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.

Spatial and temporal microbial pollution patterns in a tropical estuary during high and low river flow conditions.

Spatial and temporal patterns of coastal microbial pollution are not well documented. Our study examined these patterns through measurements of fecal indicator bacteria (FIB), nutrients, and physiochemical parameters in Hilo Bay, Hawai'i, during high and low river flow. >40% of samples tested positive for the human-associated Bacteroides marker, with highest percentages near rivers. Other FIB were also higher near rivers, but only Clostridium perfringens concentrations were related to discharge. During storms, FIB concentrations were three times to an order of magnitude higher, and increased with decreasing salinity and water temperature, and increasing turbidity. These relationships and high spatial resolution data for these parameters were used to create Enterococcus spp. and C. perfringens maps that predicted exceedances with 64% and 95% accuracy, respectively. Mapping microbial pollution patterns and predicting exceedances is a valuable tool that can improve water quality monitoring and aid in visualizing FIB hotspots for management actions.

Use of tissue plasminogen activator for femoral artery thrombosis following transcatheter coil occlusion of patent ductus arteriosus.

Femoral artery thrombosis is an uncommon but potentially serious complication following pediatric cardiac catheterization. Management options include heparin infusion, thrombolytic therapy, and surgical thrombectomy. The use of thrombolytic agents following coil occlusion of shunts, collaterals, and patent ductus arteriosus (PDA) may be successful in resolving the femoral arterial thrombosis but may also reopen the device-occluded vessel. We report the successful use of tissue plasminogen activator for management of femoral artery thrombosis in a child following transcatheter PDA coil occlusion in which the PDA remained occluded.

Amplatzer septal occluder closure of secundum atrial septal defects in the presence of persistent left superior vena cava to coronary sinus.

Secundum atrial septal defects (ASDs) are routinely closed using transcatheter devices. In patients with left superior vena cava (LSVC) draining to the coronary sinus (CS), the device must not obstruct CS drainage. We report five cases of successful ASD device closure without obstructing flow from the LSVC or dilated CS.

Impact of genetic polymorphisms on heart failure prognosis.

Recent progress in genomic applications have led to a better understanding of the relationship between genetic background and cardiovascular diseases such as heart failure. The broad variability in heart failure patient outcome is in part secondary to modifier genes, i.e. genes that are not involved in the genesis of a disease but modify the severity of the phenotypic expression once the disease has developed. The strategy most commonly used to identify modifier genes is based on association studies between the severity of the phenotype and the sequence variation(s) of selected candidate gene(s). Using this strategy, several polymorphisms of the beta 1 and beta 2-adrenergic receptors genes and the angiotensin converting enzyme gene have been correlated to the prognosis of patients with heart failure. Recently, we have applied an experimental strategy, known as genome mapping, for the identification of heart failure modifier genes. Genome mapping has previously been used with success to identify the genes involved in the development of both monogenic and multifactorial diseases. We have shown that the prognosis of heart failure mice, induced through calsequestrin overexpression, is linked to two Quantitative Trait Loci localized on chromosomes 2 and 3. Using both strategies (candidate gene and genome mapping) should allow us to identify a number of modifier genes that may provide a more rational approach to identify patients with the worst prognosis and to predict their response to therapy.

Peripartum cardiomyopathy presenting as lower extremity arterial thromboembolism. A case report.

BACKGROUND: Although venous thromboembolism has been associated with peripartum cardiomyopathy, there have been no prior reports of lower extremity arterial thromboembolism complicating cardiac failure. CASE: A 38-year-old woman, gradiva 5, para 5, presented on postpartum day 9 with left pedal parasthesia. Lower extremity angiography found acute thrombotic emboli in the left popliteal artery, right tibial artery and right peroneal artery. When respiratory decompensation ensued, a transthoracic echocardiogram revealed global hypokinesis and a left ventricular ejection fraction of 30%. The patient had an uneventful recovery after treatment with digoxin, furosemide and intravenous heparin. CONCLUSION: Lower extremity arterial thromboembolism may be the initial manifestation of peripartum cardiomyopathy.

Identification and molecular characterization of CALM/AF10fusion products in T cell acute lymphoblastic leukemia and acute myeloid leukemia.

The t(10;11)(p12-p13;q14-q21) observed in a subset of patients with either acute lymphoblastic leukemia or acute myeloid leukemia has been shown to result in the fusion of AF10 on chromosome 10 with CALM (also named CLTH) on chromosome 11. AF10 was originally identified as a fusion partner of MLL in the t(10;11)(p12-p13;q23) observed in myeloid leukemia. CALM is a newly isolated gene, cloned as the fusion partner of AF10 in the monocytoid cell line, U937. In order to understand the relationship between MLL, AF10, CALM and the leukemic process, fluorescence in situ hybridization and reverse transcriptase polymerase chain reaction were used to study a series of nine leukemia patients with a t(10;11). Six had myeloid leukemia (AML-M0, AML-M1, AML-M4 and AML-M5) and three had T cell lymphoblastic leukemia. We identified four different CALM/AF10 fusion products in five patients and AF10/CALM reciprocal message in one. We conclude that fusion of CALM and AF10 is a recurring abnormality in both lymphoid and myeloid leukemias of various types including AML-M5, and that the breakpoints in the two types of leukemia do not differ. Our data indicate that the CALM/AF10 fusion product on the der(10) chromosome is critical to leukemogenesis. Leukemia (2000) 14, 100-104.

Characterization of drug-resistant cell lines by comparative genomic hybridization.

The development of resistance to cytostatic agents is a serious obstacle to the success of cancer therapy and has been the focus of many research efforts. Traditionally, cell lines are selectively cultured in the presence of cytostatic agents and the biochemical and cytogenetic properties of the cell lines are then analyzed. In order to better understand the mechanisms by which drug resistance is mediated, we have analyzed three cell lines, each derived from the parent line K562, which are resistant to vincristine, mitoxantrone, or idarubicin, using comparative genomic hybridization (CGH). In each case, CGH successfully identified amplifications and/or deletions unique to the drug-resistant selected cell lines. Further characterization of the genetic regions identified in the CGH analysis could greatly contribute to our understanding of acquired drug resistance, and could potentially impact the clinical management of cancer.

Myeloid malignancies induced by alkylating agents in Nf1 mice.

Therapy-related acute myeloid leukemia and myelodysplastic syndrome (t-AML and MDS) are severe late complications of treatment with genotoxic chemotherapeutic agents. Children with neurofibromatosis type 1 (NF1) are predisposed to malignant myeloid disorders that are associated with inactivation of the NF1 tumor suppressor gene in the leukemic clone. Recent clinical data suggest that NF1 might be also associated with an increased risk of t-AML after treatment with alkyating agents. To test this hypothesis, we administered cyclophosphamide or etoposide to cohorts of wild-type and heterozygous Nf1 knockout mice. Cyclophosphamide exposure cooperated strongly with heterozygous inactivation of Nf1 in myeloid leukemogenesis, while etoposide did not. Somatic loss of the normal Nf1 allele correlated with clinical disease and was more common in 129/Sv mice than in 129/Sv x C57BL/6 animals. Leukemic cells showing loss of heterozygosity at Nf1 retained a structural allele on each chromosome 11 homolog. These studies establish a novel in vivo model of alkylator-induced myeloid malignancy that will facilitate mechanistic and translational studies.

1p and 3p deletions in meningiomas without detectable aberrations of chromosome 22 identified by comparative genomic hybridization.

Meningioma is a common tumor of the meninges covering the central nervous system. Although generally a benign tumor, meningioma often recurs and is malignant in 5-10% of all cases. Loss of chromosome 22 loci, and specifically inactivation of the NF2 tumor suppressor gene, is considered one of several critical steps in the tumorigenesis of meningioma. However, cytogenetic and molecular investigations have failed to detect either aberrations of chromosome 22 or mutations in the NF2 gene in approximately 40% of all tumors, thus making it apparent that an alternative mechanism(s) is responsible for the development of a large fraction of meningiomas. This subset of meningiomas is not distinct with regard to clinical and histopathological features from tumors showing deletions on chromosome 22. It is, therefore, important to attempt the elucidation of molecular pathway(s) that may operate in the tumorigenesis of these tumors. We used comparative genomic hybridization (CGH) to identify regions of the genome other than chromosome 22, contributing to the development of meningioma. We analyzed 25 tumors that had undergone detailed LOH analysis on chromosome 22 and were shown to contain no detectable deletions. Two benign, malignancy grade I, meningiomas showed concurrent deletion of 1p and 3p. These results suggest that loss of both 1p and 3p may contribute to meningioma tumorigenesis. This may represent genetic changes that are alternative to deletions on chromosome 22.

Passive immunization of ewes against an inhibin-like peptide increases follicle-stimulating hormone concentrations, ovulation rate, and prolificacy in spring-mated ewes.

The objective of this experiment was to determine whether passive immunization against a synthetic inhibin-like peptide (alpha-IF) increases FSH secretion and reproductive performance of ewes bred in the spring. Crossbred ewes were assigned to three treatment groups of 10 ewes each. Progesterone-releasing pessaries (CIDR-G) were inserted and left in place for 12 d. The CIDR-G were removed on April 7 (0 h), and three rams were introduced. A single 1.8-mL i.m. injection containing 0, 315-, or 630-reference preparation-2 (RP-2) kU semipurified alpha-IF-antibody (Ab) was given at -48 h. Antibody solution was prepared by ammonium sulfate precipitation and concentration of ovine immune sera that had been generated against alpha-IF-human-alpha-globulin. After the alpha-IF-Ab injection, plasma alpha-IF-Ab titers and FSH concentrations increased within 6 h, peaked 12 to 24 h later, and then decreased. At 12 h after injection, FSH concentrations were increased (P = .05) 28 and 42% over control values in ewes injected with 315- and 630-RP-2 kU alpha-IF-Ab, respectively. All ewes expressed estrus and ovulated, except one control that did not ovulate. Ovulation rate (OR) was increased (P < .0001) by alpha-IF-Ab treatment. Mean OR was 1.0 in control ewes, 1.7 in ewes given 315-RP-2 kU, and 2.5 in ewes injected with 630-RP-2 kU. Fertility (ewes lambing/ewes exposed) from breeding at the induced-synchronized estrus tended (P = .09) to be greater for ewes injected with 630-RP-2 kU alpha-IF-Ab.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of passive immunization of ewes against an inhibin-peptide on gonadotropin levels, ovulation rate, and prolificacy.

The experimental objectives were to determine whether injection of semi-purified (sp; ammonium sulfate-precipitated) and highly purified (hp; immunoaffinity-purified) ovine antibody (Ab) against an inhibin-peptide fragment (alpha-IF) before the preovulatory period would 1) stimulate FSH secretion in a dose-response manner, 2) induce an increase in ovulation rate, and 3) affect pregnancy rate and prolificacy (lambs born alive per ewe lambing). During the early breeding season, estrus was synchronized in 30 2-yr-old crossbred ewes through use of progesterone-releasing pessaries (CIDR-G). Two doses (330 and 660 laboratory reference preparation [RP-2] kU) of sp- and hp-alpha-IF-Ab were injected i.m. 48 h before CIDR-G removal (6 ewes per group). Six other ewes received control solution. Plasma alpha-IF-Ab titers peaked at 12 h postinjection. Plasma FSH levels were higher (p < 0.02) in alpha-IF-Ab-treated ewes than in control ewes from 12 to 24 h postimmunization. Magnitudes of FSH increases were similar in ewes administered sp- and hp-alpha-IF-Ab and were greater (p < 0.05) in ewes receiving 660 than in those receiving 330 RP-2 kU. Compared to control values, the higher alpha-IF-Ab dose increased FSH levels by 44 +/- 5% and the lower dose increased the levels by 22 +/- 3%. Plasma LH levels were similar among passively immunized and control sheep. Ovulation rate was increased (p < 0.0005) by alpha-IF-Ab treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Parent-of-origin effects in multiple endocrine neoplasia type 2B.

Multiple endocrine neoplasia type 2B (MEN 2B) is characterized by medullary thyroid carcinoma, pheochromocytomas, mucosal neuromas, ganglioneuromas, and skeletal and ophthalmic abnormalities. It is observed as both inherited and sporadic disease, with an estimated 50% of cases arising de novo. A single point mutation in the catalytic core region of the receptor tyrosine kinase, RET, has been observed in germ-line DNA of MEN 2B patients. We have analyzed 25 cases of de novo disease in order to determine the parental origin of the mutated RET allele. In all cases the new mutation was of paternal origin. We observe a distortion of the sex ratio in both de novo MEN 2B patients and the affected offspring of MEN 2B transmitting males. These results suggests a differential susceptibility of RET to mutation in paternally and maternally derived DNA and a possible role for imprinting of RET during development.

Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B.

Multiple endocrine neoplasia type 2B (MEN 2B) is a human cancer syndrome characterized by medullary thyroid carcinoma (MTC), pheochromocytomas, mucosal neuromas, ganglioneuromas of the intestinal tract, and skeletal and ophthalmic abnormalities. It appears both as an inherited disorder and as de novo disease. Sequence analysis of germ-line DNA from MEN 2B patients revealed the existence of the same point mutation in the RET protooncogene in 34 unrelated individuals. This sequence difference was not observed in 93 unaffected individuals, including the normal parents of 14 de novo MEN 2B patients. The mutation (ATG-->ACG) results in the replacement of methionine with threonine within the catalytic core region of the tyrosine kinase domain. We propose that this amino acid replacement effects substrate interactions and results in dominant oncogenic activity by the RET protein. Missense mutations in the extracellular ligand-binding domain of the RET protooncogene previously have been associated with two other disorders [MEN 2A and familial MTC (FMTC)] in which MTC is observed. MEN 2B represents the third form of heritable MTC known to be an allele of RET. Alterations in two different functional domains of the putative receptor protein tyrosine kinase are implicated in development of MTC.

Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC.

Multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC) are dominantly inherited conditions which predispose to the development of endocrine neoplasia. Evidence is presented that sequence changes within the coding region of the RET proto-oncogene, a putative transmembrane tyrosine kinase, may be responsible for the development of neoplasia in these inherited disorders. Single strand conformational variants (SSCVs) in exons 7 and 8 of the RET proto-oncogene were identified in eight MEN 2A and four FMTC families. The variants were observed only in the DNA of individuals who were either affected or who had inherited the MEN2A or FMTC allele as determined by haplotyping experiments. The seven variants identified were sequenced directly. All involved point mutations within codons specifying cysteine residues, resulting in nonconservative amino acid changes. Six of the seven mutations are located in exon 7. A single mutation was found in exon 8. Variants were not detected in four MEN 2B families studied for all exon assays available, nor were they detectable in 16 cases of well documented sporadic medullary thyroid carcinoma or pheochromocytoma that were tested for exon 7 variants. Coinheritance of the mutations with disease and the physical and genetic proximity of the RET proto-oncogene provide evidence that RET is responsible for at least two of the three inherited forms of MEN 2. Neither the normal function, nor the ligand of RET are yet known. However, its apparent involvement in the development of these inherited forms of neoplasia as well as in papillary thyroid carcinoma suggest an important developmental or cell regulatory role for the protein.

Active and passive immunoneutralization of inhibin increases follicle-stimulating hormone levels and ovulation rate in ewes.

Two experiments were conducted to determine effects of active and passive immunoneutralization of inhibin on FSH secretion and ovulation rate. A synthetic peptide (alpha-IF) matching the N-terminus of the alpha-subunit of ovine inhibin was coupled to human alpha-globulin (h alpha-G) and used as an immunogen. In experiment 1, estrus was synchronized in 10 sheep that had been actively immunized against alpha-IF-h alpha-G or h alpha-G. Plasma FSH levels were similar in the two groups of ewes at -52 and -48 h (0 h = onset of estrus). In alpha-IF-h alpha-G-immunized ewes, FSH increased from -48 to -44 h (18.8-22.1 ng/ml), and then fell to 16.2 ng/ml by 0 h. In h alpha-G-immunized ewes, FSH decreased from -48 to 0 h (17.6-7.2 ng/ml). Ovulation rate was higher in alpha-IF-h alpha-G- than h alpha-G-immunized ewes (9.4 vs. 2.4). In experiment 2, antibodies (Ab) were extracted from sera obtained from experiment 1 ewes and then were injected i.v. into 12 other ewes. Estrus was synchronized twice during the breeding season using progesterone-releasing pessaries (CIDR-G). One day before CIDR-G withdrawal, alpha-IF-h alpha-G and h alpha-G Ab were administered in a crossover design. After injection of Ab against alpha-IF-h alpha-G, plasma FSH increased from 0 to 24 h post-injection (10.9-21.5 ng/ml), after which levels fell to 14.2 ng/ml by onset of the preovulatory LH surge.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of a growth hormone-releasing factor analogue and an estradiol-trenbolone acetate implant on somatotropin, insulin-like growth factor I, and metabolite profiles in growing Hereford steers.

Hereford steers (290 +/- 6 kg of BW) were implanted (n = 4) with 140 mg of trenbolone acetate (TBA) and 28 mg of estradiol-17 beta (E2 beta) or nonimplanted (controls, n = 4). In Trial 1, effects of a single i.v. injection of 0, 20, 40, or 80 micrograms of a growth hormone-releasing factor (1-29 NH2) analogue (GRFa) on release of endogenous somatotropin (ST) were evaluated in a double 4 x 4 Latin square design. Plasma samples (n = 21) were obtained from -20 to 240 min after GRFa injection. Area under the ST response curve (AUC) increased (P = .009) in a dose-dependent manner (.2, 2.6, 3.6, 4.3 mg.min-1.mL-1, respectively). Mean ST concentration was not affected (P = .238) by implant but AUC was greater (P = .009) in implanted than in control steers. There was no interaction (P = .460) between dose of GRFa and presence of implant. In Trial 2, 80 micrograms of GRFa was administered at 12-h intervals to the same eight steers. Response of ST (AUC) to the first and last (13th) i.v. injection of GRFa was similar and not affected by implant. Before GRFa administration, plasma insulin-like growth factor I (IGF-I) concentrations were greater (P = .039) in implanted than in control steers (272 vs 164 ng/mL). Administration of GRFa increased plasma IGF-I (P = .0001), decreased plasma urea N (PUN) (P = .0001), and did not alter plasma glucose (P = .447) in both control and implanted steers. Data indicate that effects of GRFa and TBA/E2 beta on plasma IGF-I and PUN concentrations were additive in this study.