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Despite currently available antithrombotic therapies, venous thromboembolism (VTE) remains a major cause of morbidity and mortality. Fondaparinux sodium (pentasaccharide), the first in a new class of antithrombotic agents developed for the prevention and treatment of VTE, inhibits thrombin generation by selectively inhibiting factor Xa. Fondaparinux exhibits complete bioavailability by the subcutaneous route and is rapidly absorbed, reaching its maximum concentration approximately 2 h post dosing. It has a terminal half-life of 13 to 21 h, permitting once-daily dosing. Fondaparinux's reproducible linear pharmacokinetic profile exhibits minimal intrasubject and intersubject variability, suggesting that individual dose adjustments will not be required for the vast majority of the population and that there will be no need for routine hemostatic monitoring. At therapeutic concentrations (2 mg/L), fondaparinux exhibits94% binding to its target protein, antithrombin. Within this same concentration range there is no specific binding by fondaparinux to plasma proteins commonly involved in drug binding, indicating a low potential for drug-drug interactions by protein displacement. Unlike antithrombotic agents prepared from animal extracts (heparins), fondaparinux is chemically synthesized; this leads to batch-to-batch consistency and the absence of potential risk of contamination problems. In recently completed phase III clinical trials in VTE prevention in major orthopedic surgery, fondaparinux showed significant superiority over the low-molecular-weight heparin enoxaparin, providing an overall50% (P0.001) reduction in VTE risk without increasing clinically important bleeding. Additional clinical data support its potential benefits in other venous and arterial thrombotic disorders. In view of these collective findings, fondaparinux is expected to play a major role in the prevention and treatment of venous and arterial thrombotic disease.

Following preliminary evidence from observational studies, we test the potential relationship between whole-body vibration (WBV) and prostate cancer in a cohort study.WBV exposure was assigned based on occupation in 1991 and 1,107,700 participants were followed for incident prostate cancer until the end of 2003. Adjusted hazard rate ratios (HRs) were calculated using Cox proportional hazards modeling.17,922 incident prostate cancer cases were observed. WBV-exposed men in Natural and Applied Sciences Occupations had a 37% elevated risk of prostate cancer (95% CI 1.09-1.72) and WBV-exposed men in Trades, Transport, and Equipment Operators Occupations had a 9% reduced risk (95% CI 0.86-0.97). Independent of WBV exposure, small but significant differences in risk were seen for several occupational categories.We found no consistent relationship between WBV and prostate cancer. Further research could focus on other exposures or specific occupations in the studied categories to determine what may be contributing to the observed differences in prostate cancer risk.

Using multiple-cause-of-death data, this study examines diabetes mellitus as a cause of mortality. During the 2004-to-2008 period, diabetes mellitus was listed as either the underlying cause or a contributing cause of 119,617 deaths. It was more than twice as likely to be a contributing than the underlying cause of death. When it was identified as the underlying cause of death, diabetes mellitus was rarely the only cause. The diabetes mellitus mortality rate was relatively high among males, older individuals, and people living in lower-income neighbourhoods. Provincial/Territorial differences in rates of death from diabetes mellitus were considerable. When diabetes mellitus was the underlying cause of death, cardiovascular diseases were listed as a contributing cause most often, and when diabetes mellitus was a contributing cause, cardiovascular diseases were most likely to be the underlying cause.

Finger fillet flaps have been used to treat a variety of complex hand deformities providing stable soft tissue coverage and preventing pathologic contractures. Fillet flaps have not been reported in the coverage of segmental extensor tendon deficit in an adjacent digit. A 20-year-old man involved in a motor vehicle crash sustaining a 30% total body surface area burn, primarily to left arm and bilateral lower extremities. In particular, his left index finger extensor mechanism was disrupted with exposure of the proximal interphalangeal (PIP) joint. In addition, the middle finger had a segmental exposure of the extensor tendon. The nonfunctional index finger was sacrificed to provide coverage, via a forked fillet finger flap, of the exposed extensor tendon at the PIP and metacarpophalangeal (MCP) joints. Total active motion of left fingers at 12 months consisted of the third digit 0 to 86 degrees at the MCP joint, 0 to 88 degrees at the PIP joint and 0 to 33 degrees at the distal interphalangeal joint. Gross grip strength improved to 26 lb at 1 year follow-up. Adequate soft tissue coverage of extensor tendons can be challenging in the traumatic hand. With this novel approach of a forked finger fillet flap we were able to provide adequate soft tissue coverage of exposed tendons and joints improving the patient's strength and active range of motion especially in the middle finger. Prevention of postburn boutonnière deformity was an additional benefit.

This study quantifies differences in life expectancy between residents of Inuit Nunangat and people in the rest of Canada; estimates the contribution of specific causes of death to the differences; and examines these differences over time, by sex and by age group.A geographic approach was used to decompose differences in life expectancy for residents of Inuit Nunangat, compared with people living outside this geographic area. Differences in life expectancy by cause, sex, and age group were calculated using the discrete method of decomposition and were applied to abridged life tables. Causes of death were classified according to Global Burden of Disease categories. Attributable causes of death were calculated for causes amenable to medical intervention and for smoking-related diseases.The largest contributor to life expectancy differences between males in Inuit Nunangat and the rest of Canada was injury, particularly self-inflicted injury at ages 15 to 24. For females, the largest contributors were malignant neoplasm and respiratory disease at ages 65 to 79.The gap in life expectancy between residents of Inuit Nunangat and the rest of Canada can be attributed to specific groups of causes occurring within specific age ranges.

Many First Nations children live in communities that face diverse social and health challenges compared with their non-Aboriginal peers, including some of the most socio-economically challenging situations in Canada. These differences can be seen in broad indicators of the social determinants of health. Studies of mortality in Aboriginal populations across Canada are often restricted by the lack of Aboriginal identifiers on national death records. While some studies have utilised a record-linkage approach, this is often not possible for the entire country or for recent data. Some researchers have adopted a geographic approach and examined mortality and morbidity in areas that have a high percentage of Aboriginal identity residents, and have uniformly reported elevated rates of mortality and morbidity compared with other areas. The purpose of this article was to examine child and youth mortality (aged 1 to 19 years) in areas where a high percentage of the population identified as First Nations in comparison with areas where there is a low percentage of Aboriginal identity residents.Using a geographic threshold table approach, areas with a high percentage of Aboriginal identity peoples were classified as either First Nations, Métis, or Inuit communities based on the predominant identity group. The upper one-third of the total Aboriginal population distribution was used as a cut-off for high percentage First Nations areas, where 97.7% of the population aged 1-19 were of First Nations identity in 2006 (Age-standardized mortality rates for children and youth in high-percentage First Nations identity areas were significantly higher than in low-percentage Aboriginal identity areas. The rate ratio for all-cause mortality for boys was 3.2 (CI: 2.9-3.6) for 2005-2007 and 3.6 (CI: 3.2-4.2) for girls. Mortality rates for injuries had the largest difference, with rate ratios of 4.7 (CI: 4.0-5.5) and 5.3 (CI:4.5-6.3) for boys in 2000-2002 and 2005-2007 and 5.5 (CI: 4.4-6.8) and 8.3 (CI: 6.8-10.1) for girls in the same period.A strength of this study is that it is the first to use national-level vital statistics registration data across two time periods to report mortality by cause for children and youth living in high-percentage First Nations areas. Vital events were geographically coded to high-percentage First Nations identity areas and compared with low-percentage Aboriginal identity areas at the Dissemination Areas level. This area-based methodology allows for mortality to be calculated for children and youth by sex and by detailed cause of death for multiple time periods. The results provide key evidence for the persistent differences in the causes of death for children and youth living in high-percentage First Nations identity areas.

INTRODUCTION: Many First Nations children live in communities that face diverse social and health challenges compared with their non-Aboriginal peers, including some of the most socio-economically challenging situations in Canada. These differences can be seen in broad indicators of the social determinants of health. Studies of mortality in Aboriginal populations across Canada are often restricted by the lack of Aboriginal identifiers on national death records. While some studies have utilised a record-linkage approach, this is often not possible for the entire country or for recent data. Some researchers have adopted a geographic approach and examined mortality and morbidity in areas that have a high percentage of Aboriginal identity residents, and have uniformly reported elevated rates of mortality and morbidity compared with other areas. The purpose of this article was to examine child and youth mortality (aged 1 to 19 years) in areas where a high percentage of the population identified as First Nations in comparison with areas where there is a low percentage of Aboriginal identity residents. METHODS: Using a geographic threshold table approach, areas with a high percentage of Aboriginal identity peoples were classified as either First Nations, Metis, or Inuit communities based on the predominant identity group. The upper one-third of the total Aboriginal population distribution was used as a cut-off for high percentage First Nations areas, where 97.7% of the population aged 1-19 were of First Nations identity in 2006 (N=140 779). Mortality rates were then calculated for high-percentage First Nations identity areas and compared with low-percentage Aboriginal identity areas, excluding high-percentage Metis or Inuit identity areas. Deaths were aggregated for the 3 years surrounding the 2001 and 2006 census periods, and a total of 473 deaths were recorded for 2000-2002 and 493 deaths for 2005-2007. Analysis was facilitated via the correspondence of six-digit residential postal codes on vital statistics records to census geographical areas using automated geo-coding software (Statistics Canada; PCCF+). RESULTS: Age-standardized mortality rates for children and youth in high-percentage First Nations identity areas were significantly higher than in low-percentage Aboriginal identity areas. The rate ratio for all-cause mortality for boys was 3.2 (CI: 2.9-3.6) for 2005-2007 and 3.6 (CI: 3.2-4.2) for girls. Mortality rates for injuries had the largest difference, with rate ratios of 4.7 (CI: 4.0-5.5) and 5.3 (CI:4.5-6.3) for boys in 2000-2002 and 2005-2007 and 5.5 (CI: 4.4-6.8) and 8.3 (CI: 6.8-10.1) for girls in the same period. CONCLUSION: A strength of this study is that it is the first to use national-level vital statistics registration data across two time periods to report mortality by cause for children and youth living in high-percentage First Nations areas. Vital events were geographically coded to high-percentage First Nations identity areas and compared with low-percentage Aboriginal identity areas at the Dissemination Areas level. This area-based methodology allows for mortality to be calculated for children and youth by sex and by detailed cause of death for multiple time periods. The results provide key evidence for the persistent differences in the causes of death for children and youth living in high-percentage First Nations identity areas. Language: en

Experience with internet information resources and services suggests the creative destruction of the classical, paper-based process of scientific and scholarly communication, and of the professions and enterprises that realize that process. A modernized, at least partially network-based process is rapidly, if unevenly, becoming established. The characteristics of an emergent, completely network-based process is the subject of a growing number of digital library research and development initiatives. These processes are discussed in the context of the transformation, real and imagined, of the value-chain of productive relationships between authors and readers of intellectual works.

Described in this unit are basic protocols frequently used in the research of human immunodeficiency viruses (HIVs). Provided are methods for propagating and quantifying HIV, as well as recommendations for long-term storage. Background information about these methods is also provided and includes their advantages, disadvantages, and troubleshooting. Curr. Protoc. Microbiol. 28:15J.1.1-15J.1.24. © 2013 by John Wiley & Sons, Inc. Keywords: HIV-1; HIV-2; retroviruses; primary isolates; T cell line–adapted (TCLA) viruses; molecular clones; reporter viruses; focus-forming unit; radioactive reverse transcriptase assay; p24 ELISA

The Internet information environment has become home to a diverse and rapidly growing population of communities. These and other communities have begun to consider how the Internet experience might become the rule rather than the exception of 21st Century life and enterprise. This paper will explore three lessons that can be drawn from the current or close future Internet information environment and which call attention to places where fundamental shifts in thinking may be possible, even necessary, if the full potential of the Internet, and of networks like the Internet is to be realized for communication and publication.

N-Hydroxyureas based on the 1,4-benzodioxan template were prepared from appropriately substituted 1,4-benzodioxan-2-methanols as the key intermediates and evaluated in the in vitro guinea pig polymorphonuclear leukocyte 5-lipoxygenase (5-LO) assay for their 5-LO inhibitory activity. Placement of a 7-phenoxy or 7-p-fluorophenoxy substituent resulted in a dramatic increase in in vitro potency. Selected compounds were subsequently assayed in an ex vivo dog model of LTB4 synthesis at a dose of 1.0 mg/kg. The 7-phenoxy derivatives 16 and 17 showed modest duration of action (DA) in this dog model. The 6-regioisomers 21 and 22 were less potent. Replacement of the 7-phenoxy group of 16 with the p-fluorophenoxy moiety enhanced the DA dramatically. Compound 18 (CGS 25667), which had an IC50 value of 100 nM in the in vitro guinea pig 5-LO assay, had a DA of 8.5 h (zileuton, DA = 8.5 h) at the oral dose of 1.0 mg/kg. Optical antipodes (24, 26) of 18 were independently synthesized in high (> 95%) enantiomeric purity from commercially available optically active glycidyl tosylates and evaluated. In the in vitro assay, the 2S-(-)-enantiomer (24, CGS 25997, IC50 = 85 nM) was found to be twice as active as the 2R-(+)-counterpart (26, CGS 25998, IC50 = 180 nM). In the ex vivo experiment, 24, which dose dependently inhibited plasma 5-LO activity, was shown to be significantly longer acting than 26, with a DA of 8.4 h when dosed orally at 1.0 mg/kg.

Hospital records lack information about country of birth. This study describes a method for calculating hospitalization rates by the percentage of foreign-born in Census Dissemination Areas (DAs).Data from the 2006 Census were used to classify DAs by the percentage of the foreign-born population who lived in them. Quintile and tercile thresholds were created to classify DAs as having low to high percentages of foreign-born residents. This information was appended to the 2005/2006 Hospital Morbidity Database via postal codes. Age-sex standardized hospitalization rates were calculated for low to high foreign-born concentration DAs, nationally and subnationally.Nationally, quintile thresholds had better discriminatory power to detect variations in hospitalization rates by foreign-born concentration, but tercile thresholds produced reliable results at subnational levels. All-cause hospitalization rates were lowest among residents of the high foreign-born concentration terciles. Similar gradients emerged in hospitalization rates for heart disease, diseases of the circulatory system, and mental health conditions. The pattern varied more at the subnational level.With this approach, administrative data can be used to calculate hospitalization rates by foreign-born concentration.

Because Vital Statistics data do not include information on Inuit identity in all jurisdictions, mortality rates cannot be calculated specifically for Inuit. However, Inuit in Canada are geographically concentrated--78% live in Inuit Nunangat, and 82% of the area's total population identify as Inuit. While there are limitations, geographic approaches can be employed to calculate mortality for the population of that area.The Vital Statistics Database (1994 to 2008) and population estimates were used to calculate age-standardized mortality rates (ASMRs) in five-year intervals around the 1996 and 2006 Census years. Mortality rates were calculated for 1- to 19-year-olds living in Inuit Nunangat and those living elsewhere in Canada.The ASMR in 2004-2008 for 1- to 19-year-olds in Inuit Nunangat was 188.0 deaths per 100,000 person-years at risk, five times the rate (35.3) elsewhere in Canada. The disparity had not narrowed over the previous decade. In Inuit Nunangat, injuries were responsible for 64% of deaths of children and teenagers, compared with 36% in the rest of Canada.The persistently high mortality rates for children and teenagers living in Inuit Nunangat, compared with the rest of Canada, are important in understanding the health and socio-economic situation of residents of this region.

Background The identification of phenotypic features of the HIV-1 envelope glycoprotein that correlate with neutralization breadth is an important goal of HIV vaccine research. Recently we compared the immunogenic potential of two gp120s differing in their ability to utilize CD4; B33 (highly macrophage topic) and LN40 (non-macrophage tropic). Using a DNA prime protein boost regimen in New Zealand White Rabbits, LN40-primed sera displayed enhanced breadth compared to the B33-primed group, with differences in immunogenicity between groups modulated by specific residues within and flanking the V3 loop and the CD4bs. To better understand the role of these residues in eliciting breadth, we introduced reciprocal mutations between LN40 and B33 at these critical positions.

Administrative datasets often lack information about individual characteristics such as Aboriginal identity and income. However, these datasets frequently contain individual-level geographic information (such as postal codes). This paper explains the methodology for creating Geozones, which are area-based thresholds of population characteristics derived from census data, which can be used in the analysis of social or economic differences in health and health service utilization.With aggregate 2006 Census information at the Dissemination Area level, population concentration and exposure for characteristics of interest are analysed using threshold tables and concentration curves. Examples are presented for the Aboriginal population and for income gradients.The patterns of concentration of First Nations people, Métis, and Inuit differ from those of non-Aboriginal people and between urban and rural areas. The spatial patterns of concentration and exposure by income gradients also differ.The Geozones method is a relatively easy way of identifying areas with lower and higher concentrations of subgroups. Because it is ecological-based, Geozones has the inherent strengths and weaknesses of this approach.

Surgical site infection remains a concern in orthopedic surgery, and contamination of C-arm covers is a potentially modifiable risk factor.A single-cohort study was conducted using 30 consecutive patients undergoing operative fracture fixation. Cultures were obtained from the C-arm cover after initial draping and every 20 min thereafter. The total number of persons in the operating room (person-hours/h of study time) and the number of door openings were recorded. The C-arm position changes and the time to contamination were monitored.The median time from the start of the operation to contamination was 20 min. There was a 17% contamination rate on initial draping, 50% at 20 min, 57% at 40 min, and 80% by 80 min. The C-arms in five cases were not contaminated during the surgery. Time to contamination correlated significantly with lateral position changes (correlation [r]=0.64; p=0.003) but was not related to C-arm position changes (r=0.22; p=0.34), number of door openings (r=0.20; p=0.39), or person-hours/h (r=0.04; p=0.85).Contamination of the C-arm drape occurs often and early during surgery for orthopedic fractures. We recommend minimal contact with the C-arm to avoid contamination of the surgical field.

We conducted a study to compare 3 methods of measuring knee range of motion: visual estimation by physicians, hand goniometry by physical therapists, and radiographic goniometry. We hypothesized that reliability would be high within and across all techniques. We found intrarater and interrater reliability to be satisfactory for visual estimation, hand goniometry, and radiographic goniometry. Interrater reliability across methods did not agree satisfactorily. Between-methods differences in estimating knee range of motion may result from variations in technique among physicians and physical therapists.

A rapidly expanding number of organizations have begun to use high‐performance, completely digital networks, like the Internet, to coordinate activities and to develop products and services that serve very wide geographic areas. Now, primarily as a result of the Clinton Administration′s National Information Infrastructure initiative, the entire nation has begun to buzz with talk of the whys, wherefores, and how‐tos of making this way to doing business the rule rather than the exception of twenty‐first‐century life and enterprise. This paper surveys the politics and economics of the contemporary networking scene, and presents four general stratgies for making progress in the current climate of great change and uncertainty.

HIV-1 circulates within an infected host as a genetically heterogeneous viral population. Viral intrahost diversity is shaped by substitutional evolution and recombination. Although many studies have speculated that recombination could have a significant impact on viral phenotype, this has never been definitively demonstrated. We report here phylogenetic and subsequent phenotypic analyses of envelope genes obtained from HIV-1 populations present in different anatomical compartments. Assessment of env compartmentalization from immunologically discrete tissues was assessed utilizing a single genome amplification approach, minimizing in vitro -generated artifacts. Genetic compartmentalization of variants was frequently observed. In addition, multiple incidences of intercompartment recombination, presumably facilitated by low-level migration of virus or infected cells between different anatomic sites and coinfection of susceptible cells by genetically divergent strains, were identified. These analyses demonstrate that intercompartment recombination is a fundamental evolutionary mechanism that helps to shape HIV-1 env intrahost diversity in natural infection. Analysis of the phenotypic consequences of these recombination events showed that genetic compartmentalization often correlates with phenotypic compartmentalization and that intercompartment recombination results in phenotype modulation. This represents definitive proof that recombination can generate novel combinations of phenotypic traits which differ subtly from those of parental strains, an important phenomenon that may have an impact on antiviral therapy and contribute to HIV-1 persistence in vivo .

Interdigital neuralgia affects a significant number of individuals, with an average age of presentation in the sixth decade and a 4- to 15-fold increased prevalence in women. Historical descriptions date back to the 19th century. Nonoperative treatment with shoe modifications, metatarsal pads, and injections provides relief for most, but long term, 60% to 70% of patients eventually elect to have surgery. Although excision can be performed through a dorsal or plantar approach, we prefer the dorsal incision to prevent scar formation on the plantar aspect of the foot. Satisfactory results are common but not certain with reports of excellent or good ranging from 51% to 93%.

Recurrent or persistent symptoms following surgical neurectomy for an interdigital neuroma are quite common, because of incorrect initial diagnosis, true neuroma formation, nerve stump adhesions, accessory nerve branches, or an adjacent web space neuroma. The clinical presentation of a recurrent neuroma is similar to the initial presentation. Recurrent symptoms usually occur within the first 12 months after surgery. The physical examination coupled with diagnostic nerve blocks is critical for diagnosis. Conservative therapy, although not particularly effective in treating true recurrent neuromas, may help to alleviate pain. With proper isolation of the instigating neuroma, revision surgical excision can be effective.

Objective To describe community-driven alcohol policy for 78, primarily First Nations, Metis and Inuit, communities in Canada's three northern territories (Yukon, Northwest Territories and Nunavut) between 1970 and 2008. This is a first step to understanding the policy-oriented prevention system that has evolved in these areas over time. Methods Regulatory data were compiled from Part II of the Territorial Gazette Indices and the Revised Statutes and Regulations of each territory. Regulations were categorized as open, restricted, prohibited or other. Results The number of communities with some form of regulation has increased steadily over time with half of the sample communities adopting some form of regulation between 1970 and 2008. The use of prohibition as a policy choice peaked in 1980 but has remained relatively steady since that time. There has been a steady increase in the adoption of other kinds of restrictions. Communities with regulations tend to have smaller and younger populations, a greater percentage of people with First Nations, Metis or Inuit origin and are more geographically isolated than those with no regulation. Conclusions This is the first time alcohol control policies have been compiled and described for the Canadian north. The dataset records the collective energies being put into community problem solving and provides a means to interpret the prevalence of health and social problems linked to alcohol use in these communities over time.

Identification of immunogens capable of eliciting broadly neutralizing antibody (NAb) responses against HIV-1 is a major goal toward the development of an AIDS vaccine. Despite significant progress in understanding the structural features of the HIV-1 envelope glycoprotein (Env) and the discovery of multiple broadly neutralizing monoclonal antibodies with defined antigenic structures, the design of optimal Env immunogens to elicit broad NAbs remains a major challenge. As the structural determinants of Env immunogenicity remain unclear, we assessed two closely related Env antigens isolated from the same HIV-1-infected patient with different phenotypic features to identify what may result in a favorable immunogenic profile. One Env, B33, isolated from brain, was highly macrophage tropic with a high CD4 affinity, while the other, LN40, isolated from the lymph nodes, was poorly macrophage tropic with a low CD4 affinity. Using a DNA prime-protein boost approach, rabbits primed with LN40 Env antigen had a NAb response against heterologous primary isolates, while B33 Env antigens were capable of eliciting NAbs against only homologous and sensitive viral isolates. Further analysis revealed that the specificity of NAbs elicited by the LN40 antigen mapped to limited residues within or flanking the CD4 binding site. Certain key structural determinants were identified that could differentiate primary Env immunogens based on their potential to elicit broader NAbs. This progress will facilitate the rational design of effective HIV-1 vaccine formulations with optimal Env antigens.

Ebselen is a seleno-organic anti-inflammatory compound with glutathione peroxidase-like activity that has the unique characteristic of mediating the isomerization of 5-HETE and LTB4 to their biologically inactive trans isomers, both directly in fluid phase and indirectly through metabolic pathways in stimulated peripheral blood leukocytes. LTB4 is an inflammatory mediator with potent chemotactic activity for neutrophilic leukocytes. We studied the effects of ebselen on the chemotactic and chemokinetic responses with human-blood-derived neutrophils. With the use of 120-microns-thick 5-microns-pore durapore filters and low BSA concentrations (0.05%) in the chemotaxis buffers, ebselen was evaluated for its effect on both chemotactic and chemokinetic responses to LTB4, C5a, and fMLP. Ebselen at 3-20 microM concentrations inhibited both chemotactic and chemokinetic responses to optimal concentrations of LTB4 without altering chemotactic responses to C5a or fMLP. Likewise, ebselen at 20 microM specifically inhibited LTB4-stimulated transendothelial migration of neutrophils, while not altering responses to C5a nor fMLP.

The CD4 binding site (CD4bs) on the HIV-1 envelope plays a major role in determining the capacity of R5 viruses to infect primary macrophages. Thus, envelope determinants within or proximal to the CD4bs have been shown to control the use of low CD4 levels on macrophages for infection. These residues affect the affinity for CD4 either directly or indirectly by altering the exposure of CD4 contact residues. Here, we describe a single amino acid determinant in the V1 loop that also modulates macrophage tropism. Thus, we identified an E153G substitution that conferred high levels of macrophage infectivity for several heterologous R5 envelopes, while the reciprocal G153E substitution abrogated infection. Shifts in macrophage tropism were associated with dramatic shifts in sensitivity to the V3 loop monoclonal antibody (MAb), 447-52D and soluble CD4, as well as more modest changes in sensitivity to the CD4bs MAb, b12. These observations are consistent with an altered conformation or exposure of the V3 loop that enables the envelope to use low CD4 levels for infection. The modest shifts in b12 sensitivity suggest that residue 153 impacts on the exposure of the CD4bs. However, the more intense shifts in sCD4 sensitivity suggest additional mechanisms that likely include an increased ability of the envelope to undergo conformational changes following binding to suboptimal levels of cell surface CD4. In summary, we show that a conserved determinant in the V1 loop modulates the V3 loop to prime low CD4 use and macrophage infection.

HIV-1 R5 viruses predominantly use CCR5 as a coreceptor to infect CD4+T cells and macrophages. While R5 viruses generally infect CD4+T cells, research over the past few years has demonstrated that they vary extensively in their capacity to infect macrophages. Thus, R5 variants that are highly macrophage tropic have been detected in late disease and are prominent in brain tissue of subjects with neurological complications. Other R5 variants that are less sensitive to CCR5 antagonists and use CCR5 differently have also been identified in late disease. These latter variants have faster replication kinetics and may contribute to CD4 T-cell depletion. In addition, R5 viruses are highly variable in many other properties, including sensitivity to neutralizing antibodies and inhibitors that block HIV-1 entry into cells. Here, we review what is currently known about how HIV-1 R5 viruses vary in cell tropism and other properties, and discuss the implications of this variation on transmission, pathogenesis, therapy and vaccines.

Objectives. The objective of this article is to measure the contributions of age groups and causes of death to differences in mortality and life expectancy between residents of Inuit Nunangat and the rest of Canada. Study design. The geographic area of coverage includes communities within Inuit Nunangat, with the addition of Inuvik in the Northwest Territories. Deaths were compiled for 2 5-year periods, 1994 through 1998 and 1999 through 2003, with the mid-year centred on the 1996 and 2001 censuses. Methods. Abridged life tables were constructed according to the revised Chiang method. Age decomposition of differences in life expectancy and cause-deleted life tables were calculated using a discrete approach. The age groups and causes contributing to differences in life expectancy between Inuit Nunangat and the rest of Canada were calculated. Results. Specific age groups contribute more to the difference in life expectancy between Inuit Nunangat and the rest of Canada. For males, over 50% of the difference in life expectancy is due to excess mortality before 25 years of age, while for females nearly 65% is due to excess mortality after the age of 60. Conclusions. Cancer is a major contributor to the difference in life expectancy between residents of Inuit Nunangat and the rest of Canada; reduction in cancer rates would make the greatest contribution to gains in life expectancy. There are clear gender differences in life expectancy and mortality, with the total effect of mortality being greatest for males between 15 and 25 years of age and for females over the age of 60. (Int J Circumpolar Health 2010; 69(1):38-49) Keywords: Inuit, Canada, life expectancy, mortality, Inuit Nunangat

We reviewed two similar groups of patients with medial osteoarthritis of the knee treated by unicompartmental arthroplasty. The group receiving an Oxford meniscal-bearing implant, with no medial release, showed significantly better mechanical alignment than that receiving a fixed-bearing implant. Under-correction, with its ominous mechanical implications, was much more common with the fixed-bearing design. Over-correction was rare and was seen in both designs about equally. Degenerative stenosis of the intercondylar notch was common and appeared to put the anterior cruciate ligament at risk of rupture, especially after correction of the varus deformity. We consider that postoperative leg alignment and soft-tissue balance after unicompartmental knee replacement are determined more by the implant design and the surgical technique than by any variation in soft-tissue contracture. Release of the medial collateral ligament is not necessary for realignment, but a generous notchplasty is often needed to allow normal anterior cruciate ligament function.

We investigated paternal effects on seedling performance in relation to patterns of fruit abortion in Campsis radicans using a series of 14 experiments with various combinations of pollen donors and recipients. In eight experiments significant paternal effects on three or four dependent performance variables were detected by multivariate ANCOVA. These effects were independent of seed weight, which was controlled in the experimental design and in the statistical analysis. In six of the eight experiments with significant results the favored pollen recipient sired the more vigorous offspring. In general, therefore, patterns of fruit abortion with respect to outcross donor enhance progeny fitness. Maternal discrimination is reduced, however, when pollen from several outcross donors is deposited on the same stigma, a likely occurrence in nature. Discriminntion among pollen from different outcross donors is also less important than the ability to discriminate between self- and cross-pollen because the latter di...

The author notes: ��although a scientist may understand a science to the extent that he or she does science, a second level of understanding, that of understanding his or her understanding, may be absent.� Philosophy of science is about that second level of understanding. That philosophy forms the basis of how and why a scientist conducts research, and conditions the judgments a scientist forms about the value and validity of the results of that research. Peters also addresses implications for library and information science

It is frequently argued that social inequality and residential segregation are directly associated. Given that social inequality has increased in recent times or has stabilized at high levels while residential segregation has remained high, there is a factual basis for making such an association. Underlying this association is an assumption about the symmetry between social differences and spatial forms. The theoretical and epistemological correlation of this assumption is that society reflects itself in space: an unequal society is reflected in segregated cities. Therefore, society can be understood without any reference to its spatial dimensions. At its extreme, this perspective holds that society would have no relation to space, which is absurd. A similar perspective is found in the new field of “global cities” research where researchers focus their attention on the spatial “effects” of economic globalization. In particular, the post-Fordist economy seems to exist ex ante its effects on the city and the space.

Latin American megacities have developed within a specific set of cultural, social, and economic conditions that continue to exert tremendous influence over the daily lives of individuals and families within them (Gilbert, 1996). The combination of inequitable economic opportunities, unequal social divisions, formal and informal urban development patterns, and weak land-use planning create divergent and highly localized patterns of spatial segregation within the major cities of Latin American (Sabatini, 2003). Other physical geographic influences (such as abrupt mountain features and coastal boundaries) also exert considerable influence on the shape of the urban environment in Latin America, with many of the poorest neighborhoods located in environmentally degraded and marginal areas. As a result of these and other urban development factors, large divisions between the elite and poorer classes have emerged in Latin American megacities.

Because of their favorable effects on renal hemodynamics, calcium antagonists may have a major role in the prevention and management of certain types of acute renal dysfunction. In fact, verapamil (VP) was shown to prevent cyclosporin A (CsA)-induced decreases in RBF in mice and in cadaver renal transplant (CRT) recipients. The study presented here of 59 cadaver renal transplant patients evaluates the outcome from perioperative treatment with VP (N = 30) administered intraoperatively into the renal artery (10 mg) followed by oral administration of 120 mg every 8 to 12 h for 14 days versus no drug (N = 29). Early immunosuppression included azathioprine, corticosteroids, and antilymphocyte globulin with subsequent overlapping with CsA on days 5 and 6. Actuarial graft survival at 1 yr was different when the two groups were compared (P less than 0.05). Estimated graft survival at 1 yr for VP patients was 93.3 compared with 72.4% in control patients. The improved graft survival was most striking in repeat transplants with 90% graft survival at 1 yr for VP recipients versus 37.5% for controls. Compared with controls, VP recipients had significantly improved renal parenchymal diastolic blood flow velocities on the first day after surgery (7.8 versus 5.8 cm/s). By day 7, GFR were greater with VP (44 +/- 29 mL/min) versus controls (28 +/- 22 mL/min). Of VP patients, 67% (18 of 24) had GFR greater than 30 mL/min versus 33% (9 of 26) for control patients. Similarly, on the seventh day, 77% (21 of 30) of VP patients had serum creatinines less than 2.0 mg% versus 34% (10 of 29) for controls.(ABSTRACT TRUNCATED AT 250 WORDS)

The records of 280 patients who underwent pelvic lymphadenectomy and radical cystectomy for transitional cell carcinoma of the bladder between 1971 and 1986 were reviewed. A total of 42 patients had either 1 (stage pN1) or more than 1 (stage pN2) positive lymph nodes (20 and 22 patients, respectively). The over-all 3-year survival rate for patients with positive lymph nodes was 27%, and it was 30 and 18.5% for stages pN1 and pN2 disease, respectively. Kaplan-Meier survival curves revealed a sustained survival advantage for stage pN1 over pN2 disease for the first 3 years (p less than 0.05) but the difference was not significant at 5 years of followup. Eleven patients with negative lymph nodes but local extension of tumor into the prostatic stroma and/or ducts had a 5-year survival rate of 36%, which equaled the survival of 49 stage pT3b,pN0 cancer patients in the same series. Surgical mortality for the entire population of 280 patients was 2.1% and there was no increase in mortality or morbidity among the node positive patients. Based on the findings of improved survival of stages pN1 and pT3b,N0 cancer patients compared to stage pN2 cancer patients, the tumor, nodes and metastasis classification offers more specific prognostic information than does a single designation of Jewett stage D disease.

The human monoclonal antibody b12 recognizes a conserved epitope on gp120 that overlaps the CD4 binding site. b12 has neutralizing activity against diverse human immunodeficiency virus type 1 (HIV-1) strains. However, we recently reported that b12 sensitivity of HIV-1 envelopes amplified from patient tissues without culture varied considerably. For two subjects, there was clear modulation of b12 sensitivity, with lymph node-derived envelopes being essentially resistant while those from brain tissue were sensitive. Here, we have mapped envelope determinants of b12 resistance by constructing chimeric envelopes from resistant and sensitive envelopes derived from lymph node and brain tissue, respectively. Residues on the N-terminal flank of the CD4 binding loop conferred partial resistance. However, a potential glycosylation site at residue N386 completely modulated b12 resistance but required the presence of an arginine at residue 373. Moreover, the introduction of R373 into b12-sensitive NL4.3 and AD8 envelopes, which carry N386, also conferred b12 resistance. Molecular modeling suggests that R373 and the glycan at N386 may combine to sterically exclude the benzene ring of b12 W100 from entering a proximal pocket. In summary, we identify residues on either side of the CD4 binding loop that contribute to b12 resistance in immune tissue in vivo. Our data have relevance for the design of vaccines that aim to elicit neutralizing antibodies.

Human immunodeficiency virus type 1 (HIV-1) R5 isolates that predominantly use CCR5 as a coreceptor are frequently described as macrophage tropic. Here, we compare macrophage tropism conferred by HIV-1 R5 envelopes that were derived directly by PCR from patient tissue. This approach avoids potentially selective culture protocols used in virus isolation. Envelopes were amplified (i) from blood and semen of adult patients and (ii) from plasma of pediatric patients. The phenotypes of these envelopes were compared to those conferred by an extended panel of envelopes derived from brain and lymph node that we reported previously. Our results show that R5 envelopes vary by up to 1,000-fold in their capacity to confer infection of primary macrophages. Highly macrophage-tropic envelopes were predominate in brain but were infrequent in semen, blood, and lymph node samples. We also confirmed that the presence of N283 in the C2 CD4 binding site of gp120 is associated with HIV-1 envelopes from the brain but absent from macrophage-tropic envelopes amplified from blood and semen. Finally, we compared infection of macrophages, CD4+T cells, and peripheral blood mononuclear cells (PBMCs) conferred by macrophage-tropic and non-macrophage-tropic envelopes in the context of full-length replication competent viral clones. Non-macrophage-tropic envelopes conferred low-level infection of macrophages yet infected CD4+T cells and PBMCs as efficiently as highly macrophage-tropic brain envelopes. The lack of macrophage tropism for the majority of the envelopes amplified from lymph node, blood, and semen is striking and contrasts with the current consensus that R5 primary isolates are generally macrophage tropic. The extensive variation in R5 tropism reported here is likely to have an important impact on pathogenesis and on the capacity of HIV-1 to transmit.

The complex nature of urban space within Latin America’s major cities limits the applicability of many empirical measures of segregation. However, the development of integrated spatial measures allows for the measurement of highly localised patterns of segregation between multiple groups across multiple dimensions. This paper presents a methodology for integrating spatial analysis and GIS tools as an explicit part of investigating the nature and patterns urban segregation. Using Lima, Peru and an example, the related processes of segregation and fragmentation are unpacked across multiple social dimensions and spatial scales. Additionally, this paper empirically tests the theoretical proposition that social groups in Latin America are becoming increasingly fragmented rather than segregated.

This paper develops a methodology for integrating Remote Sensing and GIS techniques to identify low income informal homestead subdivisions (AKA colonias) in peri-urban areas of US metropolitan areas. Unlike their self-build counterparts in Latin American cities, housing production is self-managed (trailers and manufactured homes), situated on poorly or un-serviced lots. Now that we have begun to understand the logic and rationale underpinning their existence, and know where (spatially), and what (physical) “footprints”, to look for, this paper will present data for central Texas in order to report on the methodology adopted to identify and quantify these peri-urban settlement phenomena

Complete envelope genes were amplified from autopsy brain tissue of five individuals who had died of AIDS and had neurological complications. Lymph node samples were included for two of the patients. Nineteen different envelope clones from the five patients had distinct V1V2 sequences. Thirteen of the envelopes were functional and conferred fusigenicity and infectivity for CD4+CCR5+cells. Infectivity and cell-cell fusion assays showed that most envelopes used both CCR5 and CCR3. One brain-derived envelope used a broad range of coreceptors, while three other brain envelopes from one individual were restricted to CCR5. However, there was no correlation between tissue of origin and coreceptor use. Envelopes showed two very distinct phenotypes depending on their capacity to infect macrophages and to exploit low levels of CD4 and/or CCR5 for infection. Envelopes that were highly fusigenic and tropic for macrophages were identified in brain tissue from four of the five patients. The enhanced macrophage tropism correlated with reduced sensitivity to inhibition by Q4120, a CD4-specific antibody, but not with sensitivity to the CCR5 inhibitor, TAK779. The highly macrophage-tropic envelopes were able to infect cells expressing low levels of CD4 and/or CCR5. Comparison with several well-characterized macrophage-tropic envelopes showed that the four identified patient envelopes were at the top limit of macrophage tropism. In contrast, all four lymph node-derived envelopes exhibited a non-macrophage-tropic phenotype and required high levels of CD4 for infection. Our data support the presence of envelopes that are highly fusigenic and tropic for macrophages in the brains of patients with neurological complications. These envelopes are able to infect cells that express low levels of CD4 and/or CCR5 and may have adapted for replication in brain macrophages and microglia, which are known to express limited amounts of CD4.