Voluntary sustainability standards could significantly reduce detrimental impacts of global agriculture.

Voluntary sustainability standards (VSS) are stakeholder-derived principles with measurable and enforceable criteria to promote sustainable production outcomes. While institutional commitments to use VSS to meet sustainable procurement policies have grown rapidly over the past decade, we still have relatively little understanding of the (i) direct environmental benefits of large-scale VSS adoption; (ii) potential perverse indirect impacts of adoption; and (iii) implementation pathways. Here, we illustrate and address these knowledge gaps using an ecosystem service modeling and scenario analysis of Bonsucro, the leading VSS for sugarcane. We find that global compliance with the Bonsucro environmental standards would reduce current sugarcane production area (-24%), net tonnage (-11%), irrigation water use (-65%), nutrient loading (-34%), and greenhouse gas emissions from cultivation (-51%). Under a scenario of doubled global sugarcane production, Bonsucro adoption would further limit water use and greenhouse gas emissions by preventing sugarcane expansion into water-stressed and high-carbon stock ecosystems. This outcome was achieved via expansion largely on existing agricultural lands. However, displacement of other crops could drive detrimental impacts from indirect land use. We find that over half of the potential direct environmental benefits of Bonsucro standards under the doubling scenario could be achieved by targeting adoption in just 10% of global sugarcane production areas. However, designing policy that generates the most environmentally beneficial Bonsucro adoption pathway requires a better understanding of the economic and social costs of VSS adoption. Finally, we suggest research directions to advance sustainable consumption and production.

Early inflammation precedes cardiac fibrosis and heart failure in desmoglein 2 murine model of arrhythmogenic cardiomyopathy.

The study of a desmoglein 2 murine model of arrhythmogenic cardiomyopathy revealed cardiac inflammation as a key early event leading to fibrosis. Arrhythmogenic cardiomyopathy (AC) is an inherited heart muscle disorder leading to ventricular arrhythmias and heart failure due to abnormalities in the cardiac desmosome. We examined how loss of desmoglein 2 (Dsg2) in the young murine heart leads to development of AC. Apoptosis was an early cellular phenotype, and RNA sequencing analysis revealed early activation of inflammatory-associated pathways in Dsg2-null (Dsg2-/-) hearts at postnatal day 14 (2 weeks) that were absent in the fibrotic heart of adult mice (10 weeks). This included upregulation of iRhom2/ADAM17 and its associated pro-inflammatory cytokines and receptors such as TNFα, IL6R and IL-6. Furthermore, genes linked to specific macrophage populations were also upregulated. This suggests cardiomyocyte stress triggers an early immune response to clear apoptotic cells allowing tissue remodelling later on in the fibrotic heart. Our analysis at the early disease stage suggests cardiac inflammation is an important response and may be one of the mechanisms responsible for AC disease progression.

The use of a measure of acute irritation to predict the outcome of repeated usage of hand soap products.

BACKGROUND: Healthcare-associated infection is an important worldwide problem that could be reduced by better hand hygiene practice. However, an increasing number of healthcare workers are experiencing irritant contact dermatitis of the hands as a result of repeated hand washing. This may lead to a reduced level of compliance with regard to hand hygiene. OBJECTIVES: To assess whether a measure of acute irritation by hand soaps could predict the effects of repeated usage over a 2-week period. METHODS: In a double-blind, randomized comparison study, the comparative irritation potential of four different hand soaps was assessed over a 24-h treatment period. The effect of repeated hand washing with the hand soap products over a 2-week period in healthy adult volunteers on skin barrier function was then determined by assessment of transepidermal water loss (TEWL), epidermal hydration and a visual assessment using the Hand Eczema Severity Index (HECSI) at days 0, 7 and 14. RESULTS: A total of 121 subjects from the 123 recruited completed phase 1 of the study. All four products were seen to be significantly different from each other in terms of the irritant reaction observed and all products resulted in a significantly higher irritation compared with the no-treatment control. Seventy-nine of the initial 121 subjects were then enrolled into the repeated usage study. A statistically significant worsening of the clinical condition of the skin as measured by HECSI was seen from baseline to day 14 in those subjects repeatedly washing their hands with two of the four soap products (products C and D) with P-values of 0·02 and 0·01, respectively. Subclinical assessment of the skin barrier function by measuring epidermal hydration was significantly increased from baseline to day 7 after repeated hand washing with products A, B and D but overall no significant change was seen in all four products tested by day 14. A statistically significant increase in TEWL at day 14 was seen for product A (P = 0·02) indicating a worsening of skin barrier function. This effect was also seen initially for product D at day 7 although this was then lost at day 14. Further regression analysis was then performed to see if the acute irritant test data for each product correlated with the skin barrier data from the repeated usage component of the study. This showed that the results of acute irritant testing of the individual products did not predict the results of chronic use of hand soaps. CONCLUSIONS: The results from phase 2 of our study confirm the work of previous studies that show that regular exposure to irritants in daily life leads to stratum corneum damage and impairment of the skin barrier. Although significant differences were seen between the products in phase 1 of the study, regression analysis showed that the results of patch testing of the individual products did not predict the results of chronic use of hand soaps. When designing a study to assess the effects of cumulative use of a product on the skin, the study should mirror the use conditions of the product as closely as possible.

Protein kinase Cepsilon is required for macrophage activation and defense against bacterial infection.

To assess directly the role of protein kinase C (PKC)epsilon in the immune system, we generated mice that carried a homozygous disruption of the PKCepsilon locus. PKCepsilon(-/-) animals appeared normal and were generally healthy, although female mice frequently developed a bacterial infection of the uterus. Macrophages from PKCepsilon(-/-) animals demonstrated a severely attenuated response to lipopolysaccharide (LPS) and interferon (IFN)gamma, characterized by a dramatic reduction in the generation of NO, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-1beta. Further analysis revealed that LPS-stimulated macrophages from PKCepsilon(-/-) mice were deficient in the induction of nitric oxide synthase (NOS)-2, demonstrating a decrease in the activation of IkappaB kinase, a reduction in IkappaB degradation, and a decrease in nuclear factor (NF)kappaB nuclear translocation. After intravenous administration of Gram-negative or Gram-positive bacteria, PKCepsilon(-/-) mice demonstrated a significantly decreased period of survival. This study provides direct evidence that PKCepsilon is critically involved at an early stage of LPS-mediated signaling in activated macrophages. Furthermore, we demonstrate that in the absence of PKCepsilon, host defense against bacterial infection is severely compromised, resulting in an increased incidence of mortality.

A double-blind, randomized study to assess the effectiveness of different moisturizers in preventing dermatitis induced by hand washing to simulate healthcare use.

BACKGROUND: Healthcare-associated infection is an important worldwide problem that could be reduced by better hand hygiene practice. However, irritant contact dermatitis of the hands as a result of repeated hand washing is a potential complication that may be preventable by the regular use of an emollient. OBJECTIVES: To assess the effect of moisturizer application after repeated hand washing (15 times daily) vs. soap alone. METHODS: In a double-blind, randomized study, the effect of five different moisturizers on skin barrier function was determined by assessment after repeated hand washing over a 2-week period in healthy adult volunteers. Assessments of transepidermal water loss (TEWL), epidermal hydration and a visual assessment using the Hand Eczema Severity Index (HECSI) were made at days 0, 7 and 14. RESULTS: In total, 132 patients were enrolled into the study. A statistically significant worsening of the clinical condition of the skin as measured by HECSI was seen from baseline to day 14 (P = 0.003) in those subjects repeatedly washing their hands with soap without subsequent application of moisturizer. No change was seen in the groups using moisturizer. Subclinical assessment of epidermal hydration as a measure of skin barrier function showed significant increases from baseline to day 14 after the use of three of the five moisturizing products (P = 0.041, 0.001 and 0.009). Three of the five moisturizers tested led to a statistically significant decrease in TEWL at day 7 of repeated hand washing. This effect was sustained for one moisturizing product at day 14 of hand washing (P = 0.044). CONCLUSIONS: These results support the view that the regular application of moisturizers to normal skin offers a protective effect against repeated exposure to irritants, with no evidence of a reduction in barrier efficiency allowing the easier permeation of irritant substances into the skin as has been suggested by other studies. Regular use of emollient in the healthcare environment may prevent the development of dermatitis.

Dog mastocytoma cells produce transforming growth factor beta 1.

Transforming growth factor-beta (TGF beta) promotes deposition of extracellular matrix and is associated with fibrotic conditions both in experimental animals and in humans. Although a role for mast cells has been suspected in the pathogenesis of fibrosis, no potent mediator capable of stimulating fibroblast growth or extracellular matrix deposition has been identified in mast cell supernatants. We report here the constitutive production of TGF beta 1 by four dog mastocytoma cell lines. TGF beta 1 was identified by characteristic biologic activity, blockade of biologic effect by specific neutralizing antibody, and by recognition of a band with the appropriate migration by western blot. TGF beta 1 mRNA, but not TGF beta 2 or TGF beta 3 mRNA, was also produced constitutively by all four cell lines. Quantitation by bioassay revealed baseline TGF beta secretion of approximately 1 ng/10(6) cells over 48 h. Stimulation of mastocytoma cells with phorbol ester increased the rate of release of TGF beta 1, most markedly in the first 30 min after stimulation, without increasing TGF beta 1 mRNA. Dog mastocytoma cells produced TGF beta 1 primarily in a latent form, inactive until treated with acid. Both pure TGF beta 1 and TGF beta-containing mastocytoma cell-conditioned media inhibited mitogenesis and proliferation in dog mastocytoma cell lines, suggesting that mast cell tumor lines would not grow preferentially based on their ability to produce TGF beta. These studies may make possible further investigation of the mechanism by which mast cells contribute to the induction of fibrosis.

The changing profile of the patient undergoing coronary artery bypass surgery.

The first 100 consecutive patients undergoing isolated coronary artery bypass surgery in 1975 were evaluated with respect to the incidence of operative risk factors and outcome. When compared with an identically selected group from 1985, there was significant worsening of the preoperative condition over the decade with regard to mean age (p less than 0.0005), presence of congestive heart failure (p less than 0.05), left ventricular dysfunction (p less than 0.05), severity of coronary artery disease (p less than 0.001) and incidence of emergency operation (p less than 0.05). More patients in 1985 had associated medical diseases such as diabetes (p less than 0.01) and chronic lung disease (p less than 0.005). There was an increase in the occurrence of vascular diseases (hypertension, renal dysfunction, peripheral vascular and cerebrovascular disease) (p less than 0.05). Overall operative mortality increased from 1 to 8% (p less than 0.05) over the decade. Despite the deterioration in the clinical profile of the patient undergoing coronary bypass surgery, elective procedures were still performed with low mortality. The significant increase in overall mortality was chiefly in patients undergoing emergency operation (p less than 0.05). There were also increases in operative morbidity including low output syndrome (p less than 0.01) and respiratory (p less than 0.005) and neurologic (p = 0.06) complications.

Effect of ventricular function on the exercise hemodynamics of variable rate pacing.

To determine the effect of ventricular function on the exercise hemodynamics of variable rate pacing, 16 selected patients underwent paired, double-blind, randomized exercise tests in single rate demand (VVI) or variable rate (VVIR) pacing modes. Ejection fraction and cardiac index were determined by two-dimensional and Doppler echocardiography at baseline and during peak exercise. Baseline ejection fraction ranged from 14 to 73% and was less than 40% in 6 patients (Group 1) and greater than or equal to 40% in 10 patients (Group 2). Duration of exercise was longer during the VVIR mode (502 s) than during the VVI mode (449 s) (p less than 0.01) and unrelated to baseline ejection fraction. Heart rate during exercise increased 9% in the VVI mode and 35% in the VVIR mode (p less than 0.005). Cardiac index increased 49% in the VVI mode and 83% in the VVIR mode. Analysis of variance for repeated measures showed a significant effect of pacing mode (p less than 0.01) and exercise (p less than 0.001), but not baseline ejection fraction, on cardiac index. Baseline ejection fraction did not correlate with the increase in cardiac index in either pacing mode or with the difference in increase between modes. There was no significant difference between Groups 1 and 2 in exercise duration, peak heart rate-blood pressure (rate-pressure) product, baseline or peak heart rate or baseline or peak cardiac index. Therefore, in selected patients, VVIR pacing during exercise results in an increase in heart rate, duration of exercise and cardiac index that is unrelated to the degree of baseline left ventricular dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)

High incidence of myocarditis by endomyocardial biopsy in patients with idiopathic congestive cardiomyopathy.

Thirty-five patients with unexplained congestive heart failure were evaluated with endomyocardial biopsy. Utilizing microscopic, ultrastructural and immunofluorescent studies, samples were classified as exhibiting either no inflammation (cardiomyopathy) or active lymphocytic myocarditis, grade I to IV. Twenty-two (63%) of the patients had inflammatory changes. Of these 22 patients, 18 had low grade I or II inflammation, 7 were treated with immunosuppressive agents with improvement in 5 and stabilization in 1. One patient died of progressive congestive heart failure. Three of four patients with high grade III or IV myocarditis died after a fulminant course. The results suggest that inflammatory myocarditis may be more common than previously suspected and add evidence that there may be ongoing inflammation in many cases of congestive cardiomyopathy.

Studies of HIV-2 promoter activity and cell specific ablation.

We have a developed a retroviral mediated molecular ablation method to specifically eliminate HIV Tat-expressing cells. This approach utilizes the Tat-inducible HIV-2 promoter and a conditional toxin gene. The Herpes Simplex Virus thymidine kinase gene product is toxic to mammalian cells only after treatment with Ganciclovir (GCV) or other nucleoside analogues. We demonstrate here that certain promoter modifications can decrease basal expression while retaining the ability to be transactivated. Furthermore, we show that a HIV-2 promoter thymidine kinase gene cassette transduced via retroviral vectors into tissue culture cells can specifically promote the ablation of HIV-Tat expressing cells in the presence GCV. We also show that there is a large differential in HIV-thymidine kinase gene transcription and lethal drug dose between Tat-expressing cells and Tat-negative cells.

Bone brittleness varies with genetic background in A/J and C57BL/6J inbred mice.

The contribution of genetic and environmental factors to variations in bone quality are understood poorly. We tested whether bone brittleness varies with genetic background using the A/J and C57BL/6J inbred mouse strains. Whole bone four-point bending tests revealed a 70% decrease in postyield deflection of A/J femurs compared with C57BL/6J, indicating that A/J femurs failed in a significantly more brittle manner. Cyclic loading studies indicated that A/J femurs accumulated damage differently than C57BL/6J femurs, consistent with their increased brittleness. Differences in matrix composition also were observed between the two mouse strains. A/J femurs had a 4.5% increase in ash content and an 11.8% decrease in collagen content. Interestingly, a reciprocal relationship was observed between femoral geometry and material stiffness; this relationship may have contributed to the brittle phenotype of A/J femurs. A/J femurs are more slender than those of C57BL/6J femurs; however, their 47% smaller moment of inertia appeared to be compensated by an increased tissue stiffness at the expense of altered tissue damageability. Importantly, these differences in whole bone mechanical properties between A/J and C57BL/6J femurs could not have been predicted from bone mass or density measures alone. The results indicated that bone brittleness is a genetically influenced trait and that it is associated with genetically determined differences in whole bone architecture, bone matrix composition, and mechanisms of cyclical damage accumulation.

Long-term results of myocardial revascularization.

During 1970 to 1977, among 1,733 patients who underwent isolated coronary bypass grafting, the operative mortality was 2.5 percent. Actuarial 5 year survival is 88.1 percent. At an average follow-up of 46 months (range 13 to 108), 90 percent of patients remain angina-free or with symptomatic improvement. The 5 year survival rate of patients with single vessel coronary artery disease is 97.9 percent. In patients with multivessel disease, operative survival appears to be favorably influenced by the presence of normal preoperative ventricular function. Late survival is significantly better in patients with multivessel disease with normal preoperative ventricular function or with complete revascularization. Risk of perioperative myocardial infarction has been appreciably reduced by the introduction of cold potassium chloride cardioplegia. Late myocardial infarction has occurred at an average annual risk of 1.46 percent. These data show that long-term survival and a small incidence of late myocardial infarction after myocardial revascularization are more likely in patients who undergo complete revascularization before significant left ventricular myocardial damage has occurred.

Exercise capacity during the first year after cardiac transplantation.

Few data are available examining the influence of perioperative clinical parameters on exercise capacity after cardiac transplantation. Accordingly, 40 patients were studied by metabolic exercise testing early (1 to 3 months) and late (6 to 12 months) after cardiac transplantation. Various clinical parameters, including congestive heart failure class, length of hospital stay, age, cold ischemic time and histologic evidence of rejection were correlated with exercise capacity after transplantation. As expected, peak exercise capacity correlated inversely with both age and length of hospital stay. There was no correlation with preoperative congestive heart failure class or heart rate at rest. Interestingly, there was a statistically significant correlation between cold ischemic time and exercise capacity after transplantation. In addition, increased episodes of rejection during the first 6 months after transplantation resulted in statistically lower exercise capacity at 6 to 12 months after the operation. Thus, ischemic damage during transport of the donor organs and subclinical damage during early rejection may affect clinical status after heart transplantation and may only be apparent during increased physical demand such as exercise.

Coronary artery bypass surgery in patients aged 80 years or older.

Between August 1980 and January 1986, 23 patients aged 80 years or older underwent coronary artery bypass grafting (CABG) operations. These patients had a higher incidence of severe left main coronary artery narrowing (p less than 0.0001), 3-vessel coronary artery disease (p less than 0.05) and moderate to severe left ventricular dysfunction (p less than 0.05) than patients in the Coronary Artery Surgery Study registry older than 65 years. Of 14 patients undergoing elective simple CABG procedures, none died; of 19 elective cases overall, 2 patients died (11%). Three of 4 patients undergoing emergency procedures (75%) and 4 of 6 patients (67%) requiring intraaortic balloon counterpulsation died. Significant complications occurred in 9 of 18 survivors (50%). All operative survivors improved at least 1 New York Heart Association class, with a mean classification improvement of 3.7 to 1.6 (p less than 0.0001); 13 of 16 long-term survivors were in class I or II. Actuarial survival at 1 and 2 years is 94% and 82%, respectively. CABG can be performed electively in octogenarian patients with increased but acceptable mortality and morbidity risks. Functional improvement and long-term survival are excellent.

Implantation technique for the Novacor left ventricular assist system.

The Novacor left ventricular assist system (Baxter Healthcare Corp., Novacor Div., Oakland, Calif.) is currently undergoing clinical investigation as a bridge to cardiac transplantation. The original animal and clinical protocols recommended placement of the pump/energy converter within the peritoneal space. During preclinical cadaver fitting trials, we determined that it might be difficult to place this device in the peritoneal cavity of tall, slender patients, patients having a small muscular abdomen, and many women. We were also concerned that peritoneal placement would increase the risk and severity of infection and that abdominal organs might be injured by direct contact with the pump. In studies in cadavers, we therefore developed a technique using preperitoneal placement of the pump/energy converter. This technique has now been used successfully in more than 200 patients. A detailed description of this insertion technique is presented to facilitate its current use for the implantation of temporary devices and to plan for the implantation of permanent systems.

Working heart model of heterotopic heart-lung transplantation in rats.

A technique for a working heart model of heterotopic heart-lung transplantation is described. The donor aorta and left pulmonary artery are anastomosed to the recipient's abdominal aorta in an end-to-side fashion. Arterial blood from the recipient's abdominal aorta enters the donor left heart via the donor left lung and is ejected into the donor ascending aorta by the transplanted left ventricle. With this model, the donor left ventricle performs work comparable to that of the native heart without hypoxia. This model is easily reproducible and can be applied to various studies, including long-term assessments of cardiac remodeling, long-term efficacy of cardiac preservation, and posttransplantation ventricular performance under more physiologic conditions.

Eight years' experience with bridging to cardiac transplantation.

Although bridging to cardiac transplantation has become a therapeutic option for transplant candidates whose condition deteriorates while they are awaiting a donor heart, short-term efficacy has not been proved and long-term survival has not been reported. We retrospectively reviewed data on 44 patients who had circulatory assist devices placed as a bridge to transplantation between May 1985 and April 1993. The 35 male and nine female patients ranged in age from 12 to 65 years (mean 43.8 years). Thirty-one patients were supported with 32 Thoratec (18 left ventricular, 14 biventricular), 11 Novacor, and two Jarvik J-7-70 devices. The duration of device support was from 4 hours to 440 days (mean 45.5 days). Fifteen patients did not receive a donor organ because of infection (ten patients), renal failure (five patients), bleeding (nine patients), cerebrovascular accident (three patients), ventricular fibrillation (one patient), and right heart failure (one patient), and all died. Two patients were weaned from support and survived without transplantation. Twenty-seven patients underwent transplantation, and 26 survived (96%). Overall survival was 64% (28/44). Duration of survival ranged from 2 to 96 months (mean 35 months). Among the 28 hospital survivors, there were four late deaths (all transplant recipients) at 3, 6, 14, and 68 months. Posttransplantation actuarial survivals at 1, 5, and 8 years are 88%, 83%, and 66%. Twenty-three of the 24 patients presently alive are in New York Heart Association functional class I. These data demonstrate the short- and long-term efficacy of bridging to transplantation with circulatory support devices. The excellent survival and full functional recovery of patients undergoing transplantation ensure that donor organs are not being "wasted" on the sickest patients.

Coronary vascular responses to nitroglycerin following aorta-coronary saphenous vein grafting in dogs.

Phasic coronary arterial flow responses to nitroglycerin were evaluated in 15 open-chest greyhounds before and after aorta-coronary saphenous vein grafting. Coronary flow was measured with electromagnetic probes proximal and distal to the vein graft site. Simultaneous measurements of branchiocephalic flow, aortic and left atrial pressure, left ventricular pressure, and dp/dt were made. Grafts were placed during normothermic hemodilution cardiopulmonary bypass and induced ventricular fibrillation. Before grafting, intravenous nitroglycerin (0.6 mg.) elicited an abrupt rise in diastolic coronary flow which decreased as aortic pressure fell and systolic coronary flow increased. However, after grafting, nitroglycerin elicited no change in diastolic coronary flow, whereas systolic coronary flow increased and aortic pressure fell. In 6 control dogs treated similarly except for aorta-coronary grafting, coronary flow responses to nitroglycerin were unchanged. These acute experiments suggest that, in dogs with aorta-coronary saphenous vein grafts, the coronary dilating effect of nitroglycerin is virutally abolished.

The rationale for operative therapy of symptomatic single-vessel coronary artery disease.

During an 8 year interval, 184 patients with symptomatic single-vessel disease underwent coronary artery bypass grafting (CABG). There were no operative deaths and only one late cardiac death (5 year cumulative survival 97.9%). At 48 months mean follow-up, 91% are angina free or improved. The low incidence of perioperative and late myocardial infarction (MI) and the preservation of ventricular function seen on follow-up catheterization suggest that coronary bypass operations yield significant benefits in severely symptomatic patients with single-vessel disease. Evidence is presented which supports the idea that single-vessel coronary artery disease may be a unique manifestation of coronary atherosclerosis and not one stage in a continuum.