Are all RAS mutations the same? Coexisting KRAS and NRAS mutations in a caecal adenocarcinoma and contiguous tubulovillous adenoma.

Mutations of the human Kirsten rat sarcoma viral oncogene homologue (KRAS) and the highly homologous human neuroblastoma RAS viral oncogene homologue (NRAS) are associated with resistance to antiepidermal growth factor receptor therapies in patients with colorectal cancer. In this report, we describe a caecal adenocarcinoma that contains both KRAS c.35G>T (G12V) and NRAS c.34G>A (G12S) mutations. The adenocarcinoma arises from a contiguous high-grade tubulovillous adenoma, which also carries the identical KRAS and NRAS mutations, supporting their common origin. While KRAS mutations are common in colorectal cancers, NRAS mutations are relatively rare and the coexistence of multiple RAS mutations is not documented, presumably reflecting similar functions of wild-type and mutant forms of RAS. Recent experimental evidence has suggested that KRAS and NRAS may in fact mediate distinct biological processes in the colon, and this unusual case potentially illustrates the hypothesis clinically. Characterisation of the diverse and divergent functions of RAS family members and mutant forms of RAS in the colon form important considerations for the development of RAS-targeting therapeutics.

Evaluation of a farm safety day program: participants and non-participants over a one-year follow-up period.

Farm safety day programs are attended each year by thousands of children in rural communities. This evaluation of a national farm safety day program assessed changes in knowledge and reported behaviors among safety day participants, aged 8 to 13 years, and a comparison group of children who did not attend a safety day. The outcome evaluation involved a quasi-experimental design with participants and non-participants, measured with a pre-test, three-month telephone follow-up, and one-year telephone follow-up survey. The study included 621 children from a sample of 28 safety days administered throughout North America and 413 non-participants recruited from the same or nearby communities. The survey instruments measured participants' knowledge of safety hazards, knowledge of appropriate safety behaviors, and current practices with regard to safety behaviors. While both participants and non-participants showed improved safety knowledge and safe behavior scores over time, there were significantly greater increases in knowledge and behaviors for the safety day participants than for the non-participants. Improvements occurred for all age levels and were sustained through the one-year follow-up assessment. This study contributes to the body of evidence that such safety programs can have a long-term effect on the knowledge and safe practices of children who attend them.

Minor pathological changes are induced by naltrexone-poly(DL-lactide) implants in pregnant rats.

Oral naltrexone is used to treat alcohol and heroin dependence but is associated with poor patient compliance. Sustained-release preparations have been developed to overcome noncompliance. Many sustained-release preparations are composed of polymers combined with naltrexone. Limited data indicate that polymers induce variable levels of tissue reactivity and that naltrexone may increase this effect. A slow-release subcutaneous naltrexone-poly (DL-lactide) implant is currently being trialed to treat heroin dependence in Western Australia. A minority of women fall pregnant and, although tissue reactivity in nonpregnant humans is relatively minor, detailed chronological data during pregnancy are lacking. Histological changes in pregnant rats were assessed; a single active tablet containing poly[trans-3,6-dimethyl-1,4-dioxyane-2,5-dione] (DL-lactide) loaded with 25 mg of naltrexone was implanted subcutaneously, and tissue response was compared with inactive polymer implantation. Rats were timed mated at 13-26 days postimplant. Tissue assessment up to 75 days by a pathologist showed that naltrexone induced chronic inflammatory response in a dose-dependent manner, although still at a low level. Furthermore, for inactive implants, minimal foreign body reaction and fibrosis, together with low-level inflammation, suggested good long-term biocompatibility. We conclude that the Australian naltrexone-poly(DL-lactide) implant is tolerated in pregnant rats, reinforcing its potential role for managing alcohol and heroin dependence in pregnant humans.

The community benefits of farm safety day camps.

In addition to the direct impact of a farm safety day camp on its participants' knowledge and safety awareness, there are extended and indirect effects that occur through the wider dispersion of information and the involvement and cooperation of community members. Reports completed by 228 coordinators of farm safety day camps, report forms completed by 5,037 volunteers at farm safety day camps, and telephone interviews with 924 parents of farm safety day camp participants were analyzed for evidence of the impact of the camps beyond the immediate knowledge gained by the children who participated. These data indicate that the indirect benefits to a community include enhanced safety awareness within the wider community as children and adult volunteers disseminate the information they learned, as well as enhanced community strength and cohesiveness resulting from the cooperation of many individuals and organizations in achieving a common goal.

Histological changes over time around the site of sustained release naltrexone-poly(DL-lactide) implants in humans.

In order to assess the histological tissue changes over time around the site of implant, tissue biopsies were taken at 1 to 38 months post-implant from 54 (34 male) consenting human subjects who had received the Australian subcutaneous naltrexone-poly(DL-lactide) implant for heroin dependence. The implant consists of multiple tablets containing compressed naltrexone-poly[trans-3,6-dimethyl-1,4-dioxane-2,5-dione] (DL-lactide) loaded microspheres. Assessment of tissue samples by pathologists showed an early phase (up to 12 months post-implant) of inflammation, foreign body reaction, and fibrosis. This subsided gradually over the next 12 months until tissue returned to normal by 25+ months. Sufficient evidence was not available to conclude that the poly(DL-lactide) implant matrix was totally biodegradable within the study period. While implant material was not identified in most of the latter biopsies, its presence was noted in one biopsy at 26 months post-implant. Nevertheless the study results did demonstrate the implant's biocompatibility by the lack of inflammation, foreign body reaction, and fibrosis detected by 25+ months. It seems highly probable that surgical technique rather than the implant itself was associated with the additional finding of fat necrosis. Moderate fat necrosis was observed as a common feature of biopsies carried out during the first 6 months following implant. It subsided to mild levels over the next 18 months, and was notably absent by 25+ months. The results of the study indicated that the Australian naltrexone-poly(DL-lactide) implant is well tolerated and may have a role for use in the management of medical conditions such as heroin dependence.

Safety-related knowledge and behavior changes in participants of farm safety day camps.

Significant resources are devoted to conducting farm safety day camps throughout North America, but the impact and effectiveness of these programs has not been systematically demonstrated. This project assessed changes in safety-related knowledge and behaviors among participants in the Progressive Farmer Farm Safety Day Camp program. A written pre-test and a three-month telephone post-test were administered to three samples of participants, ages 8 to 13, in camps held in 1999, 2000, and 2001. A sample of 20 to 30 camps was included in each year of the study, with a total sample of 1,780 participants for all three years. The pre-test and post-test contained questions related to first aid and to safety around animals, ATVs, farm equipment, flowing grains, and tractors. Three scores were computed from responses to 20 knowledge and behavior items. A knowledge score indicated the number of 8 knowledge items answered correctly, a behavior risk score indicated the amount of risk exposure for the child based on 8 behavior items, and an ATV safety gear risk score indicated, for those who rode ATVs, the level of risk due to lack of proper safety gear (4 items). From pre-test to post-test, there was an increase in knowledge scores and a decrease in behavior risk scores and ATV safety gear risk scores. These changes were consistent both for males and females, for farm residents and non-farm residents, and across all ages in the sample. These results support claims for the effectiveness of farm safety day camps for increasing knowledge and improving safe practices among camp participants.

Hopelessness and violence among inner-city youths.

OBJECTIVES: Ethnographic literature on inner-city life argues that adolescents react to their uncertain (and objectively bleak) future by abandoning hope; this, in turn, leads them to engage in risk behaviors, including violence, with considerable frequency. This study empirically measures the pervasiveness of hopelessness and uncertainty about the future among inner-city adolescents and documents the link between hopelessness, uncertainty, and risk behavior. METHODS: We surveyed a sample of 583 adolescents (aged 9-19) living in public housing in Huntsville, AL; this constitutes 80% of the eligible population. Each participant in the survey received $10. Their responses yielded empirical distributions for hopelessness, uncertainty about the future, and four violent behaviors. Using OLS regression, we examined the effect of hopelessness on these violent behaviors. RESULTS: Hopelessness about the future was relatively rare, affecting only 20-30% of the respondents. However, it was a strong predictor of fighting and carrying a knife for females, and of carrying a knife, carrying a gun, and pulling a knife or gun on someone else for males. Uncertainty about the future was more prevalent, but unrelated to the violent behaviors. CONCLUSIONS: These results suggest that the conclusions of the ethnographic literature are only partially valid: While hopelessness is, in fact, strongly related to risk behavior, it is not nearly so prevalent as is generally assumed.

How children die in hospital.

A retrospective analysis was performed to describe the course of terminal care provided to dying hospitalized children in terms of symptom assessment and management, and communication and decision-making, at the end of life. Seventy-seven of 236 infants and children who died after hospital admission in Edmonton, Canada between January 1996 and June 1998 met entry criteria. Only children who died after a minimum hospitalization of 24 hours in the case of chronic illness or after a minimum hospitalization of 7 days following an acute event were included. Unanticipated deaths were excluded. Eighty-three percent of children died in intensive care settings (64/77), and 78 % (60/77) were intubated prior to their death. Symptoms were recorded in narrative progress notes. Five of 77 (6%) charts contained specific pain assessment and treatment records. Opioid analgesia was provided in 84 % of all cases (65/77). Six (8 %) patients had do not resuscitate (DNNR) orders preceding final hospital admission and 56/71 (79%) remaining patients had documented discussion resulting in DNR decision during final hospital admission. Median time from DNR to death was < 1 day. Mode of death was withdrawal of therapy in 33/77 (43 %), no cardiopulmonary resuscitation (CPR) in 26/77 (34 %), andfailed CPR in 13/77 (17%). Five children were declared brain dead. In only one case was there evidence in the medical record of the possibility of death being discussed explicitly with the patient. Decision-making regarding end-of-life issues in this pediatric population was deferred very close to the time of death, and only after no remaining curative therapy was available. Acuity of care was very high prior to death. Children are rarely told that they are dying.

A new disorder of hyaluronan metabolism associated with generalized folding and thickening of the skin.

OBJECTIVE: To describe and characterize a new disorder of hyaluronan metabolism associated with marked abnormalities of cutaneous tissue and to determine whether a relationship with a phenotypically similar disorder in the shar-pei dog exists. METHODS: Biopsy specimens of the skin of a child with extreme cutaneous thickening and folding were examined by light and electron microscopy. The concentration of hyaluronan and the activity of hyaluronidase were measured in the patient's serum and plasma, respectively, and the activity of hyaluronan synthase was examined in cultured dermal fibroblasts. Hyaluronan concentration was also measured in the plasma of 23 shar-pei and 34 control dogs. RESULTS: The patient's skin displayed gross accumulation of hyaluronan, and the serum concentration of hyaluronan was markedly elevated (up to 3100 microg/L) during infancy. Hyaluronan synthase activity of cultured dermal fibroblasts was increased, whereas hyaluronidase activity in plasma was normal (5.5 +/- 0.08 IU/L). Plasma hyaluronan concentration was higher in the shar-pei dogs than in control dogs (median, 378 microg/L vs 73 microg/L, respectively). CONCLUSION: The child we describe has a novel disorder of hyaluronan metabolism, which appears to result from abnormal control of hyaluronan synthesis. An analogous disorder may be present in the shar-pei dog.

Exposure to alcohol in utero: Influence on cognitive function and learning in a northern elementary school population.

OBJECTIVES: To establish the prevalence of fetal alcohol exposure; to compare physical, behavioural and learning patterns of children with significant alcohol exposure in utero with those of a group of children exposed to minimal alcohol; to assess the usefulness of a fetal alcohol syndrome (FAS)/fetal alcohol effect (FAE) score; and to provide feedback to parents, schools and communities. DESIGN: Parent questionnaire, complete physical examinations of children, psychometric tests of the children using elements of the Pediatric Early Elementary Examination (PEEX) and the Pediatric Examination of Educational Readiness (PEER), ADD-H comprehensive teachers rating scale (ACTeRS) score, the newly developed FAS/FAE Score, and the Brigance Comprehensive Inventory of Basic Skills to assess language and mathematical achievement. Testers were blinded to the results of the assessments and questionnaires. SETTING: Grades 1 to 3 at Sir Alexander MacKenzie School in Inuvik, Northwest Territories. RESULTS: Twenty-four per cent of mothers reported frequent or binge drinking, and 76% of mothers reported abstinence or moderate alcohol intake. There were significant ethnic differences; none of the Caucasian mothers reported frequent or binge drinking during pregnancy compared with 40% of Inuvialuit and 33% of Indian mothers. Children with exposure to frequent or binge drinking in utero had smaller palpebral fissures (2.3+/-0.1 cm versus 2.5+/-0.3 cm, P<0.01), smaller palpebral fissure to intercanthal distance ratios (0.77+/-0.05 versus 0.86+/-0.10, P<0.01) and smaller head circumferences (52.1+/-1.6 cm versus 53.6+/-1.6 cm, P<0.01) than those exposed to moderate drinking or abstinence. Children exposed to frequent or binge drinking in utero also demonstrated poorer coordination (P<0.005) and cortical function (P<0.01), attention problems, hyperactivity (ACTeRS), and poorer scholastic achievement in language (P<0.001) and mathematics (P<0.01) than their minimally exposed counterparts. In children in grades 2 and 3, a significant negative correlation was found between FAS/FAE scores and language (r=-0.55, P<0.001) and mathematical achievement (r=-0.28, P=0.20). CONCLUSIONS: The prevalence of drinking during pregnancy in the northern population studied was high, and exposure in utero was associated with physical abnormalities, difficulties with coordination and cortical function, and significant delays in language and mathematical achievement. The FAS/FAE score may be useful in predicting success or failure in language development.

Pararetrovirus-crucifer interactions: attack and defence or modus vivendi?

Abstract The compatible infection of plants by viruses usually leads to the development of systemic symptoms. Symptom expression of this kind is generally understood to be a host response that indicates an inability of the host to defend itself from attack. We have been studying compatible interactions between the plant pararetrovirus cauliflower mosaic virus (CaMV) and its crucifer hosts in order to understand the relationship between viral activity, symptom expression and plant defence. A CaMV protein (P6) appears to play a major role in eliciting symptom expression. This host response leads to a regulation of the viral multiplication cycle that is associated with leaf mosaics. The host regulation of CaMV appears to operate at the transcriptional level through an effect on the 35S promoter, or at the post-transcriptional level by a process that is akin to gene silencing, and can lead to host recovery depending upon the genetic background of the host. The plant apex is a focus for antiviral defence mechanisms, presumably because viral infection of the apical meristem would rapidly compromise the ability of the plant to generate new leaves and flowers for reproduction. The balance of interactions between CaMV and crucifers can provide a sustainable source of host plants to ensure viral propagation and viral exposure allows the host to adapt and develop its repertoire of defence mechanisms.

Transmission electron microscopic pathoanatomy of congenital trigger thumb.

Previous studies of trigger digits in children have been limited to gross morphology and light-microscopic histology. Nine children with 11 trigger thumbs formed a preliminary study group for electron-microscopic evaluation of tendon nodules and A-1 pulleys. This pathoanatomic investigation was not previously reported. Comparison was made with light-microscopic sections. Large amounts of mature collagen was observed. Fibroblasts with prominent rough endoplasmic reticulum were present. No degenerative or inflammatory changes were noted in either tendon or sheath. We believe that although the etiology of trigger digits is still uncertain, an infectious, inflammatory, or degenerative process is unlikely.

IgA nephropathy and thin basement membrane disease in association with Crohn disease.

There have been a wide variety of reported renal parenchymal diseases associated with inflammatory bowel disease, ranging from interstitial nephritis to amyloidosis to immune complex glomerulonephritis. Two pediatric cases of renal parenchymal pathology in association with Crohn disease are presented. The first is an 11-year-old child who presented with recurrent bouts of gross hematuria, biopsy-proven IgA nephropathy, and later developed Crohn disease 4 years after the initial presentation. Her renal function is normal with persistent isolated microscopic hematuria. The second case is that of a 9-year-old male who presented with the classic gastrointestinal manifestations of Crohn disease, later developed hematuria and proteinuria, and was found on a renal biopsy to have thin basement membrane disease. There have been several reported cases of IgA nephropathy associated with inflammatory bowel disease; but to our knowledge, this is the first case of thin basement membrane disease occurring in conjunction with Crohn disease. Discussion focuses on the relationship of IgA nephropathy with inflammatory bowel disease with additional comments on thin basement membrane disease.

The determinants of trust and credibility in environmental risk communication: an empirical study.

This study examines a key component of environmental risk communication; trust and credibility. The study was conducted in two parts. In the first part, six hypotheses regarding the perceptions and determinants of trust and credibility were tested against survey data. The hypotheses were supported by the data. The most important hypothesis was that perceptions of trust and credibility are dependent on three factors: perceptions of knowledge and expertise; perceptions of openness and honesty; and perceptions of concern and care. In the second part, models were constructed with perceptions of trust and credibility as the dependent variable. The goal was to examine the data for findings with direct policy implications. One such finding was that defying a negative stereotype is key to improving perceptions of trust and credibility.

Roles of the 35S promoter and multiple overlapping domains in the pathogenicity of the pararetrovirus cauliflower mosaic virus.

Elements associated with the 35S promoter involved in generating the pregenomic RNA (35S RNA) of the pararetrovirus cauliflower mosaic virus have been extensively studied in heterologous systems, but little is known about their role in viral pathogenicity. To investigate these elements, premature termination codons were progressively inserted into the 3' end of the adjacent gene VI to dissect it from colinear 35S enhancer sequences. The ability to cause a systemic infection in plants was retained with loss of up to 40 amino acids from the gene VI polypeptide, but truncations into a putative zinc finger proved lethal. In the 35S promoter, removal of the TATA box also abolished infectivity. However, upstream deletions encompassing the 35S enhancer showed that the sequence between -207 and -56 from the cap site comprised nonessential elements, although complete removal of this fragment caused loss of infectivity even when domain spacing was restored by linker insertion. Two separate enhancer domains (-207 to - 150 and -95 to -56) were identified, of which either one or the other, but not both, was required for infectivity. Some mutations affected the cellular levels of viral RNAs in unexpected ways, as with removal of the as-1 enhancer element causing an increase in 35S RNA. Others altered the relative abundance of nuclear and cytoplasmic viral DNAs. Mutations in promoter domains thought to be involved in regulating tissue-specific expression did not significantly affect virus accumulation in leaves versus roots, whereas gene VI mutants showed reduced root accumulation. We conclude that elements associated with the cauliflower mosaic virus 35S promoter contain extensive nonessential regions that can behave differently in their proper context than as isolated elements.

Industry response to SARA Title III: pollution prevention, risk reduction, and risk communication.

This paper reports results from a survey designed to: (1) evaluate changes in industrial pollution prevention practices since the passage of the landmark environmental legislation, the Emergency Planning and Community Right-to-Know Act of 1986, also known as SARA Title III, and (2) identify those factors that may contribute to an industrial facility engaging in pollution prevention and risk communication activities. The survey was conducted under a Cooperative Agreement between the U.S. Environmental Protection Agency and the Columbia University Center for Risk Communication. Evidence from the survey indicates that a wide variety of waste and pollution reduction activities have been undertaken since passage of the Act. Virtually all facilities surveyed in the pulp and paper, chemical, and petroleum and refining industries reported that they had reduced pollutants or wastes on at least one of ten measures, including reducing toxic air emissions. Most facilities indicated paying more attention to pollution prevention activities as a result of SARA Title III and half reported that their communication activities have also increased.

Risk communication: a tool for behavior change.

This chapter presents some of the theories and models underpinning effective communication practice. It also emphasizes the central role of communication in achieving effective program implementation. Whether the communication is aimed at changing the attitudes and behavior of professionals, various segments of the public, or other target audiences, the basic approach is the same. The following checklist provides a guide to program planners (Arkin 1991): Commit adequate time, effort, and resources to communication planning and pretesting. Begin by singling out specific issues and specific target audiences. Then design messages based on the target audiences' values, needs, and interests. Conduct (or review existing) market research on the target audience to understand what will motivate them. Pretest messages and materials with the target audience to assure understanding and relevance to their needs and interests. Make sure that messages and materials appear where the target audience will pay attention to them (for sensitive issues, community and interpersonal channels that allow interactive discussion are very important). Produce public service announcements that are of high quality, community specific, marketed to stations, and targeted to audiences likely to see them when public service air time is available (such as fringe viewing times). Combine public service announcements with news and other uses of the mass media (e.g., building on related news) to increase exposure to issues. Use a combination of the mass media and community channels that will reach the target audience. Work collaboratively with other organizations, including drug treatment facilities, law enforcement and social service agencies, and other community organizations that have complementary strengths. Begin to coordinate efforts as early as possible in program planning. Use a multipronged communication strategy to focus on what an individual should do, how the individual can start to change, and factors that help reinforce individual change, such as peer approval and community support. Track progress and identify when, and what kind of, changes are needed in communications. Combine communications with other strategies needed to support change (e.g., access to treatment or positive alternatives to drug use). Set reasonable, short-term communication objectives to reach the long-term goal. Then, commit to communications as one program component over the long term. It is important to remember that one-shot campaigns are unlikely to have a lasting effect and that progress is incremental.

Involving the patient can free resources.

Involving the patient in the scheduling of theatres by a Diary Booking System improves patient choice and thus the quality of service offered. To assess the feasibility and cost effectiveness of such a system, a trial was conducted within ENT surgery. One consultant's theatre schedules were analysed before and after the introduction of a diary booking system. A second consultant's schedules, not using a diary booking system, were analysed to confirm the absence of seasonal variation or other factors. The trial consisted of three months' schedules before introduction and three months after introduction. The feasibility of the system was confirmed. The trial reduced cancellations by 32% and failures to attend by 68%. The introduction of the Diary Booking System increased the number of operations conducted by nearly one per session.

Effects of taipan (Oxyuranus scutellatus) venom on erythrocyte morphology and blood viscosity in a human victim in vivo and in vitro.

The case of a snake handler with envenoming due to Australian taipan (Oxyuranus scutellatus) showing marked morphological changes in his red blood cells is presented. The red cells underwent sphero-echinocytic transformation and in subsequent experiments in vitro the effects of taipan venom on red cells were further characterized. Taipan venom induced sphero-echinocytic transformation at nanogram/ml concentrations and led to a marked increase in whole blood viscosity. These changes have not been featured in previous reports of taipan envenomation and are reported to highlight the diagnostic value of blood film examination in cases of suspected envenomation. The significance of the hyperviscosity, and consequent reduction in blood fluidity, is unknown and requires further investigation.