Measuring the 3-30-300 rule to help cities meet nature access thresholds.

The 3-30-300 rule offers benchmarks for cities to promote equitable nature access. It dictates that individuals should see three trees from their dwelling, have 30 % tree canopy in their neighborhood, and live within 300 m of a high-quality green space. Implementing this demands thorough measurement, monitoring, and evaluation methods, yet little guidance is currently available to pursue these actions. To overcome this gap, we employed an expert-based consensus approach to review the available ways to measure 3-30-300 as well as each measure's strengths and weaknesses. We described seven relevant data and processes: vegetation indices, street level analyses, tree inventories, questionnaires, window view analyses, land cover maps, and green space maps. Based on the reviewed strengths and weaknesses of each measure, we presented a suitability matrix to link recommended measures with each component of the rule. These recommendations included surveys and window-view analyses for the '3 component', high-resolution land cover maps for the '30 component', and green space maps with network analyses for the '300 component'. These methods, responsive to local situations and resources, not only implement the 3-30-300 rule but foster broader dialogue on local desires and requirements. Consequently, these techniques can guide strategic investments in urban greening for health, equity, biodiversity, and climate adaptation.

90-day nose-only inhalation toxicity study of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in Sprague-Dawley rats.

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is one of the key tobacco-specific nitrosamines that plays an important role in human lung carcinogenesis. Repeated dose inhalation toxicity data on NNK, particularly relevant to cigarette smoking, however, is surprisingly limited. Hence, there is a lack of direct information available on the carcinogenic and potential non-carcinogenic effects of NNK via inhalational route exposure. In the present study, the subchronic inhalation toxicity of NNK was evaluated in Sprague Dawley rats. Both sexes (9-10 weeks age; 23 rats/sex/group) were exposed by nose-only inhalation to air, vehicle control (75% propylene glycol), or 0.2, 0.8, 3.2, or 7.8 mg/kg body weight (BW)/day of NNK (NNK aerosol concentrations: 0, 0, 0.0066, 0.026, 0.11, or 0.26 mg/L air) for 1 h/day for 90 consecutive days. Toxicity was evaluated by assessing body weights; food consumption; clinical pathology; histopathology; organ weights; blood, urine, and tissue levels of NNK, its major metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), and their glucuronides (reported as total NNK, tNNK, and total NNAL, tNNAL, respectively); tissue levels of the DNA adduct O6-methylguanine; blood and bone marrow micronucleus (MN) frequency; and bone marrow DNA strand breaks (comet assay). The results showed that NNK exposure caused multiple significant adverse effects, with the most sensitive endpoint being non-neoplastic lesions in the nose. Although the genotoxic biomarker O6-methylguanine was detected, genotoxicity from NNK exposure was negative in the MN and comet assays. The Lowest-Observed-Adverse-Effect-Level (LOAEL) was 0.8 mg/kg BW/day or 0.026 mg/L air of NNK for 1 h/day for both sexes. The No-Observed-Adverse-Effect-Level (NOAEL) was 0.2 mg/kg BW/day or 0.0066 mg/L air of NNK for 1 h/day for both sexes. The results of this study provide new information relevant to assessing the human exposure hazard of NNK.

Surveillance of RNase P, PMMoV, and CrAssphage in wastewater as indicators of human fecal concentration across urban sewer neighborhoods, Kentucky.

Wastewater surveillance has been widely used as a supplemental method to track the community infection levels of severe acute respiratory syndrome coronavirus 2. A gap exists in standardized reporting for fecal indicator concentrations, which can be used to calibrate the primary outcome concentrations from wastewater monitoring for use in epidemiological models. To address this, measurements of fecal indicator concentration among wastewater samples collected from sewers and treatment centers in four counties of Kentucky (N = 650) were examined. Results from the untransformed wastewater data over 4 months of sampling indicated that the fecal indicator concentration of human ribonuclease P (RNase P) ranged from 5.1 × 101 to 1.15 × 106 copies/ml, pepper mild mottle virus (PMMoV) ranged from 7.23 × 103 to 3.53 × 107 copies/ml, and cross-assembly phage (CrAssphage) ranged from 9.69 × 103 to 1.85 × 108 copies/ml. The results showed both regional and temporal variability. If fecal indicators are used as normalization factors, knowing the daily sewer system flow of the sample location may matter more than rainfall. RNase P, while it may be suitable as an internal amplification and sample adequacy control, has less utility than PMMoV and CrAssphage as a fecal indicator in wastewater samples when working at different sizes of catchment area. The choice of fecal indicator will impact the results of surveillance studies using this indicator to represent fecal load. Our results contribute broadly to an applicable standard normalization factor and assist in interpreting wastewater data in epidemiological modeling and monitoring.

Wastewater Sample Site Selection to Estimate Geographically Resolved Community Prevalence of COVID-19: A Sampling Protocol Perspective.

Wastewater monitoring for virus infections within communities can complement conventional clinical surveillance. Currently, most SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) clinical testing is voluntary and inconsistently available, except for a few occupational and educational settings, and therefore likely underrepresents actual population prevalence. Randomized testing on a regular basis to estimate accurate population-level infection rates is prohibitively costly and is hampered by a range of limitations and barriers associated with participation in clinical research. In comparison, community-level fecal monitoring can be performed through wastewater surveillance to effectively surveil communities. However, epidemiologically defined protocols for wastewater sample site selection are lacking. Herein, we describe methods for developing a geographically resolved population-level wastewater sampling approach in Jefferson County, Kentucky, and present preliminary results. Utilizing this site selection protocol, samples (n = 237) were collected from 17 wastewater catchment areas, September 8 to October 30, 2020 from one to four times per week in each area and compared to concurrent clinical data aggregated to wastewater catchment areas and county level. SARS-CoV-2 RNA was consistently present in wastewater during the studied period, and varied by area. Data obtained using the site selection protocol showed variation in geographically resolved wastewater SARS-CoV-2 RNA concentration compared to clinical rates. These findings highlight the importance of neighborhood-equivalent spatial scales and provide a promising approach for viral epidemic surveillance, thus better guiding spatially targeted public health mitigation strategies.

14-Day Nose-Only Inhalation Toxicity and Haber's Rule Study of NNK in Sprague-Dawley Rats.

4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is one of the key tobacco-specific nitrosamines that plays an important role in human lung carcinogenesis. However, repeated inhalation toxicity data on NNK, which is more directly relevant to cigarette smoking, are currently limited. In the present study, the subacute inhalation toxicity of NNK was evaluated in Sprague Dawley rats. Both sexes (9-10 weeks age; 16 rats/sex/group) were exposed by nose-only inhalation to air, vehicle control (75% propylene glycol), or 0.8, 3.2, 12.5, or 50 mg/kg body weight (BW)/day of NNK (NNK aerosol concentrations: 0, 0, 0.03, 0.11, 0.41, or 1.65 mg/L air) for 1 h/day for 14 consecutive days. Toxicity was evaluated by assessing body and organ weights; food consumption; clinical pathology; histopathology observations; blood, urine, and tissue levels of NNK, its major metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), and their glucuronides (reported as total NNK, tNNK, and total NNAL, tNNAL, respectively); O6-methylguanine DNA adduct formation; and blood and bone marrow micronucleus frequency. Whether the subacute inhalation toxicity of NNK followed Haber's Rule was also determined using additional animals exposed 4 h/day. The results showed that NNK exposure caused multiple significant adverse effects, with the most sensitive endpoint being non-neoplastic histopathological lesions in the nose. The lowest-observed-adverse-effect level (LOAEL) was 0.8 mg/kg BW/day or 0.03 mg/L air for 1 h/day for both sexes. An assessment of Haber's Rule indicated that 14-day inhalation exposure to the same dose at a lower concentration of NNK aerosol for a longer time (4 h daily) resulted in greater adverse effects than exposure to a higher concentration of NNK aerosol for a shorter time (1 h daily).

Toxicokinetic and Genotoxicity Study of NNK in Male Sprague Dawley Rats Following Nose-Only Inhalation Exposure, Intraperitoneal Injection, and Oral Gavage.

The tobacco-specific nitrosamine NNK [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone] is found in tobacco products and tobacco smoke. NNK is a potent genotoxin and human lung carcinogen; however, there are limited inhalation data for the toxicokinetics (TK) and genotoxicity of NNK in vivo. In the present study, a single dose of 5 × 10-5, 5 × 10-3, 0.1, or 50 mg/kg body weight (BW) of NNK, 75% propylene glycol (vehicle control), or air (sham control) was administered to male Sprague-Dawley (SD) rats (9-10 weeks age) via nose-only inhalation (INH) exposure for 1 h. For comparison, the same doses of NNK were administered to male SD rats via intraperitoneal injection (IP) and oral gavage (PO). Plasma, urine, and tissue specimens were collected at designated time points and analyzed for levels of NNK and its major metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and tissue levels of DNA adduct O6-methylguanine by LC/MS/MS. TK data analysis was performed using a non-linear regression program. For the genotoxicity subgroup, tissues were collected at 3 h post-dosing for comet assay analysis. Overall, the TK data indicated that NNK was rapidly absorbed and metabolized extensively to NNAL after NNK administration via the three routes. The IP route had the greatest systemic exposure to NNK. NNK metabolism to NNAL appeared to be more efficient via INH than IP or PO. NNK induced significant increases in DNA damage in multiple tissues via the three routes. The results of this study provide new information and understanding of the TK and genotoxicity of NNK.

A rapid assessment of wastewater for genomic surveillance of SARS-CoV-2 variants at sewershed scale in Louisville, KY.

In this communication, we report on the genomic surveillance of SARS-CoV-2 using wastewater samples in Jefferson County, KY. In February 2021, we analyzed seven wastewater samples for SARS-CoV-2 genomic surveillance. Variants observed in smaller catchment areas, such as neighborhood manhole locations, were not necessarily consistent when compared to associated variant results in downstream treatment plants, suggesting catchment size or population could impact the ability to detect diversity.

Nonanimal toxicology testing approaches for traditional and deemed tobacco products in a complex regulatory environment: Limitations, possibilities, and future directions.

The evaluation of tobacco products is complex due to a multitude of factors including product diversity, limited testing standards, and variability in user behavior. Alternative approaches in current testing paradigms have limitations that generally truncate their applicability beyond screening for hazard identification; this is also true for toxicological evaluations of tobacco products. In a regulatory context, results from tobacco product toxicity assessments are extrapolated to the in vivo condition to assess human health relevance at the individual and population level. A key limitation of alternative approaches is the difficulty and uncertainty in extrapolating results to adverse outcomes relevant to chronic tobacco exposures in humans. This difficulty and uncertainty are increased when comparing toxicological outcomes between tobacco products. Given that the interpretation and quantification of differences in assay results (e.g., mutagenicity) for tobacco product comparison may be inconclusive, the predictive value of these approaches for human risk of relevant downstream pathologies (e.g., carcinogenesis) can be limited. Development and validation of fit-for-purpose alternative approaches that are predictive of human toxicity and dose response assays with adequate sensitivity and specificity for product comparisons would help advance the field of predictive toxicology.

Proposed Mode of Action for Acrolein Respiratory Toxicity Associated with Inhaled Tobacco Smoke.

This article presents a mode of action (MOA) analysis that identifies key mechanisms in the respiratory toxicity of inhaled acrolein and proposes key acrolein-related toxic events resulting from the inhalation of tobacco smoke. Smoking causes chronic obstructive pulmonary disorder (COPD) and acrolein has been previously linked to the majority of smoking-induced noncancer respiratory toxicity. In contrast to previous MOA analyses for acrolein, this MOA focuses on the toxicity of acrolein in the lower respiratory system, reflecting the exposure that smokers experience upon tobacco smoke inhalation. The key mechanisms of acrolein toxicity identified in this proposed MOA include (1) acrolein chemical reactivity with proteins and other macromolecules of cells lining the respiratory tract, (2) cellular oxidative stress, including compromise of the important anti-oxidant glutathione, (3) chronic inflammation, (4) necrotic cell death leading to a feedback loop where necrosis-induced inflammation leads to more necrosis and oxidative damage and vice versa, (5) tissue remodeling and destruction, and (6) loss of lung elasticity and enlarged lung airspaces. From these mechanisms, the proposed MOA analysis identifies the key cellular processes in acrolein respiratory toxicity that consistently occur with the development of COPD: inflammation and necrosis in the middle and lower regions of the respiratory tract. Moreover, the acrolein exposures that occur as a result of smoking are well above exposures that induce both inflammation and necrosis in laboratory animals, highlighting the importance of the role of acrolein in smoking-related respiratory disease.

Application of multivariate statistical procedures to identify transcription factors that correlate with MRP2, 3, and 4 mRNA in adult human livers.

Multidrug resistance-associated proteins 2-4 (MRP2-4) are membrane efflux transporters critical for the hepatic clearance of pharmaceuticals and endogenous chemicals. Little is known about the constitutive regulation of MRP2-4 mRNA in normal human liver. The purpose of this study was to identify transcription factors whose expression significantly correlates with MRP2-4 mRNA in human liver specimens. Ninety adult human livers were profiled for mRNA expression of MRP2-4 as well as aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), pregnane X receptor (PXR), peroxisome proliferator-activated receptor alpha (PPAR alpha) and gamma (gamma), liver X receptor alpha (LXR alpha), farnesoid X receptor (FXR), glucocorticoid receptor (GR), retinoid X receptor alpha (RXR alpha), hepatocyte nuclear factor 1 alpha (HNF1 alpha) and 4 alpha (4 alpha), and nuclear factor E2-related factor 2 (Nrf2) transcription factors. Using linear regression and stepwise selection of partial R(2)-values, CAR, HNF1 alpha, and PPAR alpha mRNA exhibited the greatest correlation with MRP2, 3, and 4, respectively. Interindividual variation in the expression of the identified transcription factors may account for the variability in constitutive mRNA levels of MRP2-4. The multivariate approach presented in this study should aid in predicting signalling pathways that participate either directly or indirectly in regulating hepatic drug disposition.

Pharmacokinetic parameters and mechanisms of inhibition of rat type 1 and 2 steroid 5alpha-reductases: determinants for different in vivo activities of GI198745 and finasteride in the rat.

The interaction of baculovirus expressed rat steroid 5alpha-reductase types 1 and 2 (r5AR1 and r5AR2) with 17beta-N-(2,5-bis(trifluoromethyl)phenyl)carbamoyl-4-aza-5alpha-androst-1-en-3-one (GI198745) was investigated at pH 7 and 37 degrees. This 5alpha-reductase inhibitor was found previously to be a time-dependent inhibitor of the two human 5alpha-reductase isozymes. In contrast, we demonstrate in the present study that although GI198745 is a potent time-dependent inhibitor of r5AR2, it is a classical rapid-equilibrium inhibitor of r5AR1. This type of behavior with human and rat 5alpha-reductases has been shown for the inhibitor 17beta-(N-tert-butylcarbamoyl)-4-aza-5alpha-androst-1-en-3-one (finasteride), a current therapy for benign prostatic hyperplasia. Inhibition of r5AR1 by GI198745 was competitive with testosterone and followed Michaelis-Menten kinetics with a K(i) value of 0.3 +/- 0.02 nM. Data for the inhibition of r5AR2 by GI198745 were consistent with a two-step mechanism, where K(i) is the dissociation constant for an initial enzyme-inhibitor complex and k(3) is the rate constant for the second slow step. The pseudo-bimolecular rate constant (k(3)/K(i)) for the association of GI198745 with r5AR2 was (2.0 +/- 0.4) x 10(7) M(-1) sec(-1). The high affinity of this inhibitor for r5AR2 was further demonstrated by the inability of the enzyme-inhibitor complex to dissociate after approximately 7 days of dialysis at 4 degrees. Both GI198745 and finasteride appear to inactivate r5AR2 by apparent irreversible modification, but are classical, reversible inhibitors of r5AR1. Therefore, we hypothesize that because of its pharmacokinetic parameters and increased potency against r5AR1, GI198745 is more effective than finasteride in preventing the growth of the rat prostate.

Optimizing duplex follow-up in patients with an asymptomatic internal carotid artery stenosis of less than 60%.

OBJECTIVES: The Asymptomatic Carotid Atherosclerosis Study established benefit of carotid endarterectomy for 60% to 99% asymptomatic internal carotid artery (ICA) stenosis. Optimal follow-up intervals to detect progression from < 60% to 60%-99% ICA stenosis are unknown. In a previous study from our laboratory, we found that ICAs with < 60% stenosis and peak systolic velocities (PSVs) of 175 cm/s or more on initial duplex were at high risk for progression. Prospective evaluation of this hypothesis and determination of optimal duplex follow-up intervals for asymptomatic patients with < 60% ICA stenosis form the basis of this report. METHODS: All patients who underwent initial carotid duplex examination for any indication since January 1, 1995, with at least one patent, asymptomatic, previously nonoperated ICA with < 60% stenosis; with 6 months' or greater follow-up; and with one or more repeat duplex examinations were entered into the study. On the basis of the initial duplex examination, ICAs were classified into two groups: those with a PSV less than 175 cm/s and those with a PSV of 175 cm/s or more. Follow-up duplex examinations were performed at varying intervals to detect progression from < 60% to 60%-99% ICA stenosis with criteria previously reported (both PSV > or = 260 cm/s and end-diastolic velocity > or = 70 cm/s). RESULTS: A total of 407 patients (640 asymptomatic ICAs with < 60% stenosis) underwent serial duplex scans (mean follow-up, 22 months). Three ICAs (0.5%) became symptomatic and progressed to 60%-99% ICA stenosis at a mean of 21 months (all transient ischemic attacks), whereas four other ICAs occluded without stroke during follow-up. Progression to 60%-99% stenosis without symptoms was detected in 46 ICAs (7%) (mean, 18 months). Of the 633 patent asymptomatic arteries, 548 ICAs (87%) had initial PSVs less than 175 cm/s, and 85 ICAs (13%) had initial PSVs of 175 cm/s or more. Asymptomatic progression to 60%-99% ICA stenosis occurred in 22 (26%) of 85 ICAs with initial PSVs of 175 cm/s or more, whereas 24 (4%) of 548 ICAs with initial PSVs less than 175 cm/s progressed (P <.0001). The Kaplan-Meier method was used to determine freedom from progression at 6 months, 12 months, and 24 months, which was 95%, 83%, and 70% for ICAs with initial PSVs of 175 cm/s or more versus 100%, 99%, and 95%, respectively, for ICAs with initial PSVs less than 175 cm/s (P <.0001). CONCLUSIONS: Patients with < 60% ICA stenosis and PSVs of 175 cm/s or more on initial duplex examination are significantly more likely to progress asymptomatically to 60%-99% ICA stenosis, and progression is sufficiently frequent to warrant follow-up duplex studies at 6-month intervals. Patients with < 60% ICA stenosis and initial PSVs less than 175 cm/s may have follow-up duplex examinations safely deferred for 2 years.

The pharmacokinetics and pharmacodynamics of GW395058, a peptide agonist of the thrombopoietin receptor, in the dog, a large-animal model of chemotherapy-induced thrombocytopenia.

GW395058, a PEGylated peptide agonist of the thrombopoietin receptor, stimulates megakaryocytopoiesis and has previously been shown to increase platelet counts in vivo. The pharmacokinetics and pharmacodynamics of GW395058 were characterized using a randomized, crossover study in a large-animal model (dog) of chemotherapy-induced thrombocytopenia. Nine beagle dogs received i.v. carboplatin (350 mg/m(2)) on day 0 and day 28. GW395058 (1.31 mg/kg) (n = 6) or vehicle control (n = 3) was administered on day 1 and day 29 either as an i.v. bolus or s.c. injection. After i.v. administration, peak concentrations of GW395058 occurred rapidly, while the half-life averaged approximately 56 h. Bioavailability (+/- standard deviation) of GW395058 given s.c. was 78.2% (20.9%). GW395058 (i.v. and s.c.) ameliorated the platelet nadir (p = 0.0086) and resulted in a shorter time to recovery compared to the control group. The mean nadir platelet counts following carboplatin administration were 197,000 cells/microl (80,000) for the i.v. GW395058-dose group, 183,000 cells/microl (72,000) for the s.c.-dose group and 71,000 cells/microl (38,000) for the vehicle-alone group. GW395058 reduced the thrombocytopenic effects of carboplatin in dogs. No GW395058-related adverse side effects were observed.

Patency and characteristics of lower extremity vein grafts requiring multiple revisions.

OBJECTIVES: Multiple (> 1) revisions of lower extremity vein grafts may be required to maintain patency. Characteristics of recurrent lower extremity vein graft lesions and the patency achieved after multiple revisions have not been emphasized in reports on infrainguinal vein graft stenosis. This study was performed to determine (1) the patency of multiply revised lower extremity vein grafts and (2) the timing, location, and angiographic and duplex features of the recurrent lesions. METHODS: Lower extremity vein grafts that were followed in a duplex surveillance protocol and required revisions from January 1990 through December 1998 were identified. All revisions were preceded by angiography. In multiply revised lower extremity vein grafts, the immediate preoperative angiogram and duplex examination findings, as well as the angiogram made before the previous revision and the duplex study done after the previous revision, were reviewed to characterize recurrent lesions at the time of previous and current graft revision. The patencies of grafts undergoing single and multiple revisions were compared. RESULTS: A total of 233 lower extremity vein graft revisions were performed; of these, 50 (21%) were repeat revisions. Of grafts requiring more than one revision, 98% were normal on duplex examination after the initial revision. Five-year assisted primary patency of multiply revised grafts (91%) was not different from that of grafts with a single revision (89%; P not significant). Of 60 lesions repaired in the 50 repeat revisions, 29 (48%) were at the previously revised site, and 31 (52%) were at new sites. The time between revisions was less if the same site was revised (11 +/- 2 months) than if a different site required revision (20 +/- 4 months; P <.05). Arteriographic evidence of a minor (< 50% diameter) lesion was present at the time of the initial revision in 23% of cases in which revision of a second site was subsequently required. CONCLUSION: In our experience, 21% of lower extremity vein grafts requiring initial revision ultimately require additional revisions. Multiply revised lower extremity vein grafts have excellent long-term patency. Lesions occur with equal frequency at the site of prior revision and new sites. Lesions prompting revision at new sites occur significantly later and are infrequently detected on prior imaging studies.

Revascularization of the superior mesenteric artery alone for treatment of intestinal ischemia.

OBJECTIVE: Complete revascularization is recommended by many authors for treatment of intestinal ischemia. The observation that postprandial intestinal hyperemia is limited to the superior mesenteric artery (SMA) has suggested to us that SMA revascularization alone should be adequate treatment. We preferentially manage intestinal ischemia with a single bypass graft to the SMA and herein update our results using this approach. METHODS: Patients were identified from a prospectively established vascular surgical registry. Each patient was assessed for acute versus chronic intestinal ischemia, preoperative angiographic findings, operation used, perioperative morbidity and mortality, late symptomatic relief, cause of death, and life table-determined survival and graft patency. Graft patency was determined by follow-up angiography or duplex scanning. RESULTS: Fifty bypass grafts to the SMA alone were performed in 49 patients (31 women, 18 men; mean age, 62 years) for treatment of intestinal ischemia. In all patients additional splanchnic arteries were available for bypass grafting. Operative indications were acute symptoms in 21 patients, 14 of whom had bowel infarction; chronic symptoms in 26 patients; and prophylaxis in conjunction with infrarenal aortic surgery in 3 patients. Thirty-two grafts originated from the aorta or an iliac artery, and 18 originated from an aortic graft. There were 40 prosthetic and 10 autogenous conduits. Perioperative mortality was 3% in patients with chronic symptoms and 12% overall. All survivors were symptomatically improved. Mean follow-up was 44 months. Nine-year assisted primary graft patency was 79%, and 5-year patient survival was 61%. Two late deaths occurred in patients with recurrent intestinal ischemia resulting from graft occlusions. CONCLUSIONS: Bypass grafting to the SMA alone appears to be both an effective and durable procedure for treatment of intestinal ischemia. Our results appear equal to those reported for "complete" revascularization for intestinal ischemia. When the SMA is a suitable recipient vessel, multiple bypass grafts to other splanchnic vessels are unnecessary in the treatment of intestinal ischemia.

Axillary artery anastomosis to avoid axillofemoral bypass disruption.

Acute disruption at or adjacent to axillary anastomoses of axillofemoral grafts has been sporadically reported. The cause of this serious complication is believed to be attributable to mechanical stresses on the proximal portion of the graft and anastomosis. A modification in the proximal tunneling of the axillofemoral graft, which appears to have effectively reduced the occurrence of this vexing complication, is described in this report.

International military human immunodeficiency virus/acquired immunodeficiency syndrome policies and programs: strengths and limitations in current practice.

A survey was conducted to evaluate military human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) policies and programs in 119 countries. Ninety-eight percent of the 62 respondents provide prevention education, 95% in group settings but only 53% individually. Predeployment briefings are more common than postdeployment briefings. Condoms are promoted more often than provided. Seventy-eight respondents report some form of mandatory HIV testing, and 58% perform mandatory recruit testing, with recruitment denied to HIV-positive individuals in 17%. Counseling accompanies mandatory testing less than voluntary testing. In-service care for AIDS patients is universal. Many military prevention programs can be improved through postdeployment briefings and proactive interventions involving education, condom distribution, and counseling combined with testing. Mandatory testing is often inconsistent with stated goals, and AIDS care policies may strain military budgets. Testing based on cost-benefit assessments may increase efficiency in military HIV control. Military budgets may benefit from greater civil-military cost sharing in AIDS care.

Is a single preoperative duplex scan sufficient for planning bilateral carotid endarterectomy?

PURPOSE: Duplex scanning is often the sole imaging study before carotid endarterectomy (CEA). Patients with bilateral severe internal carotid artery (ICA) stenosis may be considered for bilateral CEA. High-grade ICA stenosis, however, may artifactually elevate velocity measurements used to quantify stenosis in the contralateral ICA. It is unknown whether ipsilateral CEA will influence duplex determination of the presence of a contralateral 60% to 99% ICA stenosis. This study was performed to determine whether a single preoperative duplex scan is sufficient to plan bilateral CEA. METHODS: Preoperative and early postoperative carotid duplex scans in patients with bilateral ICA stenosis who underwent unilateral CEA were reviewed. Changes in duplex scans that determined stenosis in the ICA contralateral to the CEA were analyzed. Previously validated criteria used to determine 60% to 99% ICA stenosis were a peak systolic velocity (PSV) of 260 cm/sec or more combined with an end diastolic velocity (EDV) of 70 cm/sec or more. RESULTS: Over an 8-year period, 460 patients underwent CEA; 107 patients (23.3%) had an asymptomatic 50% to 99% contralateral ICA stenosis by standard criteria (PSV, >125 cm/sec) and an early postoperative duplex scan examination. Of these 107 patients, 38 patients (35.5%) had duplex scan criteria for 60% to 99% contralateral ICA stenosis. In these 38 patients, there was a mean postoperative PSV decrease of 47.7 cm/sec (10.1%) and a mean EDV decrease of 36.0 cm/sec (19.3%) in the ICA contralateral to the CEA. Eight of 38 (21.1%) preoperative contralateral 60% to 99% ICA lesions were reclassified as less than 60% on postoperative duplex scanning. Six of 69 (8.7%) preoperative lesions of less than 60% were reclassified as 60% to 99% on postoperative duplex scan. These six preoperative examinations were all close to the criteria for 60% to 99% stenosis (mean PSV, 232.5 cm/sec; mean EDV, 62.5 cm/sec). CONCLUSION: One-fifth of patients with apparent 60% to 99% contralateral ICA lesions before the operation have less than 60% stenosis when restudied with duplex scan after unilateral CEA. Lesions below but near the cutoff for 60% to 99% may be reclassified as 60% to 99% on the postoperative duplex scan. These findings mandate that when duplex scanning is used as the sole imaging modality before CEA, patients with severe bilateral carotid stenosis must have an additional carotid duplex examination before operation on the second side.

Pharmacokinetics and hematological effects of the PEGylated thrombopoietin peptide mimetic GW395058 in rats and monkeys after intravenous or subcutaneous administration.

GW395058, a potent PEGylated peptide human thrombopoietin receptor (HuTPOr) agonist in vitro, is being evaluated for the treatment of thrombocytopenia. GW395058 shares no sequence homology with TPO. In this report the pharmacokinetics and hematological effects of GW395058 in rats and monkeys are described. Doses eliciting thrombocytosis in rodents (2 or 10 microg/kg s.c.) produced insufficient plasma concentration data for pharmacokinetic parameter estimate calculations. At higher i.v. doses in rats (500, 1,000 or 2,000 microg/kg) serum t1/2 (half-life) values were >20 h, and the area under the concentration time curve increased proportionally with dose. In cynomolgus monkeys GW395058 plasma t1/2 values ranged from 37 to 68 h after s.c. or i.v. dosing, and similar values were observed in rhesus monkeys following s.c. dosing. Rat platelet counts increased following 2 (1.6-fold) or 10 microg/kg (fourfold) s.c. doses. Cynomolgus and rhesus monkey platelet counts did not change significantly at comparable s.c. doses, but did increase slightly (

Extrathoracic arterial grafts performed for carotid artery occlusive disease not amenable to endarterectomy.

HYPOTHESIS: Extrathoracic cervical grafts are safe and provide long-lasting stroke prevention in patients with disease not amenable to standard carotid bifurcation endarterectomy. DESIGN: Review of a prospectively maintained vascular surgical registry. SETTING: Combined university and Department of Veterans Affairs vascular surgical service. PARTICIPANTS: Patients requiring surgery for carotid atherosclerotic occlusive disease not amenable to endarterectomy from January 1988 to March 1998. INTERVENTIONS: Carotid interposition grafting, subclavian-carotid bypass, or carotid-carotid bypass. MAIN OUTCOME MEASURES: Perioperative stroke and death, and life-table determination of freedom from stroke, stroke-free survival, and graft patency. RESULTS: Sixty patients (mean age, 65.8 years; range, 36-83) underwent cervically based carotid grafting. All had greater than 70% stenosis or occlusion of the innominate, common carotid, or internal carotid arteries, and 30 (50%) had undergone at least 1 previous ipsilateral carotid endarterectomy. Indication for operation was stroke or transient ischemic attack in 46 (77%) and asymptomatic high-grade stenosis in 14 (23%). Operative procedures included 31 (52%) carotid interposition grafts, 18 (30%) subclavian-carotid grafts, and 11 (18%) carotid-carotid grafts. Mean follow-up was 29 months (range, 1-117 months). Perioperative stroke rate was 5% (3/60) all in symptomatic patients, and there were no perioperative deaths. By life-table analysis, freedom from stroke was 92% at 1 and 5 years. Stroke-free survival was 90% at 1 year and 61% at 5 years. Primary graft patency was 94% at 1 year and 84% at 5 years, with assisted primary patency of 90% at 5 years. CONCLUSION: Cervical carotid artery grafts for complicated or recurrent carotid atherosclerosis not amenable to endarterectomy are durable and provide excellent freedom from stroke with low perioperative morbidity and mortality.