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Backache among adolescents and young women is an unusual presenting feature to the Accident and Emergency Department as well as orthopaedic clinics. Here, we present a challenging case of a mullerian duct abnormality, which collectively has an incidence of 0.0001% of the population, and how its consideration and investigation will ensure optimum management in both acute and long-term.
OBJECTIVE: To review recent advances that have significantly changed the management of chronic hepatitis C virus (HCV) infection. DATA SOURCES: A MEDLINE search (2000-July 2005) was conducted using key words such as hepatitis C, interferon, pegylated interferon, and therapy. STUDY SELECTION AND DATA EXTRACTION: All articles pertaining to treatment of chronic HCV infection were identified. Studies evaluating HCV treatment in treatment-naive patients were considered for this review. DATA SYNTHESIS: Over the past several years, response to treatment for chronic HCV infection has significantly improved with the use of pegylated interferon and ribavirin therapy. Treatment response is influenced by HCV genotype and viral load, as well as patient-related factors, including adherence. CONCLUSIONS: Treatment of chronic HCV infection has improved, with overall response rates of approximately 55%. Identification and management of common adverse effects is important in maximizing adherence and response to therapy. Studies are needed to further delineate the optimum treatment of chronic HCV infection in specific patient populations.
The epidemiological studies of the severity and spread of caries of deciduous and permanent teeth in Moscow schoolchildren (n = > 20,000) aged 7-17 years in relation to the content of fluoride in the drinking water, to the use of fluorine-containing tablets and varnishes have provided evidence for the high efficiency of drinking water fluorination for the primary prevention of caries as compared with other preventive alternatives. Based on sanitary studies, two main lines are now under way in solving the problem connected with low dietary fluoride intake: the introduction of routine water-purifying fluorine generators (based on a new technology of fluorination of limited water volumes for drinking and cooking) and the setting-up of plants manufacturing bottled drinking waters containing the optimum or higher fluorine levels for provision of different population groups, primarily children and pregnant women in particular.
Tumor cell lysis can be enhanced significantly in vitro when heteroconjugate (HC) antibodies (anti-CD3 x anti-tumor mAb) are used to specifically direct lymphocyte effector cells to the tumor cell target. In order to effectively utilize HC antibodies in an immunotherapy protocol, methods must be identified for the optimum expansion, activation, and retargeting of lymphocyte-effector populations from cancer patients. In this study, we have compared the proliferative responses of different normal and renal cell carcinoma (RCC) patient lymphocyte preparations (PBL, tumor-infiltrating lymphocytes) stimulated in vitro for periods up to 12 days with a variety of growth factor combinations (anti-CD3, rIL-2, rIL-4). These activated lymphocyte preparations were then tested in vitro for their ability to kill RCC tumor cells and tumor cell lines in the presence of HC preparations (anti-CD3 mAb covalently linked to mAb reactive to different RCC tumor-associated Ag). RCC patient PBL cultured with anti-CD3 plus rIL-2 for 12 days resulted in a 3- to 160-fold expansion of effector cells. These cells, as well as tumor infiltrating lymphocytes, when retargeted with appropriate HC antibodies were capable of mediating high levels of killing of autologous tumor cells. No constitutive autologous anti-tumor cell response was detected in the absence of added HC antibodies. Of the five anti-RCC mAb tested (A6H, K29, K20, UR07, and URO 3), HC containing URO 3 x anti-CD3 and K20 x anti-CD3 elicited the highest level of tumor cell lysis by the activated lymphocyte effector cells. Together these results demonstrate that HC antibodies may be a useful imunotherapeutic reagent for directing the killing of RCC tumor cells by autologous lymphocytes.
We developed a method to derive optimum composite genotypes when the proportion of a specific breed (or combination of breeds) in the composite is constrained to a desired level. The method allows development of composites that balance net merit according to available parameters and reflects the production system and(or) risk preference, particularly when traits in the breeding objective do not represent all traits important for production. The method can also be used to evaluate the cost of constraining breed use. For example, when the true optimal composite is difficult to obtain in the time frame available to the producer, the predicted merit of the composite with breed proportion restricted to those that are obtainable in practice can be compared with the predicted merit of the true optimum composite. In a case study the method is used to optimize a tropical composite using Brahman, Charolais, and Belmont Red breeds. The proportion of Charolais is to be constrained to 50%. Using growth parameters from a tropical crossbreeding experiment, the unconstrained optimum composite was 32.5% Brahman, 11.1% Belmont Red, and 56.3% Charolais. When the proportion of Charolais in the composite was constrained to 50%, optimum proportions of Brahman and Belmont Red were 33.9% and 16.1% respectively. In the case study net merit (annualized profit per cow exposed, $), as defined by the growth parameters, was .2% less than that of the unconstrained optimum composite.
It is shown that specificity of the genetic structure in individuals with different pathologic processes is interrelated to the duration of life under the extreme conditions, and its "dynamics" is contrary to that of healthy inhabitants of the region. The extent of genetic differences between groups in man and woman samples, and also between men and women in groups does not depend on the extent of differences between these groups in frequency of nosologic forms. The latter indicate that the genotype shows nonspecific disease resistance on the whole, but not to the given pathologic process. The prevalence of the average real heterozygosity over the theoretical one in sick men and the reverse effect in healthy men points to formation of new heterozygosity optimum in the extreme conditions, leading to decline in the population genetic diversity, which rather corresponds to the specific ecology. The comparison of groups of sick and healthy individuals of different life duration in the North shows that the specific weight of genotype nonspecific resistance to diseases depends mostly on the duration of life of individuals under extreme conditions, this dependence being not linear.
Analysis of multilocus evolution is usually intractable for more than n approximately 10 genes, because the frequencies of very large numbers of genotypes must be followed. An exact analysis of up to n approximately 100 loci is feasible for a symmetrical model, in which a set of unlinked loci segregate for two alleles (labeled "0" and "1") with interchangeable effects on fitness. All haploid genotypes with the same number of 1 alleles can then remain equally frequent. However, such a symmetrical solution may be unstable: for example, under stabilizing selection, populations tend to fix any one genotype which approaches the optimum. Here, we show how the 2(n)x2(n) stability matrix can be decomposed into a set of matrices, each no larger than nxn. This allows the stability of symmetrical solutions to be determined. We apply the method to stabilizing and disruptive selection in a single deme and to selection against heterozygotes in a linear cline.
There are four primary factors to consider in genetic selection strategies: 1) accuracy of selection, 2) selection intensity, 3) effective population size, and 4) mating system. Current theory indicates that optimum response to selection is achieved by maximizing the first three factors and using a mating systems that allows optimization of reproductive characteristics in dam lines and production characteristics in sire lines. However, with limited resources, compromises among the first three factors are needed. Simulations are useful for examining those compromises. Unrealistic simplifying assumptions are necessary for analytic theoretical results and thus do not address real world breeding problems. Using simulations, the relationship between selection accuracy, which is increased by use of family selection indices or Best Linear Unbiased Prediction (BLUP), and response to selection was examined. Results show that those procedures place a great restriction on effective population size, which offsets most of their advantage, i.e., there is too little emphasis on effective population size. A revision of the methodology and a reappraisal of the results of selection theory for optimization of genetic response is required. Another relationship that is of fundamental importance in breeding programs is that between selection intensity and effective population size. Analytical results for the additive case have been developed but have never been extended to heterotic traits. A gene level simulation program was developed to examine that relationship. Results show that the optimal selection strategy depends on the trait being selected. For additive traits and in the short term (20 generations), one should maximize selection intensity. For heterotic traits, an intermediate proportion (25% of each sex) gives optimal response. In all breeding strategies, primary attention must be given to the rate of inbreeding, which is increased by increasing either accuracy of selection or selection intensity. Inbreeding reduces response to selection in two ways. First, for both additive and nonadditive traits, inbreeding is a measure of the amount of random genetic drift that has occurred. Genetic drift causes loss of favorable alleles. Once lost, those alleles can never be recovered and thus genetic drift lowers the selection limit. Second, for heterotic traits, inbreeding results in a depression of the mean caused by directional dominance.
Though survival for well-differentiated thyroid cancer is very good, specific populations suffer greater recurrence and mortality. Defining these cohorts can significantly influence prognosis and extent of treatment. This study, using a large, multi-institutional database, seeks to determine how the presence of lymph node disease in patients with well-differentiated thyroid cancer affects outcome. The Surveillance, Epidemiology, and End Results (SEER) database is a large-scale sample of 14 per cent of the U.S. population. It was used to identify patients with papillary and follicular thyroid carcinomas and identify the prognostic implications of lymph node metastasis. Additional factors, including presence of metastasis, age, and tumor size, were compared using multivariate and chi2 analyses. Of 19,918 patients identified, lymph node status was known for 9,904 (49.7%). On multivariate analysis, age > 45 years, presence of distant metastasis, large tumor size, and lymph node involvement significantly predicted poor outcome. Overall survival at 14 years was 82 per cent for node negative and 79 per cent for node positive patients (P < 0.05). This study shows that the survival of patients with well-differentiated thyroid cancer is adversely affected by lymph node metastases. The optimum treatment for this cohort needs further delineation, as particular populations are at greater risk of recurrence and death.
As part of a study on passive physical control of house-dust mites, a total of 6000 eggs from a population of Dermatophagoides pteronyssinus (Trouessart, 1897) from 17-year-old laboratory cultures were incubated at 60 temperature and relative humidity combinations between 10-35 degrees C and 55-100% RH. Eggs hatched at every combination, although mortality and development time increased between 10-20 degrees C and 30-35 degrees C and below 65% RH. Optimum conditions were 35 degrees C and 80-85% RH. In temperate dry conditions, eggs from a wild population were found to be more resistant to mortality: they developed faster, with 7 times lower mortality than eggs from the laboratory population. This may have been because the laboratory population had become acclimated to the constant near-optimum conditions at which it was kept. Therefore it has been suggested that where laboratory cultures have been used in studies relating to passive physical control, caution should be taken in applying the conclusions to wild populations in the natural house-dust environment.
Stabilizing selection is a fundamental concept in evolutionary biology. In the presence of a single intermediate optimum phenotype (fitness peak) on the fitness surface, stabilizing selection should cause the population to evolve toward such a peak. This prediction has seldom been tested, particularly for suites of correlated traits. The lack of tests for an evolutionary match between population means and adaptive peaks may be due, at least in part, to problems associated with empirically detecting multivariate stabilizing selection and with testing whether population means are at the peak of multivariate fitness surfaces. Here we show how canonical analysis of the fitness surface, combined with the estimation of confidence regions for stationary points on quadratic response surfaces, may be used to define multivariate stabilizing selection on a suite of traits and to establish whether natural populations reside on the multivariate peak. We manufactured artificial advertisement calls of the male cricket Teleogryllus commodus and played them back to females in laboratory phonotaxis trials to estimate the linear and nonlinear sexual selection that female phonotactic choice imposes on male call structure. Significant nonlinear selection on the major axes of the fitness surface was convex in nature and displayed an intermediate optimum, indicating multivariate stabilizing selection. The mean phenotypes of four independent samples of males, from the same population as the females used in phonotaxis trials, were within the 95% confidence region for the fitness peak. These experiments indicate that stabilizing sexual selection may play an important role in the evolution of male call properties in natural populations of T. commodus.
In the Division of Obstetrics of the Statewide Perinatal Center, Newark, NJ, the rate of perinatal mortality fell from 51 in 1000, to 15 in 1000, between 1971 and 1986, and increased thereafter to 28 in 1000 by 1988. This development is analyzed against the background of changes in the environment and inside the Center. It is noted that during 2 study years (1983 and 1986) in our extremely high-risk patient population, the perinatal mortality rate was kept at, or under, the national average. It appears, therefore, that with well-coordinated management and optimum use of resources, marked nationwide differences in mortality rates between white and non-white populations can be greatly reduced or eliminated. An inverse relationship between the rates of caesarean section and perinatal mortality was documented, as the former increased from 4.5% to 17%. Paradoxically, a further increase of caesarean section rates was accompanied by a parallel increase of intrauterine fetal and neonatal losses.
Bovine erythroid colonies containing eight to 100 erythroid cells were successfully cultured in methyl cellulose. The colonies required four to five days to mature and a direct linear relationship (r = 0.99) between the number of nucleated marrow cells plated and the number of colonies formed was demonstrated. Their optimum erythropoietin requirement was observed to be 1 U/ml. No second population of erythroid colonies developed either as a function of time or erythropoietin concentration. However, 1 to 5 per cent of the bovine erythroid colonies contained megakaryocytes in addition to the erythroid cells. Marrow samples from different cattle showed a wide variation in their response to erythropoietin in culture, while some produced many erythroid colonies in the absence of erythropoietin, others were observed to be entirely erythropoietin dependent. Large mixed colonies occasionally grew in methyl cellulose but their optimum culture conditions have not yet been established. Medium conditioned by phytohaemagglutinin-stimulated bovine peripheral leucocytes enhanced bovine erythroid colony growth. Bovine erythroid progenitor cells were observed to possess a sedimentation velocity of 9 +/- 1 mm per hour.
A number of earlier authors have investigated the consequences for fitness of gene differences affecting the expression of a primary character where stabilising selection is acting in favour of an optimal expression. Assuming that the mean expression must be at or close to the optimum, deviations from the mean have been taken as measures of the deviation from the optimum, and the conclusion reached that, random drift apart, stabilising selection must ultimately lead to fixation of the commoner allele. It is now shown that this approach is incorrect: in an illustrative example the mean cannot be taken as synonymous with the optimum except in the trivial case where they have precisely the same value. Where the mean departs from the optimum, even by sampling variation only, continuing selection for it is effectively self-propagating and directional away from the optimum. Deviation from the optimum itself must be used in investigating the consequences of stabilising selection. The model used here is based on the biometrical description of the effects of a gene difference on a quantitative character as used by Mather and Jinks (1982). This includes a parameter, h, which allows dominance of any magnitude in either direction to be taken into account, and is adapted for the present purpose by introducing an additional parameter, m, measuring the departure from the optimum of the mid-point, or mid-parent, which is used biometrically as the origin for measurement of the gene effects. Assuming random mating and the absence of epistasis in the effects on the primary character, it is shown that stabilising selection acting on a pair of alleles (A and a) can have any one of three possible outcomes depending on the relative values of the m and h which characterise the effects of the gene difference on the primary character, viz: (i) a stable equilibrium in the population where in respect of the primary character Aa is nearer to the optimum than both homozygotes; (ii) fixation of the fitter allele where Aa is intermediate between the homozygotes in its departure from the optimum; (iii) a theoretical unstable equilibrium leading to fixation of the commoner allele, where Aa departs further from the optimum than both homozygotes. Only outcome (i) can lead to the conservation of variation in the population. Preliminary consideration is also given to the interaction in effect on fitness of two gene pairs affecting the same character and segregating simultaneously in the population.(ABSTRACT TRUNCATED AT 400 WORDS)
The potential for sulfate reduction at low temperatures was examined in two different cold marine sediments, Mariager Fjord (Denmark), which is permanently cold (3 to 6(deg)C) but surrounded by seasonally warmer environments, and the Weddell Sea (Antarctica), which is permanently below 0(deg)C. The rates of sulfate reduction were measured by the (sup35)SO(inf4)(sup2-) tracer technique at different experimental temperatures in sediment slurries. In sediment slurries from Mariager Fjord, sulfate reduction showed a mesophilic temperature response which was comparable to that of other temperate environments. In sediment slurries from Antarctica, the metabolic activity of psychrotrophic bacteria was observed with a respiration optimum at 18 to 19(deg)C during short-term incubations. However, over a 1-week incubation, the highest respiration rate was observed at 12.5(deg)C. Growth of the bacterial population at the optimal growth temperature could be an explanation for the low temperature optimum of the measured sulfate reduction. The potential for sulfate reduction was highest at temperatures well above the in situ temperature in all experiments. The results from sediment incubations were compared with those obtained from pure cultures of sulfate-reducing bacteria by using the psychrotrophic strain ltk10 and the mesophilic strain ak30. The psychrotrophic strain reduced sulfate optimally at 28(deg)C in short-term incubations, even though it could not grow at temperatures above 24(deg)C. Furthermore, this strain showed its highest growth yield between 0 and 12(deg)C. In contrast, the mesophilic strain ak30 respired and grew optimally and showed its highest growth yield at 30 to 35(deg)C.
Darwin viewed species range limits as chiefly determined by an interplay between the abiotic environment and interspecific interactions. Haldane argued that species' ranges could be set intraspecifically when gene flow from a species' populous center overwhelms local adaptation at the periphery. Recently, Kirkpatrick and Barton have modeled Haldane's process with a quantitative genetic model that combines density-dependent local population growth with dispersal and gene flow across a linear environmental gradient in optimum phenotype. To address Darwin's ideas, we have extended the Kirkpatrick and Barton model to include interspecific competition and the frequency-dependent selection that it generates, as well as stabilizing selection on a quantitative character. Our model includes local population growth, movements over space, natural selection, and gene flow. It simultaneously addresses the evolution of character displacement and species borders. It reproduces the Kirkpatrick and Barton single-species result that limited ranges can be produced with sufficiently steep environmental gradients and strong dispersal. Further, in the absence of environmental gradients or barriers to dispersal, interspecific competition will not limit species ranges at evolutionary equilibrium. However, interspecific competition can interact with environmental gradients and gene flow to generate limited ranges with much less extreme gradient and dispersal parameters than in the single-species case. Species display character displacement in sympatry, yet the reduction in competition that results from this displacement does not necessarily allow the two species to become sympatric everywhere. When species meet, competition reduces population densities in the region of overlap, which, in turn, intensifies the asymmetry in gene flow from center to margin. This reduces the ability of each species to adapt to local physical conditions at their range limits. If environmental gradients are monotonic but not linear, the transition zone between species at coevolutionary equilibrium occurs where the environmental gradient is steepest. If productivity gradients are also introduced into the model, then patterns similar to Rapoport's rule emerge. Interacting species respond to climate change, as it affects the optimal phenotype over space, by a combination of range shifts and local evolution in mean phenotype, while solitary species respond solely by range shifts. Finally, we compare empirical estimates for intrinsic growth rates and diffusion coefficients for several species to those needed by the single-species model to produce a stable limited range. These empirical values are generally insufficient to produce limited ranges in the model suggesting a role for interspecific interactions.
In recent years a variety of studies have been carried out to compare the accuracy (generally expressed in terms of sensitivity and specificity) of commercially available anti-HTLV tests. None of these studies were performed in Brazil or in any other South American country. During the characterization of our Brazilian reference panel we evaluated the sensitivities and specificities of the Abbott HTLV EIA (100%; 89.7%) and the Biochrom HTLV-1/-2 ELISA (100%; 42.4%). Our conclusion was that both assays may be problematic in terms of correctly identifying HTLV-negative sera. We therefore adjusted the cut-off values using receiver operating characteristics (ROC). ROC analysis, which involves calculating sensitivity and specificity for several cut-off values, can be used to ascertain the co-variation in the specificity and sensitivity of any assay giving quantitative results. The optimum cut-off value for the assay in a given study population is the point that gives highest possible sensitivity in conjunction with a small false-positive fraction. Using the HTLV-1/-2 Western blot as the "gold standard", we were able to improve the specificity of the Biochrom HTLV-1/-2 assay to 95% without affecting its sensitivity of 100%. However, it seems that when using the Biochrom HTLV-1/-2 ELISA, there may be problems in separating positive and negative sera. In the case of the Abbott HTLV EIA, our ROC analysis revealed that the cut-off value suggested by the manufacturer was nearly identical to the optimum cut-off value. Adjustment will affect neither sensitivity nor specificity. However, a slight adjustment of the cut-off value result in a clearer separation of the positive and negative populations. Furthermore, we assume that this adjustment will help to avoid false-positive results when larger serum panels are investigated. Further investigations will show whether or not this problem is linked to the geographical regions where the test is performed (e.g. polyclonal stimulation due to parasitic infections in tropical countries).
BACKGROUND: Fotemustine is a nitrosourea with theoretic and preclinical advantages over the original analogs, carmustine and lomustine, in the treatment of brain tumors. This is the first pediatric Phase I study of fotemustine. METHODS: Patients younger than 21 with recurrent/resistant brain tumors were enrolled in a conventional Phase I study. Fotemustine was administered intravenously every 3 weeks at increasing dose levels starting at 100 mg/m(2). Toxicity and response data were monitored closely. RESULTS: Fifteen evaluable patients entered the study and received a total of 45 courses of fotemustine (dose range, 100-175 mg/m(2)). Myelosuppression was observed, with the dose-limiting toxicity being Grade 4 neutropenia and thrombocytopenia. Toxicity was delayed and cumulative. The maximum tolerated dose was 150 mg/m(2) every 3 weeks. There were three documented radiologic responses (20% of patients) comprising one partial response and two minor responses in patients with a sarcoma, medulloblastoma, and ependymoma, respectively. CONCLUSIONS: Fotemustine administered at a dose of 150 mg/m(2) every 3 weeks is well tolerated in children and has antitumor activity in several brain tumors. This is the first dedicated Phase I study of a single agent nitrosourea in a pediatric population. More comparative studies should be undertaken to define the optimum nitrosourea analog for use in children with brain tumors.