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The criminological literature suggests that neighbourhood walkability might produce unintended consequences, namely that walkability is associated with higher crime rates because it affords potential offenders an abundance of weakly guarded targets. To address this proposition, we investigate linear and nonlinear effects of walkability using a sample of block groups located across nine US cities. Results from our negative binomial regression models show that an index of walkability is associated with higher crime rates and that these effects are robust across cities. We also estimate crime models that test the main effects of the four indicators which comprise the walkability index, because of the recognition that certain dimensions of walkability might have a greater impact on crime.

This study examines the relationships between racial heterogeneity and crime across blocks ( N = 103,168) located in the greater Southern California region. We estimate negative binomial regression models that test for the effects of racial heterogeneity in conjunction with different functional form and spatial scaling considerations. Racial diversity in the block has a crime-reducing effect, whereas racial diversity in the area surrounding the block generally has crime-producing capabilities, although at very high levels of diversity, the effect reverses and becomes crime-reducing. We also illustrate an interaction effect between racial heterogeneity in the block and racial heterogeneity in the surrounding area. The pattern of results provides a nuanced understanding of how the racial composition of an area has consequences for crime.

The current study examines seasonality by modelling crime in small spatial units while accounting for numerous land uses (e.g. hotel, store, school and industrial) and sociodemographic characteristics. We estimate logistic regression models that predict the probability of a crime occurring in our sample of blocks in Orlando, FL over the 52 weeks of the year (i.e. block-weeks). In addition, we examined interaction terms between each land use measure and a set of measures for weeks of the year to assess seasonal effects on neighbourhood crime. Our findings reveal a (nonlinear) seasonal effect in which the risk of neighborhood crime peaks during the summer weeks and the effect of certain land uses systematically varies across weeks of the year.

Few studies have investigated how features of the land surface and the street network affect spatial crime patterns. Accordingly, for the current study, we estimated negative binomial regression mo...

Criminological research shows that vacant and dilapidated buildings contribute to higher neighbourhood crime rates. Therefore, the implication is that by physically removing these buildings from a neighbourhood, there will subsequently be a reduction in crime within that neighbourhood. In this study, we focus on the potential crime-reducing benefits of building demolitions—a change in the physical landscape, which may initiate or sustain neighbourhood revitalization. Accordingly, we examine the influence of building demolitions on crime within Philadelphia block groups from 2008 to 2018, controlling for a range of social-ecological factors known to be associated with crime rates. We also differentiate between city and private demolitions to examine the possibility that not all demolitions are created equal in relation to crime.

The current study examines the associations between demolition and crime in Los Angeles blocks. Also, the current study examines how different types of demolitions (residential and commercial) can ...

Communities and crime research presumes that purely nonresidential land uses are associated with more crime, whereas purely residential land use is associated with less crime. However, few studies ...

Although theories suggest that schools are associated with higher neighbourhood crime rates, it is not clear what particular measures of schools have a crime-producing impact when controlling for a diversity of social-ecological factors. We therefore address this question by performing a block-level analysis of schools and crime in the city of Chicago. Negative binomial regression models reveal that the presence of any school in the focal block is associated with higher violent and property crime rates and that these associations are largely robust to differing measures of schools. We also determine that concentrated disadvantage moderates the effect of school presence in the block on property crime. The implications of these findings for criminology and public policy are discussed.

Although prior studies have examined the association between the presence of various types of business facilities and crime in place, less attention has been paid to how the effects of businesses can be temporally different based on their age. We focus on four consumer-facing business types: 1) retail, 2) service, 3) restaurant, and 4) food and drug stores. For each type, we construct block level measures of the number of businesses, the average business age, and the standard deviation of business age. We estimate fixed-effects negative binomial regression models to test the effects of these measures on crime in blocks, controlling for a range of factors known to be associated with crime rates. The average age of businesses was robustly associated with lower crime rates and such pattern was most pronounced in blocks with a greater business presence.

Although criminology presumes that the physical structural qualities of neighbourhoods have important consequences for crime, there is a dearth of research to test the effects of different land uses on crime rates. Using data on a sample of Philadelphia census blocks, I compute the percentage of the block area classified into seven land use categories, and I use Poisson models to test the localized and broader spatial impact of each of these land uses on crime, controlling for key sociodemographic characteristics. The results show that to effectively understand the interplay between physical structure and crime rates, researchers should disaggregate nonresidential land uses, account for the surrounding environment in which neighbourhoods are situated and analyse a specific form of moderation.

The concentration of certain land uses has been linked to crime rates; yet, it remains to be seen whether mixed land use, defined as heterogeneity among several land uses, independently affects neighborhood crime. The goal of the current study, therefore, is to build upon the extant literature by examining how mixed land use influences crime, net of specific land uses and sociodemographic characteristics. Using data on Los Angeles block groups, a Herfindahl index was constructed of eight specific land uses to capture mixed land use, and a series of negative binomial regression models were estimated to assess the main and moderating effects of mixed land use on neighborhood crime. Although mixed land use was found to exert a deleterious influence on two crime types, concentrated disadvantage moderated the effect of mixed land use on all crime types. The implications of these findings for criminology, urban studies, and policy are discussed.

Implant dentistry has emerged as a first line of treatment to replace missing teeth for both the edentulous and partially dentate patients. Implant dentistry is accompanied by the onset of peri-implantitis (PIM). PIM is characterized by the inflammatory destruction of the implant-supporting tissues, because of biofilm formation on the implant surface. A history of periodontitis, poor oral hygiene, and smoking are considered as risk factors for PIM. Occasionally PIM is associated with iatrogenic factors, that, only recently, have been acknowledged as direct cause of PIM, i.e.: non-parallel adjacent implants or the presence of a gap, between fixture and prosthetic components. The use both of traditional protocols of nonsurgical periodontal therapy and the laser seems to be an effective alternative treatment modality for PMI. By the application of laser-assisted non-surgical peri-implant therapy the periodontal pocket depth was reduced. The present article illustrates the nonsurgical management of one case, where failure to remove residual cement, from an implant-supported dental prosthesis, seemed to cause PMI.

Studies of neighborhood crime are often limited in their ability to account for the dynamic nature of human mobility, a central tenet of prominent theoretical perspectives on the spatial distribution of crime. Yet, recent work indicates the utility of social media data for estimating the size and composition of such ambient population. In the present study, we assess whether four Twitter-derived measures are associated with crime counts across 2,348 block groups. Specifically, we focus on the density of Twitter users (and tweets), as well as the proportion of Twitter users (and tweets) that are “insiders.” We inferred Twitter users’ “insider” location from the block group in which they tweeted most frequently.

We compare the relative importance of four dimensions for explaining the micro location of robberies: 1) the micro spatial scale of street segments; 2) the meso spatial scale surrounding the street segment; 3) the temporal pattern, and 4) the macro-scale of the surrounding 2.5 miles. This study uses crime, business, and land use data from New York City and aggregates it to street segments and hours of the day. Although the measures capturing the micro-scale of the street segment explained the largest amount of unique variance, the measures capturing temporal scale across hours of the day (and weekdays) explained the next largest amount of unique variance. The measures of the characteristics in the 2.5 miles macro scale explained the next largest amount of unique variance, and combined with the measures at the meso-scale explained nearly as much of the variance as the street segment measures.

This study examines the independent effects that the number of voluntary organizations and the total amount of income they possess have on neighborhood crime, over time. Drawing upon a sample of Los Angeles census blocks from 2000 to 2010, I utilize fixed-effects negative binomial regression to estimate crime models. The number of voluntary organizations and the total amount of income they possess in the focal block, respectively, are not related to most crime types the following year. Yet, both aspects of voluntary organizations exhibit crime-reducing influences when accounting for their broader spatial impact, and controlling for numerous factors that have been shown to be associated with crime rates. The implications for communities and crime research are discussed.

Although scholars have theorized that nonprofit organizations (NPO) contribute to social control in communities, the relationship between NPO and rates of misconduct on the part of certain at-risk groups has received little empirical attention. The current study extends the literature by adopting a place-based approach to understanding differences in probationer misconduct that highlights the role of NPO in communities. Using longitudinal data from New York State counties, we analyze the linear and nonlinear influences that different NPO have on rearrest rates of probationers. Whereas most criminological theories suggest that NPO have a linear and salutary influence, we find evidence of a more nuanced process: NPO unexpectedly show evidence of exerting both salutary and deleterious influences on probationer outcomes.

Although theories posit that some types of local institutions will have a crime-producing influence in neighborhoods while others will have the opposite effect, the empirical evidence is far from conclusive. Previous studies are typically limited to analyzing cross-sectional data and one type of institution. Using longitudinal data of the number of employees of various institutions within census tracts across nine U.S. cities, the present study examines the longitudinal impact of four types of institutions on violent and property crime. Negative binomial regression models suggest that alcohol outlets and banking establishments increase criminal opportunities, whereas “third places” like coffee shops and cafes induce efficacious neighborhood control and social action. Civic and social organizations have no statistical relationship with crime.

Although numerous theories suggest that voluntary organizations contribute to lower crime rates in neighborhoods, the evidence for this proposition is weak. Consequently, we propose a dynamic perspective for understanding the relationship between voluntary organizations and neighborhood crime that involves longitudinal analyses and the measurement of the age of organizations. By using longitudinal data on a sample of census blocks (N = 87,641) located across 10 cities, we test the relationship between age-graded measures of different types of voluntary organizations and neighborhood crime rates. We use fixed-effects negative binomial regression models that focus on change within neighborhoods of the relationship between voluntary organizations and neighborhood crime. Our results show that although each type of voluntary organization is found to exhibit crime-reducing behavior in neighborhoods, we find that many of them are consistent with what we refer to as the “delayed impact scenario”—there is a pronounced delay between the placement of a voluntary organization and a neighborhood subsequently experiencing a reduction in crime. With protective effects of organizations typically not demonstrated until several years after being in the neighborhood, these patterns suggest a need for long-term investment strategies when examining organizations. Criminological theory and communities and crime research often suggest that voluntary organizations may provide important crime-control benefits to neighborhoods (Peterson, Krivo, and Harris, 2000; Sampson and Groves, 1989; Slocum et al., 2013; Triplett, Gainey, and Sun, 2003). Community voluntary organizations broadly refer to nonprofit organizations that provide services, activities, or events to the neighborhood. Voluntary organizations can contribute to neighborhood control through the provision of needed services or by creating favorable environments that facilitate the sharing of common values and goals among local residents. Thus, voluntary organizations are posited to

Although some urban sociology perspectives suggest how certain sociodeomgraphic characteristics influence nonprofit development, there is a dearth of empirical research to assess neighborhood differences in nonprofit organizations. The goal of the current study is to build upon the extant literature by examining how both concentrated disadvantage and violent crime impact nonprofit density across neighborhoods. Using data from Los Angeles census tracts from 2010 to 2012, I test for linear and nonlinear influences that these two neighborhood factors might exert on nonprofit density. Poisson regression models show that concentrated disadvantage has a nonlinear (U-shaped) effect on all forms of nonprofit density, whereas violent crime has a linear and deleterious effect on all forms of nonprofit density. These results provide important new insights for urban sociology and policy; most importantly, the extent to which neighborhoods with ongoing social problems can later respond to such problems via access to nonprofit organizations.

A common response to school violence features the use of security measures to deter serious and violent incidents. However, a second approach, based on school climate theory, suggests that schools exhibiting authoritative school discipline (i.e., high structure and support) might more effectively reduce school disorder. We tested these approaches on less serious, but more frequent, incidents of student victimization—physical, verbal, and relational bullying—using a nationally representative sample of 12- to 18-year-olds. We found that students in schools with positive school climates, as based on authoritative discipline theory, were significantly less likely to report bullying victimization. The security measures approach had no association with physical and verbal bullying and only a marginal association on relational bullying.

Whereas there is a burgeoning literature focusing on the spatial distribution of crime events across neighborhoods or micro-geographic units in a specific city, the present study expands this line of research by selecting four cities that vary across two macro-spatial dimensions: population in the micro-environment, and population in the broader macro-environment. We assess the relationship between measures constructed at different spatial scales and robbery rates in blocks in four cities: 1) San Francisco (high in micro- and macro-environment population); 2) Honolulu (high in micro- but low in macro-environment population); 3) Los Angeles (low in micro- but high in macro-environment population); 4) Sacramento (low in micro- and macro-environment population). Whereas the socio-demographic characteristics of residents further than ½ mile away do not impact robbery rates, the number of people up to 2.5 miles away are related to robbery rates, especially in the two cities with smaller micro-environment population, implying a larger spatial scale than is often considered. The results show that coefficient estimates differ somewhat more between cities differing in micro-environment population compared to those differing based on macro-environment population. It is therefore necessary to consider the broader macro-environment even when focusing on the level of crime across neighborhoods or micro-geographic units within an area.

Big data analytics, applied in the industry to leverage data collection, processing and analysis, can allow a better understanding of production system's abnormal behavior. This knowledge is essential for the adoption of a proactive maintenance approach instead of conventional time-based strategies, leading to a paradigm shift towards Condition-Based Maintenance (CBM) since decision is now based on the usage of a huge, diverse, and dynamic amounts of data as a means to optimize operational costs. This paper reports an investigation of the emerging aspects in the design and implementation of big data analytics solutions for offshore installations in order to allow predictive maintenance practices. Condition-based maintenance focuses on performing interventions based on the actual and future states (health) of a system by monitoring the underlying deterioration processes. One of the building blocks of a CBM design and implementation is the prognostic approach/system, which aims to detect, classify and predict critical failures. Considering the massive amounts of data available from a Stationary Production Unity (SPU), the use of techniques that properly deal with such a big data scenario became essential. The use of parallel processing to ingest, transform, and analyze different kinds of data in near real-time basis allows the construction of a valuable tool for implementing CBM. This paper presents a comparison of different approaches for RUSBoost and Random Forest (RF) classification, in constructing a prognostic system for a specific class of turbogenerator failures from a chosen Petrobras' Floating Production Storage and Offloading (FPSO). Besides the comparison of different classifiers, a contribution of this work lies on the use of data acquired not only from machine sensors (telemetry data) but also non-structured data regarding the most critical failures acquired from official reports, e.g. operator's machine event annotations. Those reported annotations were correlated to telemetry data to identify real critical failures, and simultaneously avoid false positives.

In this article, we explore the literature on collective efficacy and crime, but pay attention to three major challenges that confront this literature, and researchers moving forward with the concept in studies of neighborhoods. These challenges are (1) precisely defining and measuring the concept of collective efficacy; (2) determining whether the notions of general cohesion and trust in neighborhoods are really components of collective efficacy, or determinants of it; and (3) whether neighborhood crime can have feedback effects on the level of collective efficacy.

In 1996, U.S. Food and Drug Administration regulations mandated the fortification of enriched cereal-grain products with folic acid, thereby emphasizing the need for validated methods for total folates in foods, particularly cereal products. The AOAC Official Methods (944.12, 960.46) currently used for the analysis of folate in foods for compliance purposes are microbiological methods. When the fortification regulations were finalized, no Official AOAC or Approved AACC methods for folate in cereal-grain products were in place. The AOAC Official Method (992.05) for folic acid in infant formula does not incorporate important improvements in the extraction procedure and was not considered suitable for the analysis of folates in foods in general. Amicrobiological assay protocol using a trienzyme extraction procedure was prepared and submitted for comments to 40 laboratories with recognized experience in folate analysis. On the basis of comments, the method was revised to have the conjugase (gamma-glutamyl-carboxy-peptidase) treatment follow a protease treatment, to include the use of cryoprotected inoculum, and to include the spectroscopic standardization of the standard and optional use of microtiter plates. Thirteen laboratories participated in a collaborative study of 10 required and 10 optional cereal-grain products, including flour, bread, cookies, baking mixes, and ready-to-eat breakfast cereals. The majority of the participating laboratories performed the assay by the standard test tube method; others used the microtiter plate modification for endpoint quantitation with equal success. For the required products, the relative standard deviation between laboratories (RSDR) ranged from 7.4 to 21.6% for 8 fortified (or enriched) products compared with expected (Horwitz equation-based) values of 11–20%. RSDR values were higher (22.7–52.9%) for 2 unfortified cereal-grain products. For the optional products, the RSDR ranged from 1.8 to 11.2% for 8 fortified products. RSDR values were higher (27.9–28.7%) for 2 unfortified cereal-grain products. Based on the results of the collaborative study, the microbiological assay with trienzyme extraction is recommended for adoption as Official First Action.

In this article we identify social communities among gang members in the Hollenbeck policing district in Los Angeles, based on sparse observations of a combination of social interactions and geographic locations of the individuals. This information, coming from LAPD Field Interview cards, is used to construct a similarity graph for the individuals. We use spectral clustering to identify clusters in the graph, corresponding to communities in Hollenbeck, and compare these with the LAPD's knowledge of the individuals' gang membership. We discuss different ways of encoding the geosocial information using a graph structure and the influence on the resulting clusterings. Finally we analyze the robustness of this technique with respect to noisy and incomplete data, thereby providing suggestions about the relative importance of quantity versus quality of collected data., Comment: 22 pages, 6 figures (with subfigures)

The neurohypophyseal peptides arginine vasopressin (AVP) and oxytocin (OT) mediate a wide variety of peripheral and central physiological and behavioral effects by acting on four different G-protein coupled receptors, termed V1a (vascular), V1b (pituitary), V2 (renal), and OT (uterine). We recently reported that d[Cha4]AVP (A), d[Leu4]AVP (B), d[Orn4]AVP (C), and d[Arg4]AVP (D) have high affinity and are selective agonists for the human V1b receptor. However, peptides A-D were subsequently shown to be potent antidiuretic agonists in the rat and are, thus, not selective V1b agonists in the rat. Peptides A-D served as leads for the studies reported here. They were modified at position 8 by Lys, ornithine (Orn), diaminobutyric acid (Dab), and diaminopropionic acid (Dap) to give d[Cha4,Lys8]VP (1), d[Cha4,Orn8]VP (2), d[Cha4,Dab8]VP (3), d[Cha4,Dap8]VP (4), d[Leu4,Lys8]VP (5), d[Leu4,Orn8]VP (6), d[Leu4,Dab8]VP (7), d[Leu4,Dap8]VP (8), d[Orn4,Lys8]VP (9), d[Orn4,Orn8]VP (10), d[Arg4,Lys8]VP (11), d[Arg4,Orn8]VP (12), and d[Arg4,Dab8]VP (13). All peptides were synthesized by the Merrifield solid-phase method. Their binding and functional properties were evaluated in rat AVP V1a, V1b, and V2 receptors and on the rat OT receptor expressed either in native tissues or in stably transfected cells. They were also examined in rat vasopressor, antidiuretic, and in in vitro (no Mg++) oxytocic assays. Functional studies performed on chinese hamster ovary cells expressing the different AVP/OT receptors confirm that d[Cha4,Lys8]VP (1), d[Cha4,Dab8]VP (3), d[Leu4,Lys8]VP (5), and d[Leu4,Dap8]VP (8) are the first selective agonists for the rat V1b receptor. These selective V1b agonists are promising new tools for studies of the role of the V1b receptor in the rat.

In 1996, U.S. Food and Drug Administration regulations mandated the fortification of enriched cereal-grain products with folic acid, thereby emphasizing the need for validated methods for total folates in foods, particularly cereal products. The AOAC Official Methods (944.12, 960.46) currently used for the analysis of folate in foods for compliance purposes are microbiological methods. When the fortification regulations were finalized, no Official AOAC or Approved AACC methods for folate in cereal-grain products were in place. The AOAC Official Method (992.05) for folic acid in infant formula does not incorporate important improvements in the extraction procedure and was not considered suitable for the analysis of folates in foods in general. A microbiological assay protocol using a trienzyme extraction procedure was prepared and submitted for comments to 40 laboratories with recognized experience in folate analysis. On the basis of comments, the method was revised to have the conjugase (gamma-glutamyl-carboxy-peptidase) treatment follow a protease treatment, to include the use of cryoprotected inoculum, and to include the spectroscopic standardization of the standard and optional use of microtiter plates. Thirteen laboratories participated in a collaborative study of 10 required and 10 optional cereal-grain products, including flour, bread, cookies, baking mixes, and ready-to-eat breakfast cereals. The majority of the participating laboratories performed the assay by the standard test tube method; others used the microtiter plate modification for endpoint quantitation with equal success. For the required products, the relative standard deviation between laboratories (RSD(R)) ranged from 7.4 to 21.6% for 8 fortified (or enriched) products compared with expected (Horwitz equation-based) values of 11-20%. RSD(R) values were higher (22.7-52.9%) for 2 unfortified cereal-grain products. For the optional products, the RSD(R) ranged from 1.8 to 11.2% for 8 fortified products. RSD(R) values were higher (27.9-28.7%) for 2 unfortified cereal-grain products. Based on the results of the collaborative study, the microbiological assay with trienzyme extraction is recommended for adoption as Official First Action.

The purpose of the case study was, firstly, to evaluate (starting from the time the patients are admitted to the intensive care unit--ICU) a type of cardiac, pulmonary and peripheral microcirculation in patients with severe traumas by using a multi-component and invasion-free monitoring; the second purpose was to measure quantitatively the changes in the cardiac, pulmonary and peripheral hemodynamics leading to recovery or death; and finally, it was to investigate the effectiveness of applying the discriminative analysis for the sake of assessing the biological value of the controllable changes and of forecast outcome. The invasion-free monitoring system comprising the below tools was in use: an improved bio-impedance method (evaluation of the cardiac output), pulsometry (examination of the pulmonary function), transcutaneous oxygen pressure (tissue perfusion function) and arterial blood pressure (ABP--general circulation status). The results of continuously controllable invasion-free measurements were used for a prospective evaluation at the emergency unit of the county hospital, which was supervised by the university. The accumulated integral values of the deficit or excess of each controllable parameter were calculated by using the differences between the normal values and the values obtained for each patient and for the groups of survivors and dead. A probable outcome and a degree of the deficit of the pulmonary and cardiac functions as well as of the tissue-perfusion function were analyzed by using the discriminant function. The values of pure aggregate deficits (-) or excesses (+) were for the survivors and dead, respectively, as follows: cardiac index--(+)93 +/- 49.8 l/m2 versus -232 +/- 138 l/m2 (p0.07); mean ABD(-)-12 +/- 12.4 mm Hg versus -57 +/- 23.5 mm Hg (p0.066); arterial saturation(-)-1 +/- 0.09% h versus -9 +/- 2.6% h (p0.001): and tissue perfusion--(+)311 +/- 87 tor/h versus 793 +/- 175 tor/h (p0.0001). The pure aggregate value of reduced circulation, tissue perfusion and of hypoxemia degree was found to be higher in the dead versus the survivors. The invasion-free monitoring systems secure a constant real-time control over the data, which makes the circulatory malfunction revealed as soon as possible in emergency settings. The mentioned systems can be used to describe, for each patients, a temporal hemodynamic model and to evaluate quantitatively a functional-deficit severity; they also provide for composing a clear-cut and successive treatment scheme from the emergency stage to the intensive care unit.

Pulmonary artery catheterization is usually not available to critically injured patients before admission to the intensive care unit, where action to correct values derived from such monitoring may be too late. Methods allowing hemodynamic monitoring during the early stages after trauma need to be explored. We used non-invasive monitoring systems (bioimpedance cardiac output monitoring, pulse oximetry and transcutaneous oximetry) to evaluate early temporal hemodynamic patterns after blunt trauma, and compared these to invasive PA monitoring. We included prospectively 134 patients monitored shortly after admission to the emergency department. The non-invasive impedance cardiac output estimations under extenuating emergency conditions approximated those of the thermodilution method: r = 0.83, r2 = 0.69, P0.001; bias and precision were -0.02+/-0.78 l/min/m2. In the intensive care unit, these values improved further to: r = 0.91, r2 = 0.83, P0.001; bias and precision = 0.36+/-0.59 l/min/m2. Monitoring revealed episodes of hypotension, low cardiac index, arterial hemoglobin desaturation, low transcutaneous oxygen and high transcutaneous carbon dioxide tensions, and low oxygen consumption during initial resuscitation. Low flow and poor tissue perfusion were more pronounced in non-survivors by both methods. Multicomponent non-invasive monitoring systems give continuous on-line, real-time displays of physiological data that allow early recognition of circulatory dysfunction. Such systems provide information similar to that provided by the invasive thermodilution method, and are easier and safer to use.

We report the solid phase synthesis and vasodepressor potencies of the novel hypotensive peptide [1(-beta-mercapto-beta,beta-pentamethylene propionic acid)-2-O-ethyl-D-tyrosine, 3-arginine, 4-valine] arginine vasopressin, d(CH2)5[D-Tyr(Et)2, Arg3, Val4]AVP (A), its related Lys3 (B), Tyr-NH(9)2 (C), [Lys3, Tyr-NH(9)2 (D) analogs and in a preliminary structure-activity study of positions 2-4 and 7-9, 24 analogs (1-24) of A-C. Peptides 1-6, 9-14 have the following single substituents at positions 2, 3, 4, 8 and 9 in (A): 1, D-Tyr(Me)2; 2, L-Tyr(Et)2; 3, Orn3; 4, N-Me-Arg3; 5, Glu3; 6, Arg4; 9, D-Arg8; 10, Eda9; 11, Arg-NH(9)2; 12, Ala-NH(9)2; 13, desGly9; 14, desGly-NH(9)2. Peptides 15 and 16 are analogs of B which possess the following single modifications: 15, Arg-NH(9)2; 16, desGly9. Peptides 7 and 8 are analogs of (C) with the following single modification: 7, Gln4; 8, Lys8. Peptides 17-24 are analogs of A possessing the following multiple modifications: 17, [Sar7, Eda9]; 18, [Arg7, Eda9]; 19, [Arg7, Eda9--Tyr10]; 20, [Arg4, Arg-NH(9)2]; 21, [Ile4, desGly9]; 22, [Arg4, desGly9]l; 23, [Arg7, desGly9]; 24, [Arg7, Lys8, desGly9]. All 24 new peptides were evaluated for agonistic and antagonistic activities in in vivo antidiuretic (V2-receptor), vasopressor (V1a-receptor) and in in vitro (no Mg2+) oxytocic (OT-receptor) assays and like the parent peptides (A-D) (Chan et al. Br. J. Pharmacol. 1998; 125: 803-811) were found to exhibit no or negligible activities in these assays. Vasodepressor potencies were determined in anesthetized male rats with baseline mean arterial blood pressure maintained at 110-120 mmHg. The effective dose (ED), in microg 100 g(-1) i.v., required to produce a vasodepressor response of 5 cm2, area under the vasodepressor response curve (AUC) during the 5-min period following the injection of the test peptide, was determined. Therefore, the EDs measure the relative vasodepressor potencies of the hypotensive peptides. The following ED values were obtained for A-D and for peptides 1-24: A, 4.66; B, 5.75; C, 10.56; D, 11.60; 1, approximately 20; 2, approximately 30; 3, 6.78; 4, non-detectable (ND); 5, ND; 6, approximately 32; 7, ND; 8, 8.67; 9, ND; 10, 2.43; 11, 3.54; 12, 10.57; 13, 4.81; 14, ND; 15, 4.47; 16, 9.78; 17, 5.72; 18, 1.10; 19, 1.05; 20, 10.41; 21, 9.13; 22, approximately 33; 23, 3.01; 24, 1.71. A is clearly the most potent of the four original hypotensive peptides A-D. These data provide insights to which modification of A enhance, retain or abolish hypotensive potencies. Six of the new hypotensive peptides are significantly more potent than A. These are peptides 10, 11, 18, 19, 23 and 24. Peptide 19, a radioiodinatable ligand, is ten times more potent than C or D. The Gln4 modification of C and the N-Me-Arg3, Glu3, D-Arg8 and desGly-NH(9)2 modifications of A abolished hypotensive potency. By contrast, the Eda9, Arg-NH(9)2, [Sar7, Eda9], [Arg7, Eda9- -Tyr10], [Arg7, desGly9], [Arg7, Lys8, desGly9] modifications of A all led to enhancements of hypotensive potency. This initial structure-activity exploration provides useful clues to the design of (a) more potent vasodepressor peptides and (b) high affinity radioiodinatable ligands for the putative AVP vasodilating receptor. Some of the peptides here may be of value as pharmacological tools for studies on the complex cardiovascular actions of AVP and may lead to the development of a new class of anti-hypertensive agents.

We report the solid-phase synthesis and some pharmacological properties of 23 new analogs of arginine vasopressin (AVP) which have the Phe3 residue replaced by a broad variety of amino acids. Peptides 1-9 have at position 3: (1) the mixed aromatic/aliphatic amino acid thienylalanine (Thi) and the aliphatic amino acids; (2) cyclohexylalanine (Cha); (3) norleucine (Nle); (4) Leu; (5) norvaline (Nva); (6) Val; (7) alpha-aminobutyric acid (Abu); (8) Ala; (9) Gly. Peptides 10-23 have at position 3: the aromatic amino acids, (10) homophenylalanine (Hphe): (11) Tyr; (12) Trp; (13) 2-naphthylalanine (2-Nal); the conformationally-restricted amino acids (14) Pro; (15) 2-aminotetraline-2-carboxylic acid (Atc); the polar amino acids (16) Ser; (17) Thr; (18) Gln; and the charged amino acids (19) Asp; (20) Glu; (21) Arg; (22) Lys; (23) Orn. All 23 new peptides were evaluated for agonistic and, where appropriate, antagonistic activities in in vivo antidiuretic (V2-receptor) and vasopressor (V1a-receptor) assays and in in vitro (no Mg2+) oxytocic assays. The corresponding potencies (units/mg) in these assays for AVP are: 323+/-16; 369+/-6 and 13.9+/-0.5. Peptides 1-9 exhibit the following potencies (units/mg) in these three assays: (1) 379+/-14; 360+/-9; 36.2+/-1.9; (2) 294+/-21: 73.4+/-2.7; 0.33+/-0.02; (3) 249+/-28; 84.6+/-4.3; 4.72+/-0.16; (4) 229+19; 21.4+/-0.6; 2.1+/-0.2; (5) 134+/-5; 31.2+/-0.9; 28.4+/-0.2; (6) 114+/-9; 45.3+2.3; 11.3+/-1.6; (7) 86.7+/-2.5; 4.29+/-0.13; 0.45+/-0.03; (8) 15.5+/-1.5; 0.16+/-0.01; approximately 0.02: (9) 3.76+/-0.03;0.02; in vitro oxytocic agonism was not detected. These data show that the aliphatic amino acids Cha, Nle, Leu, Nva and Val are well-tolerated at position 3 in AVP with retention of surprisingly high levels of antidiuretic activity. Peptides 2-9 exhibit significant gains in both antidiuretic/vasopressor (A/P) and antidiuretic/oxytocic (A/O) selectivities relative to AVP. [Thi3]AVP appears to be a more potent antidiuretic and oxytocic agonist than AVP and is equipotent with AVP as a vasopressor agonist. The antidiuretic potencies of peptides 10-23 exhibit drastic losses relative to AVP. They range from a low of 0.018+/-0.001 units/mg for the Lys3 analog (peptide 22) to a high of 24.6+/-4.6 units,mg for the Hphe3 analog (peptide 10). Their vasopressor potencies are also drastically reduced. These range from a low of0.002 units/mg for peptide 22 to a high of 8.99+0.44 units/mg for the Atc3 analog (peptide 15). Peptides 10-23 exhibit negligible or undetectable in vitro oxytocic agonism. The findings on peptides 10-23 show that position 3 in AVP is highly intolerant of changes with aromatic, conformationally-restricted, polar and charged amino acids. Furthermore, these findings are in striking contrast to our recent discovery that position 3 in the potent V2/V1a/OT antagonist d(CH2)5D-Tyr(Et)2VAVP tolerates a broad latitude of structural change at position 3 with many of the same amino acids, to give excellent retention of antagonistic potencies. The data on peptides 1-4 offer promising clues to the design of more potent and selective AVP V2 agonists.

The solid phase synthesis of three invertebrate vasopressin-oxytocin homologs: AVP-like factor, F1(1), ([Leu2, Thr4] AVT)2 isolated from subesophageal and thoracic ganglia of Locusta migratoria3, Arg-conopressin-S4. ([Ile2, Arg4] AVT), Lys-conopressin-G4 ([Phe2, Arg4] LVT), both isolated from the venom of fish-hunting marine snails of the genus Conus and six of their analogues is reported. These analogues are: [Arg4] AVT, [Ile2] AVT, [Leu2] AVT, [Phe2, Arg4] AVT, [Arg4] LVT and [Ile2, Arg4] LVT. All peptides were tested for antidiuretic and vasopressor activities.

1. Arginine-vasopressin (VP) has both vasoconstricting and vasodilating action. We report here the discovery of four novel selective hypotensive VP analogues: d(CH2)5[D-Tyr(Et)2,Arg3,Val4]AVP; d(CH2)5[D-Tyr(Et)2,Lys3,Val4]AVP and their iodinatable Tyr-NH2(9) analogues. 2. Bioassays in rats for activities characteristic of neurohypophysial peptides showed that the four VP peptides possessed little or no V1a, V2 or oxytocin (OT) receptor agonistic or antagonistic activities. 3. In anaesthetized rats, these peptides (0.05-0.10 mg kg(-1) i.v.) elicited a marked fall in arterial blood pressure. 4. Blockade of cholinoceptors, adrenoceptors and bradykinin B2 receptors, and inhibition of prostaglandin synthesis had little effect on their vasodepressor action. 5. Classical V1a, V2 and OT receptor antagonists did not block the vasodepressor response. 6. L-NAME, 0.2 mg kg(-1) min(-1), markedly suppressed the hypotensive response to ACh but not the vasodepressor response to the hypotensive VP peptides. However, the duration of the vasodepressor response was shortened. Very high doses of L-NAME attenuated both the vasodepressor response and the duration of action. 7. These findings indicate that the vasodepressor action of these VP peptides is independent of the peripheral autonomic, bradykinin and PG systems and is not mediated by the known classical OT/VP receptors. NO does not appear to have an important role in their vasodepressor action. 8. The discovery of these novel VP peptides could lead to the development of new tools for the investigation of the complex cardiovascular actions of VP and the introduction of a new class of hypotensive agents. The two iodinatable hypotensive VP peptides could be radiolabelled as potential markers for the localization of the receptor system involved.

We report the solid-phase synthesis and some pharmacological properties of 12 position three modified analogues (peptides 1-12) of the potent non-selective antagonist of the antidiuretic (V2-receptor), vasopressor (V1a-receptor) responses to arginine vasopressin (AVP) and of the uterine contracting (OT-receptor) responses to oxytocin (OT), [1(-beta mercapto-beta,beta-pentamethylenepropionic acid)-2-O-ethyl-D-tyrosine 4-valine] arginine vasopressin [d(CH2)5D-Tyr(Et)2VAVP] (A) and two analogues of (B) (peptides 13,14), the 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid3 (Tic3) analogue of (A). Peptides 1-12 have the following substituents at position three in (A): (1) Pro; (2) Oic; (3) Atc; (4) D-Atc; (6) D-Phe; (7) Ile; (8) Leu; (9) Tyr; (10) Trp; (11) Hphe; (12) [HO]Tic; Peptide (13) is the Tyr-NH2(9) analogue of (B): Peptide (14) is the D-Cys(6) analogue of (B). All 14 new peptides were evaluated for agonistic and antagonistic activities in in vivo V2 and V1a assays and in vitro (no Mg2+)n oxytocic assays. With the exception of the D-Phe3 peptide (No. 6), which exhibits very weak V2 agonism (approximately 0.0017 U/mg), none of the remaining 13 peptides exhibit any agonistic activities in these assays. In striking contrast to their deleterious effects on agonistic activities in AVP, the Pro3, Oic3, Tyr3 and Hphe3 substitutions in (A) are very well tolerated, leading to excellent retention of V2, V1a and OT antagonistic potencies. All are more potent as V2 antagonists than the Ile3 and Leu3 analogues of (A). The Tyr-NH2(9) and D-Cys(6) substitutions in (B) are also well tolerated. The anti-V2 pA2 values of peptides 1-5 and 7-14 are as follows (1) 7.77 +/- 0.03; (2) 7.41 +/- 0.05; (3) 6.86 +/- 0.02; (4) 5.66 +/- 0.09; (5) approximately 5.2; (7) 7.25 +/- 0.08; (8) 6.82 +/- 0.06; (9) 7.58 +/- 0.05; (10) 7.61 +/- 0.08; (11) 7.59 +/- 0.07; (12) 7.20 +/- 0.05; (13) 7.57 +/- 0.1; (14) 7.52 +/- 0.06. All analogues antagonize the vasopressor responses to AVP, with anti-V1a pA2 values ranging from 5.62 to 7.64, and the in vitro responses to OT, with anti-OT pA2 values ranging from 5.79 to 7.94. With an anti-V2 potency of 7.77 +/- 0.03, the Pro3 analogue of (A) is surprisingly equipotent with (A), (anti-V2 pA2 = 7.81 +/- 0.07). These findings clearly indicate that position three in AVP V2/V1a antagonists, in contrast to position three in AVP agonists, is much more amenable to structural modification than had heretofore been anticipated. Furthermore, the surprising retention of V2 antagonism exhibited by the Pro3, Oic3, Tyr3, Trp3 and Hphe3 analogues of (A), together with the excellent retention of V2 antagonism by the Tyr-NH2(9) and D-Cys6 analogues of (B) are promising new leads to the design of potent and possibly orally active V2 antagonists for use as pharmacological tools and/or as radioiodinatable ligands and for development as potential therapeutic agents for the treatment of the hyponatremia caused by the syndrome of the inappropriate secretion of the antidiuretic hormone (SIADH).

Patients undergoing prolonged, complex oncological surgery are at increased risk of developing the adult respiratory distress syndrome (ARDS) and other organ failures. Our hypothesis is that maintaining adequate tissue perfusion and oxygenation may prevent tissue hypoxia and acidosis in pulmonary, peripheral, and splanchnic microcirculations. Experimental evidence suggests that the hypoxic, acidotic endothelium stimulates the release of cytokines, kinins, and other mediators. We developed and tested an intraoperative protocol for surgical patients likely to develop ARDS and organ dysfunction; the protocol focuses on the intraoperative period but is not limited to this time. Nitroglycerin and fluids were used to maintain tissue perfusion and prevent tissue hypoxia as reflected by transcutaneous oxygen tension values. In 155 high-risk patients, none developed ARDS. We conclude that maintenance of tissue perfusion and oxygenation in high-risk surgical patients decreases the incidence of ARDS.

The aim of the present study was to explore methods, concepts, and techniques that provide recognition of circulatory deficiencies at the earliest possible time in the patient's illness. We used both the standard invasive pulmonary artery thermodilution catheter and noninvasive hemodynamic monitoring systems consisting of a new bioimpedance cardiac output device, pulse oximetry, transcutaneous oxygen (PtCO2) and carbon dioxide tensions as well as the transcutaneous oxygen tension/fraction of inspired oxygen ratio (PtCO2/FIO2). These three noninvasive systems were used to evaluate cardiac function, pulmonary function, and tissue perfusion, respectively. This approach to early noninvasive monitoring is based on recent evidence suggesting that poor tissue perfusion and oxygenation initiate circulatory dysfunction that leads to shock and organ failure. We studied 303 acute episodes of circulatory dysfunction and shock in 261 patients in a university-run county hospital; 75 were acute traumatic injuries and 109 acute nontrauma medical emergencies on admission to the emergency department, and 77 ICU patients with an acute illness or exacerbation of their current illness. The study was a prospective, descriptive study to identify early abnormal circulatory patterns reflecting the cardiac, pulmonary, and perfusion functions associated with death and with survival. We described noninvasively monitored patterns in individual illustrative cases, in common etiologic groups, and in physiologic categories representing various abnormal functional patterns. We found that hypotensive shock usually was preceded by episodes of high flow followed by low flow and inadequate tissue perfusion indicated by reduced PtCO2; this frequent pattern was modified by associated co-morbid conditions, especially hypovolemia, limited cardiac reserve capacity, age, hypertensive states, and increased body metabolism from infection, trauma, stress, exercise, temperature, and endocrine disorders. Reduced pulmonary function occurred in 18% of emergency patients; these were usually patients with thoracic trauma, severe hypovolemia, head injuries, chronic obstructive pulmonary disease, asthma, drug overdose, and central nervous system failure (massive stroke and coma). We concluded that noninvasive measurements identify early circulatory problems reliably and provide objective criteria for physiologic analysis as well as for definition of therapeutic goals and titration of therapy.

Substitution of Asn5 in oxytocin (OT) or vasopressin (VP) invariably leads to a dramatic loss of the biological activities of the peptides. Because of this observation, few structure-activity-relationship studies of OT and VP peptides have involved modifications in the 5 position. It is now recognized that peptide agonists and antagonists may use different structural and conformational features in their interactions with the receptors. Our prior studies showed that OT and VP antagonists, unlike the agonists, tolerate amino acid substitutions in the 5 position. This opens new approaches for the design of antagonists. We describe the effects of isosteric replacement of Asn5 by diaminopropionic acid (Dap) or diaminobutyric acid (Dab) in three OT and VP antagonists: (1) the V1a (vasopressor receptor) antagonist d(CH2)5[Tyr(Me)2]AVP; (2) the OT (uterine OT receptor) antagonist d(CH2)5[Tyr(Me)2, Thr4, Tyr-NH29] OVT and (3) three selective OT antagonists, desGly-NH2,d(CH2)5[D-Tyr2, Thr4]OVT, desGly-NH2, d(CH2)5[D-Phe2, Thr4]OVT and desGly-NH2, d(CH2)5- [D-Trp2, Thr4]OVT. The Dap5 and Dab5 substitutions were tolerated remarkably well, with the less isosteric Dap5 substitution leading to a greater retention of anti-OT potency than the Dab5 substitution. Furthermore, the Dap5 and Dab5 and OT and VP antagonist analogues were surprisingly shown to be much more selective than their respective parent compounds. The Dab5 analogue of (1) was devoid of anti-OT activity. The three Dap5 analogues of (3) were devoid of anti-V1a activities. These appear to be the first single-receptor-type-selective OT and VP antagonists discovered to date. These findings could provide new leads for the development of single-receptor-type-selective receptor probes for the localization and characterization of OT and VP receptors and potential selective tocolytics for the treatment of premature labor.

To evaluate the capacity of a new thoracic electric bioimpedance system to estimate cardiac output compared with the conventional thermodilution method.Prospective, multicenter study.A university-run county hospital, a university-run U.S. Veterans Affairs hospital, and a university-affiliated U.S. military hospital.A series of 68 critically ill patients whose conditions required pulmonary artery catheter insertion.A total of 842 simultaneous pairs of cardiac output estimations by conventional thermodilution and a new thoracic electric bioimpedance system that uses an improved signal processing technique based on an all-integer-coefficient filtering technology, using a time-frequency distribution that provides a high signal/noise ratio were evaluated. The r value was .86, r2 = .74, and p.001 by regression analysis; the mean difference between the two methods relative to their average value was 16.6 +/- 12.9 (SD) %; the precision was 1.4 L/min or 0.8 L/min/m2; the bias was -0.013 L/min. The mean difference between successive pairs of thermodilution measurements was 8.6 +/- 0.6 (SD) %, which was about half the difference between simultaneous pairs of measurement by the two methods. The changes in impedance estimations were close to simultaneously measured changes in thermodilution estimates of cardiac output.The new bioimpedance system satisfactorily estimated cardiac output as measured by the thermodilution technique. The difference between the two estimations is more than made up for by the continuous noninvasive capability of the impedance system.

Objectives: The aim is to evaluate early hemodynamic patterns of patients with severe sepsis and septic shock and compare/contrast the effects of sepsis as a primary etiologic event versus sepsis as a secondary complication after trauma, surgery etc. with simultaneously monitored sympathetic (SNS) and parasympathetic nervous system (PSNS) activities measured by the variability of the heart rate (HR) and respiratory rate (RR). Setting: Level 1 university-run trauma service in a public hospital. Methods: Non-invasively monitored the early hemodynamic patterns in 208 severely septic patients beginning shortly after admission to the emergency department (ED). Simultaneously, monitored and compared the spectrum of HR and RR variability patterns, as markers of autonomic activity, with temporal hemodynamic patterns in 73 of these septic patients. The HR variability was measured to evaluate the low frequency area (LFa), which reflects SNS. The high frequency area (RFa) is indicative of PSNS activity. The LFa/RFa, reflects the relationship of SNS to PSNS. Concurrent noninvasive hemodynamic monitoring consisting of: a) cardiac output by bioimpedance, HR, and mean arterial pressure (MAP) to reflect cardiac function, b) pulse oximetry (SapO2) to reflect changes in pulmonary function, and c) transcutaneous oxygen (PtcO2) indexed to the FiO2 as a marker of tissue perfusion/oxygenation. Results: Non-survivors had higher LFa and RFa values than the survivors did. The increased RFa preceded the increases in LFa in non-survivors and a higher percentage of sympathetic activity. These changes were more marked when measured before sedation and pain medication. In survivors, these patterns were associated with increased cardiac index (CI), and HR, normal MAP, SapO2, and normal tissue perfusion indicated by PtcO2/FiO2 ratios. Nonsurvivors had relatively normal CI, hypotension, tachycardia, poor tissue perfusion, borderline SapO2, and reduced oxygen delivery. Conclusions: In the period immediately after ED admission of patients with sepsis increased ANS activity was observed more pronounced in non-survivors. This ANS activity was associated with increased HR, MAP, and CI, and a tendency toward reduced tissue perfusion/oxygenation. INTRODUCTION The aims were to evaluate early hemodynamic patterns of surviving and nonsurviving patients with severe sepsis and septic shock. Second, to compare these hemodynamic patterns with simultaneously monitored sympathetic (SNS) and parasympathetic nervous system (PSNS) activities measured by the variability of the heart rate (HR) and respiratory rate (RR); collectively known as autonomic nervous system (ANS) monitoring. Third, to compare and contrast the effects of sepsis as a primary etiologic event versus sepsis as a secondary complication after trauma, surgery, and other acute illnesses with simultaneously monitored SNS and PSNS activities measured by ANS monitoring. The present study: a) describes the patterns of sympathetic and parasympathetic activities in acute sepsis, b) relates these to the evolving temporal hemodynamic patterns, and c) describes these autonomic and hemodynamic interactions in sepsis as a primary disease, and as a complication of trauma and surgery. Rivers et al (11) showed improved outcome in septic patients with goal-directed therapy started in the emergency department (ED) based on minimally invasive monitoring. Multiple continuously monitored noninvasive hemodynamic values used in the present study provided an integrated approach to major circulatory components: cardiac, pulmonary, and tissue perfusion functions (6,8,12-21). Simultaneous measurements of hemodynamics with ANS activity provide a unique opportunity to study the role of ANS activity in the hemodynamic responses to various clinical septic conditions alone and in combination with surgery, trauma, or other acute emergencies.