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BACKGROUND. Mutational inactivation in cancer of key apoptotic pathway components, such as TP53/p53, undermines cytotoxic therapies that aim to increase apoptosis. Accordingly, TP53 mutations are reproducibly associated with poor treatment outcomes. Moreover, cytotoxic treatments destroy normal stem cells with intact p53 systems, a problem especially for myeloid neoplasms, as these cells reverse the low blood counts that cause morbidity and death. Preclinical studies suggest that noncytotoxic concentrations of the DNA methyltransferase 1 (DNMT1) inhibitor decitabine produce p53-independent cellcycle exits by reversing aberrant epigenetic repression of proliferation-terminating (MYC-antagonizing) differentiation genes in cancer cells. METHODS. In this clinical trial, patients with myelodysplastic syndrome (n = 25) received reduced decitabine dosages (0.1-0.2 mg/kg/day compared with the FDA-approved 20-45 mg/[m.sup.2]/day dosage, a 75%-90% reduction) to avoid cytotoxicity. These well-tolerated doses were frequently administered 1-3 days per week, instead of pulse cycled for 3 to 5 days over a 4- to 6-week period, to increase the probability that cancer S-phase entries would coincide with drug exposure, which is required for S-phase-dependent DNMT1 depletion. RESULTS. The median subject age was 73 years (range, 46-85 years), 9 subjects had relapsed disease or were refractory to 5-azacytidine and/or lenalidomide, and 3 had received intensive chemoradiation to treat other cancers. Adverse events were related to neutropenia present at baseline: neutropenic fever (13 of 25 subjects) and septic death (1 of 25 subjects). Blood count improvements meeting the International Working Group criteria for response occurred in 11 of 25 (44%) subjects and were highly durable. Treatment-induced freedom from transfusion lasted a median of 1,025 days (range, 186-1,152 days; 3 ongoing), and 20% of subjects were treated for more than 3 years. Mutations and/or deletions of key apoptosis genes were frequent (present in 55% of responders and in 36% of nonresponders). Noncytotoxic DNMT1 depletion was confirmed by serial BM γ-H2AX (DNA repair/damage marker) and DNMT1 analyses. MYC master oncoprotein levels were markedly decreased. CONCLUSION. Decitabine regimens can be redesigned to minimize cytotoxicity and increase exposure time for DNMT1 depletion, to safely and effectively circumvent mutational apoptotic defects. TRIAL REGISTRATION. Clinicaltrials.gov NCT01165996. FUNDING. NIH (R01CA138858, CA043703); Department of Defense (PR081404); Clinical and Translational Science Award (CTSA) (UL1RR024989); and the Leukemia and Lymphoma Society (Translational Research Program)., Introduction Although conventional cytotoxic treatments for myeloid cancers can have differing proximal actions, e.g., topoisomerase inhibition (daunorubicin) or termination of DNA chain synthesis (cytarabine), a final common pathway converges onto [...]

Reports on sources of lead contamination in the environment of children. Proposes some solutions and presents statistics that relate poverty and lead contamination. (DDR)

We examined postprandial changes in circulating growth hormone (GH), insulin, insulin-like growth factor (IGF)-I, and IGF-binding proteins (IGFBPs) in yearling coho salmon under different feeding regimes. Fish were initially fasted for 1 day, 1 wk, or 3 wk. Fasted fish were then fed, and blood was collected at 4-h intervals over 26 h. After the various periods of fasting, basal levels of insulin were relatively constant, whereas those of IGF-I, IGFBPs and GH changed in proportion to the duration of the fast. A single meal caused a rapid, large increase in the circulating insulin levels, but the degree of the increase was influenced by the fasting period. IGF-I showed a moderate increase 2 h after the meal but only in the regularly fed fish. Plasma levels of 41-kDa IGFBP were increased in all groups within 6 h after the single meal. The fasting period did not influence the response of 41-kDa IGFBP to the meal. IGFBP-1 and GH decreased after the meal to the same extent among groups regardless of the fasting period. The present study shows that insulin and IGF-I respond differently to long (weeks)- and short (hours)-term nutritional changes in salmon; insulin maintains its basal level but changes acutely in response to food intake, whereas IGF-I adjusts its basal levels to the long-term nutritional status and is less responsive to acute nutritional input. IGFBPs maintain their sensitivity to food intake, even after prolonged fasting, suggesting their critical role in the nutritional regulation of salmon growth. fasting; refeeding; growth; metabolism

Abstract: An experiment was performed to determine the relative effects of photoperiod at emergence and growth rate on smolting pattern and early male maturation rate in Sacramento River (California, USA) [...]

The investigations into the tragedies exposed flaws in systems with fragmented responsibility, unenforceable guidelines, downloaded infrastructure costs, and deregulated and/or privatized monitoring programs. May 2000: In Walkerton, Ontario, tap water […]

WHEN the Supreme Court of Canada unanimously decided in June of 2001 that the small community of Hudson, Quebec, had the legal power to ban pesticide use, community activists from […]

The article discusses the repercussions of Chapter 11 of the North American Free Trade Agreement (NAFTA) on public interest. It cites the case of Dow AgroSciences (Dow) challenging the Quebec Pesticides Management Code in 2008. The article also presents a table of selected NAFTA investor claims from January 1994 to January 2013, and focuses on the difference between Dow's claim and the call to counteract cosmetic pesticide use in Canada.

Precocious male maturation is a natural life history strategy for spring Chinook salmon . During spawning, precocious males employ a 'sneaker' strategy to fertilize eggs in competition with full-size anadromous adults. Hatchery rearing practices may increase the incidence of this phenotype beyond its natural levels. Previous research reported high rates (>40%) of precocious male maturation at age 2 (minijacks) in the Yakima River spring Chinook salmon supplementation program in Washington State. Minijack rates in wild populations are believed to be less than 5%. We compiled seasonal profiles for size, condition factor ( K), gill Na+,K+-ATPase activity, whole-body lipid levels, plasma 11-ketotestosterone (11-KT), insulin-like growth factor-I (IGF-I), and thyroxine (T4) in minijacks and immature smolts in the hatchery and during out-migration. In the hatchery, minijacks were larger and had higher K, whole-body lipid, plasma 11-KT, and IGF-I levels than smolts. Plasma T4 and gill Na+,K+-ATPase activity increased in minijacks in spring, but the levels were slightly lower than those of smolts. Most minijacks are thought to remain resident in headwater streams throughout the summer in preparation for autumn spawning. A subset of these minijacks migrate hundreds of kilometers toward the ocean in the spring, only to reverse course later in the summer in an effort to return to their natal spawning grounds. These migrating minijacks had elevated plasma 11-KT, IGF-I, and T4 levels and gill Na+,K+-ATPase activity. It is generally thought that smoltification and reproductive maturation are mutually exclusive life history events in salmonid fishes. This investigation examined the physiology of a unique phenotype in which smoltification and downstream migration appear to occur in fish that have already initiated the maturation process. These results suggest that hatchery programs with high minijack rates may produce significant numbers of fish that are maladapted for either smoltification or competing on the spawning grounds, and it is likely that they die in the freshwater environment before contributing to subsequent generations. [ABSTRACT FROM AUTHOR]

Residualism is the failure of some hatchery-reared salmonid juveniles to out-migrate as smolts with the rest of their cohort. We released hatchery-reared juveniles from domesticated- and wild-origin broodstock steelhead and measured their relative rates of residualism. The residualism rate exhibited by the offspring of wild broodstock was more than one order of magnitude greater than that of domesticated stock. Further, we experimentally manipulated the growth trajectories of juvenile offspring of wild broodstock to decrease the size variance among released fish. Our expectation was that fewer fish would be too small or too large to smolt as yèarlings. Small fish placed on an aggressive rearing regimen (reared separately from larger fish, fed more food more often) residualized at a lower rate than did comparable control fish (reared with large fish without supplemental feeding). We saw no effect of a lower feeding regimen on the residualism rate of large fish, but the lower feeding regimen did not significantly affect size during rearing. Residual steelhead were bimodally distributed by size. Most residual fish were male; among these fish, 1 l-ketotestosterone levels and visual scores of gonadal development indicated that 42% were mature or maturing. All fish showed the expected patterns of change in gill Na+,K+-ATPase and insulin-like growth factor-I (IGF-I) associated with smoltification, and small fish placed on the aggressive rearing regimen showed slightly, but significantly, higher IGF-I levels than did comparable control fish. [ABSTRACT FROM AUTHOR]

Previous studies conducted at the Cle Elum Spring Chinook Salmon Supplementation Hatchery in Washington State demonstrated that 37-49% of the male Chinook salmon released from this facility in its first years of operation precociously matured at age 2 rather than the more typical age 4. We examined the effects of altering seasonal growth rate on the incidence of age-2 male maturation in an experimental subset of that population and compared their physiological development (size, growth rate, condition factor, whole-body lipid, gill Na+,K+-ATPase activity, and plasma insulin-like growth factor-I [IGF-I]) with that of both hatchery (production) and wild fish. Altering summer and autumn rations resulted in four growth trajectories with the following size and precocious male maturation rates: the high summer−high autumn growth trajectory produced fish averaging 25 g and 69% precocious maturation; the high summer−low autumn trajectory yielded fish that averaged 18 g and exhibited 58% precocious maturation; the low summer−high autumn trajectory produced 18-g fish with 51% precocious maturation; and the low summer−low autumn trajectory yielded fish averaging 16 g and 42% precocious maturation. Production fish averaged 22 g and exhibited a 53% precocious maturation rate. The high summer growth treatments and production fish were largest among all groups and had higher plasma IGF-I, adiposity levels, and precocious male maturation rates than did the low summer growth treatments. Wild fish were significantly smaller and leaner and had much lower plasma IGF-I levels than all other groups. Gill Na+,K+-ATPase activity was not different between groups, suggesting that there was no differential effect on smoltification. Growth modulation reduced the precocious male maturation rate by 39% among experimental treatments and by 21% between production fish and the low−low treatment. However, the maturation rate and adiposity of hatchery fish differed markedly from those of wild fish, suggesting that more dramatic alterations of rearing regime may be required to further reduce the prevalence of this phenotype in cultured fish. [ABSTRACT FROM AUTHOR]

Plasma levels of the hormones insulin and insulin-like growth factor-I (IGF-I) were assessed as indices of growth for individual juvenile coho salmon . Smolts were tagged in April, introduced to seawater in May, and reared at two different feeding levels. Fish lengths and weights were obtained in June, August, September, and November. Plasma samples were obtained in September and November. There was a consistent, robust relation (over both feeding rates and sampling dates) between plasma IGF-I and the instantaneous growth in length of individual fish when growth was measured over a 6-week period. There was no consistent association between plasma insulin level and growth, size, or condition factor. Plasma IGF-I levels were also measured in postsmolt coho salmon captured in September from the Strait of Georgia and Puget Sound and were found to be similar to those in laboratory fish. [ABSTRACT FROM AUTHOR]

The Yakima River Spring Chinook Salmon Supplementation Project in Washington State is one of the most ambitious efforts to enhance a natural salmon population currently under way in the United States. Over the past 5 years we have conducted research to characterize the developmental physiology of natural and hatchery-reared wild progeny spring Chinook salmon in the Yakima River basin. Fish were sampled at the main hatchery in Cle Elum, at remote acclimation sites, and, during smolt migration, at downstream dams. Throughout these studies, we characterized the maturational state of all fish using combinations of visual and histological analyses of testes, computation of gonadosomatic indices, and measurement of plasma 11-ketotestosterone (11-KT). We established that a plasma 11-KT threshold of 0.8 ng/mL can be used to designate male fish as either immature or precociously maturing approximately 8 months prior to final maturation (1-2 months prior to release as 'smolts'). Our analyses revealed that 37-49% of the hatchery-reared males from this program undergo precocious maturation at 2 years of age and that a portion of these fish appear to residualize in the upper Yakima River basin throughout the summer. An unnaturally high incidence of precocious male maturation may result in the loss of returning anadromous adults, the skewing of female : male sex ratios, and ecological and genetic impacts on wild populations and other native species. As precocious male maturation is significantly influenced by the growth rate at specific times of year, in future studies we will alter maturation rates through seasonal growth rate manipulations. [ABSTRACT FROM AUTHOR]

Comments on author George J. Benston's article 'U.S. Banking in an Increasingly Integrated and Competitive World Economy.' Four key factors that made it more difficult for U.S. banks to compete effectively with foreign banks; Increase in employment compared to foreign competitors for the period 1972-82 but decline thereafter; Rise in the usage of foreign banks among U.S. firms.

The impact of a time-limited discussion group for relatives of patients with Alzheimer's disease, co-led by psychiatrists, was studied. Participants became more knowledgeable about the illness and more accepting of their ambivalence toward their afflicted relative. They learned new ways of coping, while struggling to achieve mastery as they began the painful process of disengagement. Follow-up studies are indicated comparing educationally-oriented with problem-oriented discussion groups. [ABSTRACT FROM PUBLISHER]