the expression of fibronectin (FN) mRNA. The rat model of coronary artery ligation was used and rats were randomly assigned to delayed reperfusion (150 min following coronary ligation) or permanent ligation. Animals were subsequently killed 1, 2, 3 and 7 days following infarction. Infarct tissue was harvested for MMP activity (zymography), FN mRNA (RNase protection analysis) and protein (immunofluorescence microscopy and Western analysis), and collagen content (hydroxyproline concentration). Infarction produced marked activation of MMP-1, -2, and -9. Reperfusion significantly attenuated the activity of these enzymes (approximately 50% reduction in MMP-1, P=0.03 and ;60% reduction in MMP-2 at 7 days, P=0.001; approximately 55% reduction in MMP-9 at 24 h and 84% reduction at 48 h, P=0.01 and 0.002, respectively). Delayed reperfusion also produced a trend toward a greater increase in FN mRNA 24 h following infarction and immunofluorescent staining suggested the presence of more FN protein at this point. These data demonstrate that delayed reperfusion alters matrix metalloproteinase activity and fibronectin mRNA expression in the infarct zone. The impact of these changes on infarct healing and their association with the improved prognosis of a patent infarct vessel following infarction will require further study.

Gastric ulcers in finishing pigs: their prevalence and failure to influence growth rate.

In an abattoir survey the stomachs of 1242 pigs from 15 farms were examined. Ulceration of the pars oesophagea was present in 22.95 per cent with a range from 4.7 to 57.4 per cent. The ulcers were graded mild in 9.5 per cent and severe in 13.4 per cent of the stomachs. Bile staining and hyperkeratinisation of the pars were significantly more common in stomachs with ulcers than in those without (P < 0.001), although the difference between the hyperkeratinisation in cases with severe ulcers and cases without ulcers was not significant. The daily liveweight gains of 208 males and 150 females from two units with a high prevalence of ulcers were calculated from their weaning weights at about five weeks of age and their slaughter weights at around 90 kg. At the abattoir their stomachs were examined for the presence of ulcers of the pars. The daily liveweight gain of the males was significantly greater than that of the females (P < 0.001), but the presence of mild or severe ulcers had no influence on the rate of gain of the pigs from either unit. The prevalence of ulcers in the males and females was 57.2 and 49.3 per cent, respectively, but the difference was not significant.

The effect of delayed reperfusion following infarction in the rat on structural changes in viable myocardium.

OBJECTIVE: Evidence indicates that patency of the infarct related artery following the completion of myocardial necrosis can attenuate ventricular remodeling. Data have also demonstrated that inhibition of infarct expansion contributes to the anti-remodeling effect of delayed reperfusion. However, the influence of a patent artery on components of the remodeling process in the viable myocardium is poorly understood. METHODS: Myocyte morphometrics (isolated cell technique) and collagen content (hydroxyproline analysis) were assessed 28 days following experimental myocardial infarction from rats with permanently ligated left coronary vessels (NRP; n = 10) compared with rats who underwent reperfusion 150 minutes after ligation (RP; n = 11) and a sham-operated group (n = 10). RESULTS: Analysis of infarct size (planimetry) in a separate group of rats demonstrated that reperfusion at this late time point did not reduce infarct size (NRP: 33 +/- 3 vs. RP: 35 +/- 5%). Myocyte length in RP rats was less than in NRP rats in viable, non-infarcted left ventricular tissue (155 +/- 3 vs. 167 +/- 4 microns, p = 0.02), in the right ventricle (154 +/- 4 vs. 167 +/- 3 microns, p = 0.02) and in the septum (158 +/- 4 vs. 169 +/- 4 microns, p = 0.05). Reperfusion also attenuated the expected increase in cell volume compared with NRP rats (left ventricle 39.4 +/- 1.7 x 10(3) vs. 44.1 +/- 1.6 x 10(3) micron 3, p = 0.06; right ventricle 36.7 +/- 1.6 x 10(3) vs. 42.7 +/- 2.0 x 10(3) micron 3, p = 0.02; septum 41.0 +/- 1.6 x 10(3) vs. 44.2 +/- 1.8 x 10(3) micron 3, p = 0.19). Hydroxyproline content increased in the viable left ventricular tissue in both the reperfused and non-reperfused groups. CONCLUSION: Reperfusion without myocardial salvage attenuates the increase in myocyte length and volume that occurs in remodeling myocardium following infarction in the rat, with no effect on the increase in collagen content. These data indicate that patency of the infarct vessel, which is known to have an inhibitory effect on infarct expansion, also has an anti-remodeling effect remote from the area perfused by this artery.

Effect of delayed intervention with ACE-inhibitor therapy on myocyte hypertrophy and growth of the cardiac interstitium in the rat model of myocardial infarction.

The effectiveness of angiotensin-converting enzyme (ACE)-inhibitor therapy in attenuating ventricular remodeling when initiated immediately following myocardial damage is clearly established. Less information, however, is available on the impact of late therapy on the remodeling process, especially its influence on the cellular components of these structural changes. The purpose of this study was to examine the effects of converting enzyme inhibitor therapy commenced 28 days following infarction in the rat on changes in cardiac myocyte dimension and the interstitium. At 28 days following infarction, myocyte cell length (153.9+/-7.3 v 131.1+/-5.9 micron, P=0.0002) and cell volume in the free wall of the left ventricle (38. 5+/-5.0 x 10(3) v31.4+/-3.1 x 10(3), P=0.009) had increased compared with sham-operated rats. Similar changes were noted in the septum and right ventricle. Captopril therapy administered between 28 and 56 days attenuated a further increase in cell length noted in an untreated group in the left ventricle (153.5+/-15.3 v 167.3+/-13.7 micron, P=0.02), right ventricle (153.8+/-20.5 v 173.8+/-2.3 micron, P=0.01) and septum (158.0+/-20.2 v 179.1+/-16.6 micron, P=0.004). There was an increase in hydroxyproline content in the right ventricle and a similar trend in the left ventricle in the untreated myocardial infarction groups. These changes were not altered by captopril therapy. In summary, even late therapy with captopril attenuates progressive myocyte remodeling, which may contribute to the ability of ACE-inhibitor therapy to slow progressive chamber enlargement following infarction.

Changes in beta-actin mRNA expression in remodeling canine myocardium.

Beta-actin, a cytoskeletal protein important in the maintenance of cytoarchitecture, has long been thought to be expressed constitutively in myocardial tissue. As such, beta-actin mRNA has been used as a control gene in a wide range of experiments. However, we have uncovered consistent changes in beta-actin mRNA expression in canine myocardium remodeling as a result of insult to the left ventricle. The experimental canine models used were either DC shock damage to the left ventricle or volume overload resulting from severe mitral regurgitation. The remodeling process in both canine models is characterized by an increase in left ventricular mass. PCR amplification using primers designed to selectively amplify the 3' end and a portion of the 3' untranslated region of beta-actin mRNA resulted in the generation of a 297 base pair product predominant only in normal canine myocardium and a 472 base pair product that became increasingly prominent from 1 to 30 days after DC shock damage to the left ventricle and from 10 to 90 days after creation of mitral regurgitation. Northern analysis showed a three-fold increase in beta-actin mRNA after either DC shock or creation of mitral regurgitation. Western analysis revealed an early increase in beta-actin protein followed by an apparent decrease to below baseline levels. These observations suggest that changes in beta-actin mRNA expression accompany the structural alterations that occur in response to myocardial damage. Whether or not the changes in beta-actin mRNA expression play a role in mediating these structural alterations remains to be determined.

Hypothetical pathways of cardiac myocyte hypertrophy: response to myocardial injury.

The heart is made up of many different cell types, including myocytes, fibroblasts and vascular cells. The cardiac myocyte, although not likely to divide, may respond to gross organ injury by a process of growth or hypertrophy. Cellular hypertrophy, though a normal biological adaptation, has the potential to contribute to the change in the shape and the size of the heart, such as occurs in chronic heart failure. We are now just beginning to understand the signals and early pathways involved in the cardiac myocyte growth response, some of which are reviewed herein.

Aggression in the demented patient: a double-blind study of loxapine versus haloperidol.

Aggression is common in dementia, with devastating social consequences. While high or low potency neuroleptics are the usual treatment of choice, they have been shown to yield inconsistent behavioral improvement and significant iatrogenic disability. This double-blind study was undertaken with aggressive demented patients to assess the efficacy and safety of a mid-potency neuroleptic, loxapine, in comparison to the more commonly prescribed high potency drug, haloperidol. Using an optimizing dosage regime, the outcome variables studied were aggression frequency and the number and nature of emergent side effects. Results demonstrated no significant difference regarding efficacy, but significantly fewer side effects with loxapine administration. The clinical and theoretical implications of these findings are discussed.

Agitation in the demented elderly: a role for benzodiazepines?

"Agitation" is a term that is used to describe a wide range of dysfunctional behaviours in geriatric populations. The term is so widely used that in many cases it loses clinical meaning and therefore a more restricted use of the term is suggested. When patients with agitation are identified it is important to look for underlying treatable pathology which is often present. Controversy surrounding the most appropriate medications is reviewed with particular reference to both neuroleptics and benzodiazepines. A randomized double-blind comparison of lorazepam and alprazolam in demented patients with agitation was carried out. While both drugs were efficacious for some patients, there were significantly more serious side-effects with lorazepam. It appears that there is a role for benzodiazepines such as alprazolam in the management of the agitated demented patient.

Control of selenium and cobalt deficiency in lambs by supplementation of oral anthelmintics.

The benefits of the inclusion of cobalt and selenium supplements in anthelmintic preparations were demonstrated in a 10 week trial with cobalt- and selenium-deficient blackface wethers. The anthelmintics were based on oxfendazole and on levamisole plus oxyclozanide; three doses provided, in total, 38 mg cobalt and 7.2 or 11.3 mg selenium. Administration of the supplements prevented the weight loss and reduction in food intake observed in unsupplemented animals. Blood glutathione peroxidase activities were restored to normal and increases in serum vitamin B12 levels were observed which were consistent with the prevention of both cobalt and selenium deficiencies.