Biomedical subjects
Publications and source records attributed to R Thompson.
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Sexual dimorphism in copulatory behavior results from organizational actions of sex steroids (permanent effects of sex steroids occurring during early development). Reproductive success depends not only on copulatory behavior, but also on mate choice, which is often sexually dimorphic as well. The clearest example is sexual partner preference: the preference of males for female sexual partners and females for males. Are organizational hormone actions responsible for sexual differentiation of sexual partner preference? The zebra finch (Taeniopygia guttata) is a potentially valuable species for addressing this question, because the birds form life-long socially monogamous pair bonds. In one experiment, both early estrogen treatment (injection with estradiol benzoate-EB-for the first 2 weeks posthatch) and unisex housing during juvenile development independently resulted in a preference for females over males in two-choice tests, and only females that experienced both EB treatment and unisex living were more likely than controls to pair with other females in colony tests. In a second experiment, females injected with an estrogen synthesis inhibitor for the first week posthatch preferred to spend time near females instead of males in two-choice tests, unlike control females. These experiments suggest that sexual partner preference may result from organizational hormone actions in this pair-bonding species. Possible neural mechanisms or sites that could underly hormonal organization of sexual partner preference in birds and mammals include the anterior hypothalamic/preoptic area, the corticomedial amygdala, and its avian homologue nucleus taeniae of the archistriatum, the septum, and peripheral sensory processes.
A pollen-specific cDNA was isolated from a cDNA library of in vitro germinated pollen of the diploid potato species Solanum berthaultii. The cDNA clone, designated SB401, hybridizes to a messenger RNA of 1.2 kb length in mature and germinated pollen. SB401 messenger RNA is absent from other parts of the plant, including other flower tissues. SB401 cDNA, which possesses a long stretch of AT-rich 5'-untranslated leader sequence, encodes a glutamic acid-rich protein (GARP) which is hydrophilic throughout and contains six imperfect repeated motifs of the sequence V-V-E-K-K-N/E-E with the di-basic amino acid residue pair (K-K) as the core within the repeats. These repeats are spaced at irregular intervals and predicted to form an alpha-helical structure. The SB401 protein was over-expressed in Escherichia coli and the purified protein was used for raising antiserum. Both E. coli-expressed and the endogenous SB401 proteins in pollen and pollen tubes appear much larger on SDS-polyacrylamide gels than their calculated molecular masses. Immunoblotting revealed the protein to be most abundant in germinated pollen. The structural features of SB401 protein and a possible role for the protein in pollen development, pollen germination, and pollen tube growth are discussed.
Pathology reports and slides were reviewed from 267 mammographically detected impalpable breast lesions, excised after hookwire localisation. There were 182 benign and 85 malignant lesions (benign to malignant ratio of 2.1:1). The invasive cancers tended to be small (mean 13 mm; 50% < or = 10 mm), of low histologic grade (38% Grade I), with a low incidence of lymph node metastases (15%). A high proportion of pure duct carcinoma in situ (DCIS) lesions (21%) was found, and an unusually high proportion of invasive lobular carcinoma (17%). Preoperative fine needle aspiration (FNA) was performed in 95 (36%) cases, including 47 (18%) sampled using sterotactic guidance and 48 (18%) sampled by palpation. The absolute sensitivity of diagnosis of malignancy was 32% and 5% respectively. In 79% of carcinomas further operation was performed, for axillary clearance or re-excision of incompletely excised tumor; this high rate was largely a result of a decision not to use frozen section diagnosis for impalpable lesions and because of the early stages of the development of preoperative needle diagnosis. 58% of invasive cancers, including seven of eight (87.5%) carcinomas with an extensive intraduct component (EIC + ve), and 72% of DCIS were incompletely excised at the first operation. Residual tumor was found in the re-excisions in 26% of EIC - ve invasive carcinomas, 71% of the EIC + ve cases and 56% of DCIS lesions. The malignant lesions had highly favourable prognostic indices. The need for concentration of experience with pre-operative FNA was highlighted. Positive excision margins were a good predictor for residual malignancy, particularly for EIC + ve cases and for DCIS lesions.
A deterministic two-loci model was developed to predict genetic response to marker-assisted selection (MAS) in one generation and in multiple generations. Formulas were derived to relate linkage disequilibrium in a population to the proportion of additive genetic variance used by MAS, and in turn to an extra improvement in genetic response over phenotypic selection. Predictions of the response were compared to those predicted by using an infinite-loci model and the factors affecting efficiency of MAS were examined. Theoretical analyses of the present study revealed the nonlinearity between the selection intensity and genetic response in MAS. In addition to the heritability of the trait and the proportion of the marker-associated genetic variance, the frequencies of the selectively favorable alleles at the two loci, one marker and one quantitative trait locus, were found to play an important role in determining both the short- and long-term efficiencies of MAS. The evolution of linkage disequilibrium and thus the genetic response over several generations were predicted theoretically and examined by simulation. MAS dissipated the disequilibrium more quickly than drift alone. In some cases studied, the rate of dissipation was as large as that to be expected in the circumstance where the true recombination fraction was increased by three times and selection was absent.
OBJECTIVE: To assess the level of increased risk, if any, of hospitalizations for aseptic meningitis after Jeryl-Lynn mumps strain measles-mumps-rubella (MMR) vaccine in the Vaccine Safety Datalink population. STUDY DESIGN: A possible increased risk of aseptic meningitis 8 to 14 days after receipt of MMR was observed in a preliminary screening analysis of automated data from the Vaccine Safety Datalink (VSD) project Year 2 analysis. To further evaluate this association a retrospective 10-year matched case-control study was undertaken in the four health maintenance organizations (HMOs) in the VSD project. Cases ascertained from a broad scan of the automated data were validated against a standard case definition. Two controls matched on age, sex, HMO and HMO membership were assigned per case. RESULTS: The VSD project involves the cooperative collection of automated vaccination and medical outcome data from four large HMOs that currently have 500,000 children younger than 7 years of age under surveillance. Review of automated screening results from the first 2 years of data revealed a possible increased risk of aseptic meningitis 0 to 14 days after MMR with a relative risk of 3.61 (95% confidence interval, 1.0 to 13.1) although the total number of cases was small. Although the automated data had suggested a possible association of aseptic meningitis with MMR containing the Jeryl-Lynn strain of mumps, review of validated hospitalized cases during the observation period did not reveal evidence of an increased risk of aseptic meningitis after MMR containing the Jeryl-Lynn strain of mumps (odds ratio < 1.0 for all analyses). CONCLUSION: Although it is recognized that hospitalized cases represent a minority of the total cases of aseptic meningitis, it is reassuring that in this evaluation no increased risk of aseptic meningitis after MMR vaccine was found.
MK-0991 (L-743,872) is a potent antifungal agent featuring long half-life pharmacokinetics. The pharmacokinetics of MK-0991 administered intravenously to mice, rats, rhesus monkeys, and chimpanzees is presented. Unique to MK-0991 is its consistent cross-species performance. The range of values for the pharmacokinetic parameters were as follows: clearance, 0.26 to 0.51 ml/min/kg; half-life, 5.2 to 7.6 h; and distributive volume, 0.11 to 0.27 liters/kg. The level of protein binding of MK-0991 was determined to be 96% in mouse and human serum. The compound exhibited high affinities for human serum albumin and at least two lipid components. The rationale for the selection of MK-0991 as a drug development candidate was based on its two- to threefold superior pharmacokinetic performance in chimpanzees over the performance of an otherwise equivalent analog, L-733,560. Once-daily dosing for MK-0991 is indicated by a graphical comparison of levels in the circulations of chimpanzees and mice. In a study of the pharmacokinetics of MK-0991 in mouse tissue, the organs were assayed following intraperitoneal administration. The area under the concentration-versus-time curves (AUC) segregated the tissues into three exposure categories relative to plasma. The tissues with greater exposure than that for plasma were liver (16 times), kidney (3 times), and large intestine (2 times). The exposure for small intestine, lung, and spleen were equivalent to that for plasma. Organs with lower levels of exposure were the heart (0.3 times that for plasma), thigh (0.2 times), and brain (0.06 times). Kinetically, drug was cleared more slowly from all tissues than from plasma, indicating that terminal-phase equilibrium had not been achieved by 24 h. Thus, some measure of accumulation is predicted for all tissues. Single daily doses of MK-0991 should provide adequate systemic levels of fungicidal activity as a result of its long half-life pharmacokinetics, wide distribution, and slowly accumulating concentrations in tissue.
L-749,345 is a carbapenem antibiotic, currently in phase II clinical trials, which possesses a broad antibacterial spectrum and extended half-life. The time courses of levels of the drugs in plasma and urinary recovery were evaluated for L-749,345, imipenem-cilastatin (IPM), and ceftriaxone (CTX) in male rhesus monkeys (Macaca mulatta) and a chimpanzee (Pan troglodytes). The chimpanzee pharmacokinetics was predictive of human results and indicated a compound that was superior to IPM and approached CTX in its ability to persist in the circulation. Levels of binding to protein, in the range of clinically relevant concentrations in serum, are virtually equivalent for L-749,345 and CTX in humans. Results of a crossover bioassay versus those of a high-pressure liquid chromatography assay of 1-g human samples showed that there were no bioactive metabolites of L-749,345. The extended half-life at elimination phase of L-749,345 allows consideration of single daily dosing. In contrast to results with IPM, the improved stability of L-749,345 with respect to hydrolysis by the renal dehydropeptidase I (0.25 times the rate of IPM) results in urinary recovery sufficient for the drug's use as a single agent.
A temporal and spatial study of malaria transmission in a suburban area of Maputo, Mozambique with a mean population density of 2,737/km2 was made from December 1992 to June 1995. A steep but continuous gradient was observed in the Plasmodium falciparum prevalence from 59.0% adjacent to the breeding sites to 5.4% only a few hundred meters distant. The entomologic inoculation rate ranged from a number too low to be determined in some districts to 20 infectious bites per person per year in the others. The risk of malaria was 6.2 times higher for individuals living less than 200 meters from the breeding sites than for individuals living 500 meters or more away from the breeding sites. In areas of high human density, mosquito and parasite dispersion is very limited, and therefore malaria control strategies could be more specifically targeted.
There are considerable similarities and overlap in the levels of disability and dependency between those who receive home-based-long-term care and those who receive long-term care on a residential basis. These similarities are demonstrated from analysis of clients of the Western Domiciliary Care and Rehabilitation Service. When services are costed, it is shown that there is a very large discrepancy in the levels of government support that clients of home-based care agencies attract compared to residents in subsidised hostels and nursing homes. This paper discusses the need for parity of funding to care providers and recognition of the economic value of the contributions of carers. It considers principles for the development of a casemix model for home-based care analogous to the Care Aggregated Module/Standard Aggregated Module (CAM)/(SAM) model applying to nursing home care.
A Tic Checklist and direct observation tic measurement procedure were developed for the assessment of Tourette syndrome in individuals with mental retardation. Using a single-subject reversal design, we applied this assessment method to the evaluation of haloperidol treatment for a subject with Tourette syndrome and severe mental retardation. Relative to baseline, haloperidol 10 mg/day produced decreases of 66% in simple motor tics, 46% in complex motor tics, 45% in simple vocal tics, and 50% in complex vocal tics. Improvement was also seen in careprovider ratings of tic severity, hyperactivity, and compulsive behaviors.
BACKGROUND: The development of family medicine in Latin America is inhibited by limited resources. Successful strategies to promote the specialty include academic exchanges between countries. Short-term faculty development opportunities are needed for foreign academic family physicians. METHODS: After 2 years of unstructured visits by Latin American physicians planning to teach family medicine, we designed a faculty development course, in Spanish, that continues to evolve through constructive feedback. This includes workshops in project planning, computer training, clinical decision making, family systems, clinical teaching, problem-based learning, and clinical epidemiology. Each fellow designs a project to be implemented subsequently in the country of origin. RESULTS: Since 1991, we have trained 37 physicians from nine Latin American countries, 27 since 1993 in the structured course. A full schedule encourages fellow to complete course objectives within 8 weeks. All participating physicians have rated highly the course content and quality. Twenty-five of the 27 course participants are or will soon begin teaching in family practice residency programs in their home countries. CONCLUSIONS: This faculty development course for Latin American physicians is perceived as an effective way to enhance academic skills. Ongoing evaluation will show how the fellowship impacts the physicians' teaching effectiveness and the development of family medicine in their countries.
In anesthetized rats, electrical stimulation of fimbria fibers evoked, in the ipsilateral lateral septum (LS), a field potential consisting of two negative components: an initial negativity (N2-3 complex wave) of high amplitude at 6.7 ms (+/- 0.8 ms; peak latency) and a slow negative wave (N4 wave) of small amplitude at 14.4 ms (+/- 2.4 ms). The N2-3 complex wave represents the monosynaptic activation of LS neurons while the N4 wave corresponds to polysynaptic activation of neurons in the mediolateral part of the LS. In this study, we investigated the effects of high-frequency stimulation of fimbria fibers on LS field potentials and compared them with those observed in the CA3 area. Tetanic stimulation of the fimbria did not change the characteristics of the N2-3 wave but induced a long-lasting increase in amplitude and slope of the N4 wave. A positive correlation was found between the magnitude of CA3 LTP and lateral septal polysynaptic potentiation of the N4 component. These results indicate that patterns of stimulation delivered to the same input fibers (fimbria fibers) produce similar changes in a polysynaptic input to the LS and in a monosynaptic input to the CA3 and emphasize the complexity of signal processing in serial networks.
This article describes an audit of children presenting at accident and emergency departments following an accident. The authors explain how the audit data informed a strategy for childhood accident prevention schemes in Newcastle for 1995/96.
The maize Opaque-2 (O2) protein is a transcription factor of the basic/leucine-zipper class, involved in the regulation of endosperm proteins including the 22kDa alpha-zein storage proteins and b32 protein. In this study we have focussed our attention on the relationship between O2 and the cyPPDK1 gene, which encodes a cytoplasmic pyruvate orthophosphate dikinase (PPDK) isoform. The results of this study showed that PPDK activity is detectable in wild-type maize endosperms, while in o2 mutant endosperms, the levels of PPDK protein, mRNA and enzymatic activity are reduced, indicating that O2 is involved in the regulation of cyPPDK1 in this tissue. By employing transient expression experiments in tobacco mesophyll protoplasts, we have demonstrated that the O2 protein can activate expression of a chloramphenicol acetyl transferase reporter gene placed under the control of the cyPPDK1 promoter. An in vitro binding assay and DNaseI footprint analysis demonstrated that a specific sequence in the cyPPDK1 promoter can be recognized and protected by maize O2 protein. The regulation by the O2 locus of cyPPDK1 reported here, and control of alpha-zein synthesis by O2 suggest that the O2 protein may play a more general role in maize endosperm development than previously thought.
Prostate tumor cells preferentially metastasize to bony sites and lymph nodes at a frequency in excess of that which would be predicted by random tumor cell dissemination. In order to determine whether chemoattractants in these organs promote organ-specific metastasis, we utilized human cell lines derived from and/or related to these organs as sources of potential chemoattractants. Secretory proteins derived from the cell lines MG-63 (osteosarcoma), SK-ES-1 (Ewing's sarcoma), and KG-1 (leukemia) stimulated chemomigration of the TSU-pr1 prostate tumor cells in a dose-dependent manner in Boyden chambers. In addition, secretory proteins from a human prostatic stromal cell line (hPS) and from the TSU-Pr1 prostate tumor cell line were also able to stimulate chemomigration of the TSU-pr1 cells through Boyden chambers. Since lymph nodes and bony sites represent organs of hematopoietic/lymphoid proliferation and activation, we undertook identification of specific cytokines present at these sites which may promote the chemomigration of prostate tumor cells. In this context, the cytokines interleukin-1 alpha, interleukin-2, interleukin-6, tumor necrosis factor-beta, transforming growth factor-beta, interferon alpha 2-a, and granulocyte-macrophage colony-stimulating factor did not stimulate chemomigration of the TSU-pr1 prostate tumor cell line. In contrast, the cytokine epidermal growth factor (EGF) stimulated chemomigration of the TSU-pr1 prostate tumor cells through the Boyden chambers in a dose-dependent manner. Western blot analysis of secretory proteins from the cell lines KG-1, SK-ES-1, MG-63, hPS, and TSU-pr1 identified EGF-immunoreactive proteins in all cases. In addition, EGF immunoreactivity was localized to the stroma of the human prostate, the osteogenic stroma of pelvic medullary bone, and the stroma within the capsule and trabeculae of pelvic lymph nodes. Hence, these results demonstrate that the cytokine EGF promotes the chemomigration of the TSU-pr1 prostate tumor cell line, and that EGF within the stroma of pelvic lymph nodes and medullary bone may act as a chemoattractant for prostate tumor cells, thereby facilitating the preferential formation of metastatic foci within these organs.
Effective process control can only be achieved through an understanding of the operating issues of the reaction. The development and use of effective and rugged analytical methods is necessary to monitor these parameters. The intent of this paper is to present some key analytical issues encountered in the synthesis of MK-0679, an LTD4 antagonist. In a key step of the compound's synthesis, a prochiral diester intermediate undergoes an enantioselective enzymatic hydrolysis (in the presence of Triton X-100) leading to the (S)-ester acid. Subsequent processing transforms the ester acid into the final product. The residual amount of the detergent in the final product, the rapid determination of the enzymatic activity and the optical purity of the final product emerged as key issues in the control of the reaction. As a solution, two techniques were utilized and are presented: flow injection analysis and HPLC.
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