Improvement in nitrogen fixation capacity could be part of the domestication process in soybean.

Biological nitrogen fixation (BNF) in soybeans is a complex process involving the interplay between the plant host and the symbiotic rhizobia. As nitrogen supply has a crucial role in growth and development, higher nitrogen fixation capacity would be important to achieve bigger plants and larger seeds, which were important selection criteria during plant domestication by humans. To test this hypothesis, we monitored the nitrogen fixation-related performance in 31 cultivated and 17 wild soybeans after inoculation with the slow-growing Bradyrhizobium diazoefficiens sp. nov. USDA110 and the fast-growing Sinorhizobium (Ensifer) fredii CCBAU45436. Our results showed that, in general, cultivated soybeans gave better performance in BNF. Electron microscopic studies indicated that there was an exceptionally high accumulation of poly-ß-hydroxybutyrate bodies in bacteroids in the nodules of all wild soybeans tested, suggesting that the C/N balance in wild soybeans may not be optimized for nitrogen fixation. Furthermore, we identified new quantitative trait loci (QTLs) for total ureides and total nodule fresh weight by employing a recombinant inbred population composed of descendants from a cross between a cultivated and a wild parent. Using nucleotide diversity (θπ), divergence index (Fst) and distribution of fixed single-nucleotide polymorphisms as parameters, we found that some regions in the total ureides QTL on chromosome 17 and the total nodule fresh weight QTL on chromosome 12 exhibited very low diversity among cultivated soybeans, suggesting that these were traits specially selected during the domestication and breeding process.

Pyrene based conjugated materials: synthesis, characterization and electroluminescent properties.

In this work, three novel pyrene cored small conjugated molecules, namely 1,3,6,8-tetrakis(6-(octyloxy)naphthalene-2-yl)pyrene (PY-1), 1,3,6,8-tetrakis((E)-2-(6-(n-octyloxy)naphthalene-2-yl)vinyl)pyrene (PY-2) and 1,3,6,8-tetrakis((6-(n-octyloxy)naphthalene-2-yl)ethynyl)pyrene (PY-3) have been synthesized by Suzuki, heck and Sonogashira organometallic coupling reactions, respectively. The effects of single, double and triple bonds on their optical, electrochemical, and thermal properties are studied in detail. These are all materials fluorescent and they have been used in organic light-emitting diodes (OLEDs) and their electroluminescent properties have been studied.

Prevalence of uridine glucuronosyl transferase 1A1 (UGT1A1) mutations in Malay neonates with severe jaundice.

A number of genetic risk factors have been implicated in the development of neonatal severe hyperbilirubinaemia. This includes mutations in the uridine glucoronosyl transferase 1A1 (UGT1A1) gene which is responsible for unconjugated hyperbilirubinemia in Gilbert's Syndrome. We studied the prevalence of UGT1A1 gene mutations in a group of Malay neonates to determine whether they are risk factors to severe neonatal jaundice. One hundred and twenty-five Malay neonates with severe hyperbilirubinemia were studied. Ninety-eight infants without severe hyperbilirubinaemia were randomly selected from healthy Malay term infants (controls). DNA from EDTA cord blood samples were examined for UGT1A1 mutations nt211G > A and nt247T > C using established Taqman SNP genotyping assays and the UGT1A1*28 variant was detected by the Agilent 2100 bioanalyzer. All samples were also screened for common Malay G6PD variants using established techniques. The frequency of UGT1A1 211G > A mutation is significantly higher in the severely hyperbilirubinemic group (13%) than the control group (4%; p = 0.015) and all the positive cases were heterozygous for the mutation. There was no significant difference in the frequency of UGT1A1*28 mutation between the severely hyperbilirubinemic (3.5%) and the control group (0.01%; p = 0.09). None of the neonates in both groups carried the nt247 T > C mutation. The prevalence of G6PD mutation was significantly higher in the severely jaundiced group than control (9% vs 4%; p = 0.04). In conclusion, nt 211 G > A alleles constitute at least 12% of UGT1A1 mutations underlying unconjugated hyperbilirubinemia and appears to be a significant independent risk factor associated with severe neonatal hyperbilirubinemia in the Malay newborns.

Real-time quantification for BCR-ABL transcripts in chronic myeloid leukaemia patients in UKMMC, Malaysia.

Molecular pathogenesis of chronic myeloid leukemia (CML) is well established and molecular monitoring for patients with CML has become an important practice in the management of patients on imatinib therapy. In the present study, we report the use of RQ-PCR method for detection of BCR-ABL fusion gene for our CML cases. We performed a two-step RQ-PCR on bone marrow aspirates or peripheral blood of 37 CML patients. Quantitative expression of BCR-ABL fusion gene was carried out relative to the expression of a housekeeping gene as endogenous control to compensate for uneven cell numbers, RNA quality, or variations in reverse transcription efficiencies. Twenty-four of these patients were pre-treated with hydroxyurea or alpha interferon prior to the imatinib therapy. Their BCR-ABL fusion gene levels were monitored for 18 months. All samples processed were evaluable. The PCR amplification efficiency of the ABL gene is 90.5% (0.2158) and the BCR-ABL gene, 93.4% (0.1573).

Genomewide Approach Validates Thiopurine Methyltransferase Activity Is a Monogenic Pharmacogenomic Trait.

We performed a genomewide association study (GWAS) of primary erythrocyte thiopurine S-methyltransferase (TPMT) activity in children with leukemia (n = 1,026). Adjusting for age and ancestry, TPMT was the only gene that reached genomewide significance (top hit rs1142345 or 719A>G; P = 8.6 × 10-61 ). Additional genetic variants (in addition to the three single-nucleotide polymorphisms [SNPs], rs1800462, rs1800460, and rs1142345, defining TPMT clinical genotype) did not significantly improve classification accuracy for TPMT phenotype. Clinical mercaptopurine tolerability in 839 patients was related to TPMT clinical genotype (P = 2.4 × 10-11 ). Using 177 lymphoblastoid cell lines (LCLs), there were 251 SNPs ranked higher than the top TPMT SNP (rs1142345; P = 6.8 × 10-5 ), revealing a limitation of LCLs for pharmacogenomic discovery. In a GWAS, TPMT activity in patients behaves as a monogenic trait, further bolstering the utility of TPMT genetic testing in the clinic.

Mortality from second tumors among long-term survivors of retinoblastoma.

BACKGROUND: Children diagnosed with retinoblastoma, a rare cancer of the eye, tend to develop and die of second primary cancers in childhood and adolescence, but few investigations have followed patients into adulthood. Retinoblastoma is frequently caused by inherited mutations of the RB1 tumor suppressor gene. Most patients with germline (hereditary) mutations have bilateral disease. PURPOSE: We sought to quantify the mortality from second malignancies among long-term survivors of retinoblastoma and to identify factors that predispose to these deaths. METHODS: A retrospective cohort study examined mortality among 1603 patients enrolled at 1 year after diagnosis of retinoblastoma during the period 1914-1984. Data on demography, family history, and retinoblastoma treatment were collected by medical chart review and questionnaire interview. Number of deaths, by cause, was compared with the corresponding expected figure based on U.S. mortality data for the general population for 1925-1990. RESULTS: Follow-up was complete for 1458 patients (91%) for a median of 17 years after retinoblastoma diagnosis. A total of 305 deaths occurred, 167 of them from retinoblastoma. There were 96 deaths from second primary tumors (relative risk [RR] = 30), 21 from other known causes (RR = 1.0), and 21 from ill-defined or unknown causes. Statistically significant excess mortality was found for second primary cancers of bone, connective tissue, and malignant melanoma and benign and malignant neoplasms of brain and meninges. Among 919 children with bilateral retinoblastoma, 90 deaths from second primary tumors occurred (RR = 60). Deaths from second tumors were more frequent among females (RR = 39) than males (RR = 22) (P = .007). The cumulative probability of death from second primary neoplasms was 26% at 40 years after bilateral retinoblastoma diagnosis, and additional cancer deaths occurred thereafter. Radiotherapy for retinoblastoma further increased the risk of mortality from second neoplasms. An excess of mortality from a second cancer, not seen in prior studies, was found among the 684 children with unilateral disease (RR = 3.1; 95% confidence interval = 1.0-7.3). CONCLUSIONS: These findings implicate germinal mutations in the retinoblastoma gene in second cancer mortality. Radiotherapy treatment for retinoblastoma appears to further enhance the inborn susceptibility to development of a second cancer. IMPLICATIONS: Patients with retinoblastoma, particularly bilateral retinoblastoma, should have careful follow-up, and interventions should be developed to reduce mortality from a second cancer.

An intelligent tutoring system for trauma management (Trauma-Teach): a preliminary report.

Trauma-Teach is an interactive software for tutoring surgical trainees on medical trauma management procedures. Users of the system interact with a virtual patient suffering from trauma injuries. The task of the user is to stabilise the virtual patient, discover the underlying injuries and decide on an appropriate management plan. Artificial intelligence techniques are used to simulate the patient's pulmonary and cardiovascular systems in real time, determine the responses and results of treatments and diagnostics accordingly, model the patient deterioration if wrong actions are taken, and give a measure of reality to the system by selecting actual trauma cases from the hospital's database.

The efficacy of sucralfate suspension in the prevention of oral mucositis due to radiation therapy.

PURPOSE: The purpose of this study was to assess the value of sucralfate suspension in prevention of oral mucositis and for reduction of oral pain in patients who develop mucositis during radiation therapy. METHODS AND MATERIALS: The study was a double-blind, placebo-controlled, randomized prospective trial of a sucralfate suspension in the prevention and management of oral mucositis during radiation therapy. Oral mucositis was assessed using a quantitative scale and symptoms were assessed using visual analogue scales. The statistical model was developed to detect a 40% reduction in mucositis. RESULTS: No statistically significant reduction in mucositis was seen. Early during radiation therapy less oral pain was reported in the sucralfate group, but as treatment progressed all patients experienced pain. Patients in the sucralfate group were prescribed topical and systemic analgesics later in the course of radiation therapy. CONCLUSION: Prophylactic oral rinsing with sucralfate did not prevent oral ulcerative mucositis. Sucralfate may reduce the experience of pain during radiation therapy.

Cancer of the tonsil: the results of ipsilateral radiation treatment.

BACKGROUND AND PURPOSE: The use of ipsilateral irradiation techniques to treat patients with carcinoma of the tonsil reduces the acute radiation reaction in the contralateral pharynx and late damage to the contralateral salivary tissue. However, this may also spare microscopic disease in apparently uninvolved contralateral lymph nodes. The purpose of this study was to analyse the survival and recurrence rates and sites of recurrance in a group of patients with carcinoma of the tonsil treated with ipsilateral techniques. MATERIALS AND METHODS: Between 1975 and 1993, 271 patients with invasive squamous cell cancer of the tonsil were referred to the Vancouver Cancer Centre (VCC). One hundred and seventy-eight received ipsilateral radiation treatment. Three received surgery only, six post-operative radiation, 12 supportive treatment only and 72 bilateral radiation treatment. In the absence of bilateral neck nodes and extensive lymphodenopathy, field sizes were generally kept small to include the primary tumour and the first echelon of nodes. The most common dose was 60 Gy in 25 daily fractions in 5 weeks (2.4 Gy per day). RESULTS AND DISCUSSION: The disease specific survival for all patients treated by radical radiation treatment was 61% at 5 years. For the 178 patients who received ipsilateral radiation treatment the overall primary tumour control rate by ipsilateral radiation treatment alone was 75% and for T1 and T2 tumours 84%. Eight (7.5%) of 101 of these patients with N0 nodes at presentation and without prior failure at the primary site, developed nodal recurrence (four within the initially radiated high dose volume). Two developed contralateral nodes, and two developed field edge nodal recurrence, one cured by surgery. In 54 patients with N1 disease, five developed nodal recurrence, two within field, two contralateral, one of whom was cured by surgery, and one at field edge. In 23 patients with N2a, N2b or N3 disease node control was achieved from radiation treatment in 11 and two more were cured by surgery. All nodal failures were within the radiated volume. Overall, 10 of the 25 patients with nodal failure were cured by subsequent surgery. CONCLUSIONS: Ipsilateral treatment of patients with carcinoma of the tonsil gives survival results that are at least as good as those reported with bilateral treatment with fewer side effects and a very low risk of failure in the contralateral neck.

Longitudinal trends in total serum cholesterol levels in a Japanese cohort, 1958-1986.

The 28-year follow-up of a Japanese cohort, having collected vast amounts of data collected on total serum cholesterol (TC), provided an exceptional opportunity to examine TC temporal trends. The longitudinal statistical method of growth-curve analysis was used to elucidate the age-related changes in TC levels and to characterize these trends in relation to sex, birth cohort, time period, place of residence, and body mass index (BMI). Japanese TC levels at initial examination were remarkably lower than those in western countries. During the study period from 1958 to 1986, TC levels increased dramatically with age in both sexes. The slope of the cholesterol growth curve was steeper for women than for men, with the difference growing larger after age 40 years. Drastic changes in Japanese behavior and lifestyle, especially westernization of the diet, are thought to have affected the TC values as time-period effects. As a result of this temporal change, which affected different cohorts at different ages, TC values were higher in members of the younger cohort. The increase of the TC values as time-period effects were larger in earlier period than in later period. These time-period effects appeared to be almost similar in men and women. The TC growth curves also varied by city of residence. Subjects in urban areas had higher TC values than subjects in rural areas. Changes associated with BMI from 1958 to 1986 were only partially responsible for the increased steepness of the TC growth curve.

Effects of radiation on the longitudinal trends of total serum cholesterol levels in the atomic bomb survivors.

The effects of radiation on the long-term trends of the total serum cholesterol levels of the Hiroshima and Nagasaki atomic bomb survivors were examined using data collected in the Adult Health Study over a 28-year period (1958-1986). The growth-curve method was used to model the longitudinal age-dependent changes in cholesterol levels. For each sex, temporal trends of cholesterol levels were characterized with respect to age, body mass index, city and birth year. We then examined whether the temporal trends differed by radiation dose. We showed that the mean growth curve of cholesterol levels for the irradiated subjects were significantly higher than that for the unirradiated subjects, and that the increase was greater for women than for men. No difference in dose response was detected between Hiroshima and Nagasaki. An increased mean level of cholesterol was evident for irradiated women in general, but a notable increase was apparent in males only for the youngest birth cohort of 1935-1945. The difference in the mean cholesterol levels between the irradiated and unirradiated subjects diminished past 70 years of age. It is not known whether this is due to natural progression or is an artifact of nonrandom variation in the rate of participation in the examinations. The maximum predicted increase at 1 Gy for women occurred at age 52 years for the 1930 cohort: 2.5 mg/dl (95% CI 1.6-3.3 mg/dl) for Hiroshima and 2.3 mg/dl (95% CI 1.5-3.1 mg/dl) for Nagasaki. The corresponding increase for men occurred at age 29 years for the 1940 cohort: 1.6 mg/dl (95% CI 0.4-2.8) for Hiroshima and 1.4 mg/dl (95% CI 0.3-2.6) for Nagasaki. Controlling for cigarette smoking did not alter the dose-response relationship. Although the difference in the mean growth curves of the irradiated and unirradiated groups was statistically significant, there was a considerable overlap in the individual growth curves of the two groups. The significant sex difference and the greater magnitude of radiation effects in women suggest that hormonal changes resulting from radiation exposure, such as accelerated menopause, is an area worth investigating to delineate the mechanisms underlying the increased cholesterol levels of the irradiated female subjects. This increase may also partially explain the increased rate of coronary heart disease seen in the atomic bomb survivors.

Noncancer disease incidence in the atomic bomb survivors: 1958-1986.

Using the longitudinal data of the Adult Health Study (AHS) cohort collected during 1958-1986, we examined for the first time the relationship between exposure to ionizing radiation and the incidence of 19 nonmalignant disorders in the A-bomb survivors. Affected individuals were ascertained through the three-digit codes of the International Classification of Diseases which are encoded in the AHS database subsequent to diagnoses made on the basis of general laboratory tests, physical examinations, and history-taking conducted during biennial AHS examinations. The disease onset time was estimated using the mid-point between the AHS examination data when the disease was initially reported and the previously attended disease-free examination date. Dosimetry System 86 organ doses judged to be most appropriate were used. Tests of dose effects were performed assuming a linear relative risk model with stratified background incidence. For the entire study period, significant excess risk was detected for uterine myoma (P < 0.001), chronic liver disease and cirrhosis (P = 0.006), and thyroid disease (P < 0.0001), defined broadly as the presence of one or more of certain noncancerous thyroid conditions. The incidence of myocardial infarction was shown to be increased (P = 0.03) in later years (1968-1986) among the younger heavily exposed AHS subjects, confirming the results of the recent Life Span Study (LSS) noncancer mortality report on coronary heart disease. The findings for uterine myoma may serve as additional evidence indicating benign tumor growth as a possible consequence of radiation exposure. Our results indicating the involvement of radiation in the development of liver diseases are consistent with the report of increased mortality from liver cirrhosis with radiation dose in the LSS cohort. An effect of age at exposure was detected for nonmalignant thyroid disease (P = 0.02), with an increased risk for those exposed who were under 20 years of age, but not for older survivors. Thus the AHS data suggest that thyroid glands in the young are more radiosensitive not only to the development of malignancies, but also to the development of nonmalignant disorders as well. The findings hold independently of the dose effects observed for thyroid cancer. This study also shows that for the period 1958-1986 new occurrences of lens opacity are not increased with radiation dose (P = 0.39) in the AHS subjects.

Relationship between cataracts and epilation in atomic bomb survivors.

Among 1713 atomic bomb survivors who underwent ophthalmological examinations from 1963-1964, the risk of cataract formation per unit dose of radiation was significantly greater for those who reported hair loss of 67% or more after exposure (the epilation group) than for those who reported less or no hair loss (the no-epilation group) (P < 0.01). Such an epilation effect has also been associated with leukemia mortality and the frequency of chromosome aberrations. Although this might be interpreted as indicating differential sensitivity to radiation between the epilation group and the no-epilation group, it could also be explained by imprecision in dose estimates. We have calculated that a 48% random error in DS86 dose estimates could be in accordance with the dose-response relationship for the prevalence of cataracts in the epilation group or the no-epilation group. Possible mechanisms for variation in radiosensitivity are discussed.

A genetic component to the variation of dehydroepiandrosterone sulfate.

Previous studies have shown wide variation in the normal range of serum concentrations of adrenal androgens, including dehydroepiandrosterone (DHA), and DHA sulfate (DHAS). Much of this variability has been shown to be due to the marked variation of the concentrations of these hormones with age. In a search for other sources of this variation, we examined the distribution of DHAS levels in 178 individuals drawn from 26 families. DHAS was chosen because of its relatively high serum concentration, long half-life, and lack of pulsatile variation. As expected, we observed a large age effect, such that it accounted for 68% of the overall variability. In addition, however, when age was factored out by appropriate polynomial regression, there was a significant genetic component to the residual variation, with a heritability of 65%. Thus there appeared to be a significant genetic determination to DHAS serum levels. The results are in accord with previous studies suggesting a genetic component to the variation in testosterone and sex hormone globulin concentrations, and the known correlation of DHAS and testosterone levels. Thus there appears to be significant genetic control of androgen concentrations in humans.

Osteonecrosis: study of the relationship of dental extractions in patients receiving radiotherapy.

Osteonecrosis is a severe complication of radiotherapy for cancer. Prevention of osteonecrosis is most important, as the condition may be chronic, progressive, and lead to pathologic fracture. The clinical experience, of 627 dental extractions at the Cancer Control Agency of British Columbia either before or after radiotherapy is presented.

Pretreatment assessment and dental management of patients with nasopharyngeal carcinoma.

Patients who present with nasopharyngeal carcinoma (NPC) require through oral and dental assessment prior to treatment of the malignancy. We assessed the oral status of 57 consecutive patients with a diagnosis of NPC. In this study, identified risk factors for NPC were seen to be different in Asian versus non-Asian patients. Epstein-Barr virus seropositivity was seen in all Asian patients and in 69% of non-Asian patients (P = 0.00006), and reported alcohol use was greater in the non-Asian patients. In this study it was found that 68% of dentate patients required dental extractions primarily due to periodontal disease. Even in patients who reported receiving regular dental care (28%) extractions prior to radiation therapy were suggested. Oral complications of radiation therapy were reported by 84% of patients, with the most common being xerostomia. Clinical diagnosis of candidiasis (16%), rampant caries (10% of dentate patients) and difficulties with dentures (25% of denture wearers) were noted. In addition to pretreatment assessment, continuing oral and dental management is needed for patients with NPC.

Using linked program and birth records to evaluate coverage and targeting in Tennessee's WIC program.

Public health nutrition programs are intended to serve low-income families who are at greater nutritional risk than the general population. Not all persons who are program-eligible are at equal risk, however. It would be desirable to evaluate a program's ability to enroll persons from higher risk backgrounds in the population (coverage) and, conversely, the extent to which those enrolled in this program are at higher risk (targeting). A method for the evaluation of coverage and targeting was developed using data from the Tennessee Women, Infants, and Children Special Supplemental Food Program (WIC) linked with birth certificates. The linked computer file was created by matching the name and date of birth in both record files. The birth records were the common source of information used to characterize the risk background for both the WIC and non-WIC participants. Maternal sociodemographic information on the birth records was used to define the health risk background of each child. The coverage and targeting of "at-risk" children were computed and compared for 50 counties or county-aggregates in Tennessee. Considerable variation in the coverage and targeting rates of at-risk children was observed among Tennessee counties, although the counties within each WIC administrative region tended to have similar coverage and targeting patterns. Using the existing data in linked program and vital records provides a direct evaluation of a program. Coverage and targeting evaluation can be used to detect underserved populations within small geographic areas.

A training workshop on late-stage dementia care for family caregivers.

Training workshops have been considered a useful intervention in helping family caregivers of people with dementia to cope with the stress of caregiving. However, there are no reports in the literature with regard to training and support of families specifically looking after individuals who are in the late stage of dementia. This paper reports the experience and evaluation of a training workshop aimed at preparing family caregivers for late-stage dementia care. Eighty-eight percent of the participants completed the client satisfaction questionnaire. The results from the questionnaire gave a very positive response, showing 90.9 percent of respondents were satisfied with the workshop, and 77.3 percent of respondents indicated that their caregiving needs were met. Eleven participants who attended this workshop joined a focus group feedback session. The Kruskal-Wallis test found no significant differences between the overall profile of the participants and that of the focus group in terms of age, gender, educational background, whether they were primary caregivers, for whom they cared (e.g., parents or spouse), or whether the care recipient stayed at home or in a nursing home. Findings from the focus group session provide a somewhat different picture from that of the questionnaire. Three focus group participants provided more critical comments of the workshop. Although the majority of the focus group agreed that the workshop had been useful, they disagreed on whether it is necessary to discuss psychosocial issues in this workshop. Findings from the focus group have enabled the project team to reflect on their design and operation of the workshop and provided valuable insight for future development as well as for further study.

Dissemination of an evidence-based intervention manual to improve managed care mammography rates.

After collaborating with the Centers for Disease Control and Prevention to develop an evidence-based mammography intervention manual, the dissemination of the manual in a managed care setting was assessed. Using qualitative methods (in-depth interviews), factors were examined that motivated use of the manual by the quality improvement units of eight Prudential HealthCare health plans. Seven of the plans implemented more intensive interventions after having received the manual than in the previous year. Factors that facilitated use of the manual and implementation of recommendations included: internal motivation, support of senior level management, adequate resources (time, personnel, and funds) to support interventions, and the organization and content of the manual itself.

Conditional survival and cause-specific mortality after autologous hematopoietic cell transplantation for hematological malignancies.

The probability of survival is conventionally calculated from autologous hematopoietic cell transplantation (aHCT). Conditional survival takes into account the changing probability of survival with time survived, but this is not known for aHCT populations. We determined disease- and cause-specific conditional survival for 2388 patients treated with aHCT over a period of 20 years at a single institution. A total of 1054 deaths (44% of the cohort) were observed: 78% attributed to recurrent disease; 9% to subsequent malignancies and 6% to cardiopulmonary disease. Estimated probability of relative survival was 62% at 5 years and 50% at 10 years from aHCT. On the other hand, the 5-year relative survival was 70, 75, 81 and 88% after having survived 1, 2, 5 and 10 years after aHCT, respectively. The cohort was at a 13.9-fold increased risk of death compared with the general population (95% confidence interval (CI)=13.1-14.8). The risk of death approached that of the general population for 10-year survivors (standardized mortality ratio (SMR)=1.4, 95% CI=0.9-1.9), with the exception of female Hodgkin's lymphoma patients transplanted before 1995 at age 40 years (SMR=6.0, 95% CI=1.9-14.0). Among those who had survived 10 years, nonrelapse-related mortality rates exceeded relapse-related mortality rates. This study provides clinically relevant survival estimates after aHCT, and helps inform interventional strategies.