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PubMed2005

Using BAC clones to characterize unbalanced chromosome abnormalities in interphase cells.

Carriers of balanced translocations usually carry alterations in gene sequences, which lead to dysfunction during early and late embryogenesis. Related spatial rearrangement causes either cumulative delay in cell cycles and/or anomalies in transcription and translation. This has also an important impact at the time of genomic activation, the longest cell cycle of preimplantation development. Carrier patients may be affected either with primary infertility or by repeated miscarriages [Hum. Reprod. 12 (1997) 2019.]. Assuming that a fraction of the germ cells is karyotypically normal, these patients would greatly benefit from efficient procedures for generation and use of breakpoint-specific DNA hybridisation probes in preconception and preimplantation genetic diagnosis (PGD) after polar body or blastomere biopsy of the embryos. The objective of this research was to design an approach of patient-specific probes for preimplantation diagnosis of chromosome translocations and which could be used eventually to select chromosomally normal embryos from balanced or unbalanced interphase cells prior to their transfer to the mother's womb. This approach was used for a couple, where the female partner was a carrier of a balanced translocation 46,XX,t(4;12)(p16.1;q24.31). First, BAC/PAC clones were chosen from specific chromosome bands from the genome sequence that hybridise adjacent to the chromosomal breakpoints or span them. Then, the probes and hybridisation conditions were optimised using unrelated normal amniocytes, lymphoblastoid cells and lymphocytes from the carrier to increase hybridisation signal intensity and decrease background. Finally, the probes were tested on target cells before they were used for mimicking preconception or preimplantation genetic diagnosis. Three slides were analysed blindly from a normal karyotype, an unbalanced and a balanced translocation. A total of 78 cells were analysed of which in the slide A 19/22 (86%) were found to be unbalanced, in slide B 25/31 (81%) were normal and in slide C 21/25 (84%) were balanced. Thus, it was demonstrated that cells with known structural abnormalities could be detected, based on hybridisation of breakpoint spanning bacterial artificial chromosome (BAC) DNA probes in interphase cells.

Adult↗

PubMed2005

Codon and amino acid usage in two major human pathogens of genus Bartonella--optimization between replicational-transcriptional selection, translational control and cost minimization.

Intra-genomic variation in synonymous codon and amino acid usage in two human pathogens Bartonella henselae and B. quintana has been carried out through multivariate analysis. Asymmetric mutational bias, coupled with replicational-transcriptional selection, has been identified as the prime selection force behind synonymous codon selection--a characteristic of the genus Bartonella, not exhibited by any other alpha-proteobacterial genome. Distinct codon usage patterns and low synonymous divergence values between orthologous sequences of highly expressed genes from the two Bartonella species indicate that there exists a residual intra-strand synonymous codon bias in the highly expressed genes, possibly operating at the level of translation. In the case of amino acid usage, the mean hydropathy level and aromaticity are the major sources of variation, both having nearly equal impact, while strand-specific mutational pressure and gene expressivity strongly influence the inter-strand variations. In both species under study, the highly expressed gene products tend not to contain heavy and/or aromatic residues, following the cost-minimization hypothesis in spite of their intracellular lifestyle. The codon and amino acid usage in these two human pathogens are, therefore, consequences of a complex balance between replicational-transcriptional selection, translational control, protein hydropathy and cost minimization.

Amino Acids↗

PubMed1997

The workload of trainees in general practice.

During their first training period in general practice the authors felt that they did not encounter the balanced workload which is the foundation for learning to be a GP. Previous studies confirmed the existence of differences in overall and specific workload between trainees and trainers. From their own experience and from the relevant literature they addressed several factors which might affect the workload of trainees. A study was undertaken to determine differences in workload between trainees and trainers, and to investigate whether certain characteristics of practice and of trainees affect the workload of trainees. Details of surgery consultations with 34 trainee-trainer partnerships were recorded in the north of the Netherlands over 2 weeks. Questionnaires were filled in by trainers, trainees and practice assistants from these 34 general practices. The total number of contacts recorded was 10,103. It was found that trainees see fewer elderly and female patients, less chronic and oncological conditions, but more minor illnesses. They see only 30% of patients with problem behavior. Factors that influence the trainees' workload, as compared to their trainers' are: list size; selection in the allocation of patients; trainee's experience prior to starting the training stage, and the trainee's sex. Except for problem behaviour, trainees generally see a cross-section of their trainer's practice population. Selection would provide a more balanced workload for trainees.

Aged↗

PubMed1983

An evaluation of perfluorochemical resuscitation after hypoxic hypotension.

The relative performance of whole blood and saline, a balanced salt-albumin solution, and Fluosol-43 were compared in an experimental animal model of combined hypoxia and hypotension. The test fluids were evaluated in terms of their respective ability to restore mean arterial pressure and provide adequate oxygen to restore and maintain a normal brain cytochrome a,a3 redox state, restore and sustain normal cerebral cortical ATP and creatinine phosphate concentrations (CP), and return cerebral cortical lactate concentrations to normal after the hypoxic-hypotensive period. With regard to ATP, CP, lactate, and cytochrome a,a3, all three test fluids performed equally well inasmuch as there were no significant differences between groups. None of the test regimens resulted in normal ATP concentration post-hypoxic hypotension. Although CP concentrations were lower than baseline after resuscitation, the difference was not statistically significant. Fluosol-43 resuscitation resulted in a significantly higher (p less than 0.05) mean arterial pressure by 120 minutes post-resuscitation. It was concluded that Fluosol-43 is an acceptable resuscitative fluid, most beneficial at extremely low hematocrits, but that selection of Fluosol-43 over balanced salt-albumin could not be supported when post-resuscitation hematocrits were in the 20 to 25% range.

Adenosine Triphosphate↗

PubMed1985

Energy intake can determine albumin synthesis in man after surgery.

Albumin synthesis rate, nitrogen balance, plasma hormone levels, and selected substrates were measured after operation in 12 patients who underwent colonic operations who were randomized to receive an intravenous fluid regimen that contained either 3.5% amino acids with 20% fat and 2.5% glucose or 3.5% amino acids with 20% fat alone. The albumin synthesis rate was higher in patients who received the first of these intravenous mixtures (357 +/- 34 mg/kg/day versus 216 +/- 22 mg/kg/day; p less than 0.01), but they also had a significantly higher intake of calories (10.2 +/- 1.1 calorie/kg/day versus 6.4 +/- 0.6 calorie/kg/day; p = 0.01). The mean albumin synthesis rate in the group who received amino acids with glucose and fat is the highest we have measured in our series of studies. Although a previous trial in a similar group of patients suggested that glucose acts on albumin synthesis by diverting uptake of amino acids into skeletal muscle, it is possible that the impressive increase in the albumin synthesis rate in patients of the present series who received supplementary glucose is related to the extra energy infused. In contrast, nitrogen balance was similar in both groups, and thus was not predictive of protein synthesis. In addition, myofibrillar protein degradation appears to be equivalent in the two groups, as indicated by 3-methylhistidine output. Plasma albumin synthesis thus may be sensitive, especially to energy intake.

Adenocarcinoma↗

PubMed2005

Nonrandom larval dispersal can steepen marine clines.

Sharp and stable clinal variation is enigmatic when found in species with high gene flow. Classical population genetic models treat gene flow as a random homogenizing force countering local adaptation across habitat discontinuities. Under this view, dispersal over large spatial scales will lower the effectiveness of adaptation by natural selection at finer spatial scales. Thus, random gene flow will create a shallow phenotypic cline across an ecotone in response to a steep selection gradient. In sedentary marine species that disperse primarily as larvae, nonrandom dispersal patterns are expected due to coastal hydrodynamics. Surprisingly sharp phenotypic and genotypic clines have been documented in marine species with high gene flow. We are interested in the extent to which nonrandom dispersal could accentuate such clines. We model a linear species range in which populations have stable and uniform densities along a selection gradient; in contrast to random dispersal, convergent advection of larvae can amplify phenotypic differentiation if coupled with a semipermeable dispersal barrier in the convergence zone. The migration load caused by directional dispersal pushes the phenotypic mean away from the local trait optimum in downstream populations, that is, near the convergence zone. A dispersal barrier is possible as a result of colliding currents if the water and larvae are mostly displaced offshore, away from suitable settlement habitat. Disjunctions in a quantitative trait were enlarged in the convergence zone by faster current flows or a more complete dispersal barrier. With advection of larvae per generation one-third as far as the average dispersal distance by diffusion, convergence on a dispersal barrier with 40% permeability generated a trait disjunction across the convergence zone of two phenotypic standard deviations. Without directional dispersal, similar clines also developed across a habitat gap, where population density was low, or across dispersal barriers with less than 1% permeability. These findings suggest that the types of hydrographic phenomena often associated with marine transition zones can strongly affect the balance between gene flow and selection and generate surprisingly steep clines given the large-scale gene flow expected from larvae.

Animal Migration↗

PubMed1998

B cell antigen receptor signalling in the balance of tolerance and immunity.

The quantity and quality of signals from the B cell antigen receptor (BCR) drives the positive and negative selection of B lymphocytes and establishes the balance of tolerance and immunity. Experiments using immunoglobulin transgenic mice and mutations in key BCR signalling components have given insight into how the antigen receptor is tuned and how thresholds for qualitatively different outcomes are established and maintained. This research also describes how genetic variants can shift the balance between autoimmunity and tolerance.

Animals↗

PubMed2006

Energetic influence on gull flight strategy selection.

During non-migratory flight, gulls (Larids) use a wide variety of flight strategies. We investigate the extent to which the energy balance of a bird explains flight strategy selection. We develop a model based on optimal foraging and aerodynamic theories, to calculate the ground speeds and airspeeds at which a gull is expected to flap or soar during foraging flight. The model results are compared with observed flight speeds, directions, and flight strategies of two species of gulls, the black-headed gull Larus ridibundus and the lesser black-backed gull Larus fuscus. The observations were made using a tracking radar over land in The Netherlands. The model suggests that, especially at combinations of low ground speed (approximately 5-10 m s(-1)), high air speed (approximately 20-25 m s(-1)) and low ground and air speed, gulls should favor soaring flight. At intermediate ground and air speeds the predicted net energy gain is similar for soaring and flapping. Hence the ratio of flapping to soaring may be higher than for other air and ground speed combinations. This range of speeds is broadest for black-headed gulls. The model results are supported by the observations. For example, flapping is more prevalent at speeds where the predicted net energy gain is similar for both strategies. Interestingly, combinations of air speed and flight speed that, according to the model, would result in a loss of net energy gain, were not observed. Additional factors that may influence flight strategy selection are also briefly discussed.

Animals↗

PubMed1985

Physiological characteristics of elite sport parachutists.

The physiological characteristics of 10 male elite sport parachutists (31.6 +/- 3.69 years of age) were determined and compared to 10 male non-sport parachutist controls (30.2 +/- 4.31 years) and other selected elite athletes. The typical sport parachutist was a highly educated (16.4 +/- 2.41 years), first born (9 out of 10), and, more often than not, single individual. During their mean 10.8 years of sport parachuting, these individuals made an average total number of 1,950 jumps (range 980 to 3,100) with a mean of 237.5 jumps during each of the last three years. Mean total free fall time was 22 h and 40 min. Compared to the non-sport parachutist control group, the elite sport parachutists were significantly higher (p less than 0.05) in aerobic power (47.4 +/- 9.04 vs. 37.2 +/- 4.67 ml X kg-1 X min-1), vital capacity (5.27 +/- 0.49 vs. 5.05 +/- 0.31 L), maximum heart rate (203.2 +/- 9.2 vs. 190.1 +/- 7.4 bpm), and back hyperextension flexibility (21.12 +/- 4.1 vs. 18.41 +/- 2.4 in). The elite sport parachutist were also significantly lower (p less than 0.05) in relative (%) body fat when compared to the control group (15.7 +/- 4.51 vs. 20.1 +/- 2.12%). The two groups were not significantly different (p greater than 0.05) with respect to resting heart rate, absolute body weight, dominant hand-grip strength, or lower back/hamstring flexibility as measured by the sit-and-reach test. Regarding somatotype, the elite sport parachutist can be classified as a balanced mesomorph. Compared to other selected elite athletes, the sport parachutists were lower in aerobic power and higher in relative body fat, yet with a summation of triceps, suprailiac, and abdominal skinfolds in the acceptable range for male athletes. The elite sport parachutists were approximately mid-range in absolute body weight and lower back/hamstring flexibility when compared to other selected elite athletes. Based on the findings of this study, there is evidence to suggest that some form of regular aerobic exercise along with a stretching and flexibility program is advisable for those individuals considering frequent participation and desiring peak performance in sport parachuting.

Adult↗

PubMed1983

The Florey lecture, 1983. Biological control, as exemplified by smallpox eradication and myxomatosis.

Biological control is an important method of dealing with plant and insect pests. The control of rabbits by myxomatosis and the eradication of smallpox by vaccination are unusual examples of biological control, in that they involve a vertebrate and a viral pest respectively. Myxomatosis is a benign disease in Sylvilagus rabbits in South America which is transmitted mechanically by mosquitoes. In the European rabbit, Oryctolagus, which is a pest in Australia and England, the virus from Sylvilagus produces a generalized disease that is almost always lethal. Myxomatosis was deliberately introduced into Australia in 1950 and into Europe in 1952. It was at first spectacularly successful in controlling the rabbit pest, but biological adjustments occurred in the virulence of the virus and the genetic resistances of rabbits. After 30 years of interaction, natural selection has resulted in a balance at a fairly high level of viral virulence. Smallpox has been a major scourge of mankind for over 1500 years. It spread from Asia to Europe in the Middle ages and from Europe to Africa and the Americas in the 15th and 16th centuries. Jenner's cowpox vaccine provided a method of control that reduced the severity of the disease during the 19th century but failed to eliminate the disease from many countries before the 1930s. Thereafter it was eradicated from Europe and North America, but remained endemic in South America, Africa and Asia. In 1967 it was still endemic in 33 countries and W.H.O. established a programme for global eradication within 10 years. The goal was achieved in 1977. Problems of the eradication programme and reasons for its success will be described.

Animals↗

PubMed1984

Dietary self-selection of laying hens inadequate to overcome the effects of high environmental temperature.

Two environmental temperatures, 21 and 30 C, were used during a 28-day experimental period. There were two groups of hens in each temperature treatment. The control groups (C) were given a conventional balanced diet and each dietary self-selection group (S-S) was provided, on an individual hen basis, three diets each one being high in energy, protein, or calcium. The S-S groups had significantly reduced egg production, which probably resulted from the significantly reduced protein intake. Egg weight and energy intake were reduced in the S-S group at 21 C while calcium intake and egg shell strength at 30 C were higher as compared to the corresponding C group. Dietary self-selection did not enable hens to regulate nutrient intake for comparable performance to hens provided one balanced diet. Also, the detrimental effects of high environmental temperature were not overcome by dietary self-selection.

Animals↗

PubMed2002

[From clone selection to danger model].

How is the balance between immune response and immune tolerance dynamically kept in the complicated immune system of human body? To answer this question, many scientists have proposed various models since 1950's. A brief introduction to these models is given in this mini-review, which might reflect the historical process in the development of immunology in the past half century.

Animals↗

PubMed1988

Free fitness that always increases in evolution.

I here introduce a free fitness function in population biology, which monotonically increases with time and takes its maximum at the evolutionary equilibrium. By suitably defining an "index" for each state, the free fitness is expressed as the average index plus an entropy term. In many cases, the index has a biologically clear meaning, such as the logarithmic population mean fitness. The technique is applicable to any Markov process model (either continuous or discrete) with a positive steady state. I discuss four examples from various branches of population biology: (1) one-locus-two-allele system of population genetics with mutation, selection, and random genetic drift; (2) evolutionary dynamics of quantitative characters; (3) a molecular evolution model; and (4) an ecological succession model. Introducing free fitness clarifies the balance between systematic forces (e.g. natural selection or successional trend toward the climax) and disturbing processes (e.g. random drift).

Animals↗

PubMedDate not supplied

Effects of epinephrine on thermoregulatory behavior in lean and obese Zucker rats in the cold.

This series of experiments examined whether epinephrine (EPI) produces the same thermoregulatory effects in the cold that have been reported for norepinephrine and isoproterenol. Lean and obese Zucker rats were trained to press a lever to activate infrared heat lamps in a cold (-8 degrees C) environment. Operant thermoregulatory behavior increased dose-dependently following EPI (0-100 micrograms/kg), but posttest colonic temperature (Tc) fell. Thermal balance calculations showed a substantial increase in net heat loss, more so in obese than lean animals. EPI is therefore thermolytic--i.e., disrupts thermal balance. A low dose (100 micrograms/kg) of the alpha-antagonist phentolamine produced a marked improvement in operant behavior, Tc, and thermal balance, whereas a comparable dose of the beta-antagonist propranolol had no beneficial effect. Increasing the dose of phentolamine worsened the responses with respect to the 100-micrograms/kg dose. The selective alpha 1-antagonist prazosin ameliorated the decrease in Tc induced by EPI but had little effect on operant behavior or thermal balance; the selective alpha 2-antagonist yohimbine had no effect on any parameter compared to EPI alone. These results suggest that the paradoxical effects of EPI in the cold are mediated by alpha-adrenoceptors, but definitive identification of the subclass of receptor involved cannot be determined.

Adipose Tissue, Brown↗

PubMed1986

Effects of inspiratory resistance loading on lung fluid balance in awake sheep.

Because pulmonary edema has been associated clinically with airway obstruction, we sought to determine whether decreased intrathoracic pressure, created by selective inspiratory obstruction, would affect lung fluid balance. We reasoned that if decreased intrathoracic pressure caused an increase in the transvascular hydrostatic pressure gradient, then lung lymph flow would increase and the lymph-to-plasma protein concentration ratio (L/P) would decrease. We performed experiments in six awake sheep with chronic lung lymph cannulas. After a base-line period, we added an inspiratory load (20 cmH2O) and allowed normal expiration at atmospheric pressure. Inspiratory loading was associated with a 12-cmH2O decrease in mean central airway pressure. Mean left atrial pressure fell 11 cmH2O, and mean pulmonary arterial pressure was unchanged; calculated microvascular pressure decreased 8 cmH2O. The changes that occurred in lung lymph were characteristic of those seen after other causes of increased transvascular hydrostatic gradient, such as increased intravascular pressure. Lung lymph flow increased twice base line, and L/P decreased. We conclude that inspiratory loading is associated with an increase in the pulmonary transvascular hydrostatic gradient, possibly by causing a greater fall in interstitial perimicrovascular pressure than in microvascular pressure.

Airway Obstruction↗

PubMed1998

Increasing amounts of dietary fiber provided by foods normalizes physiologic response of the large bowel without altering calcium balance or fecal steroid excretion.

Nine healthy, young men consumed constant diets to determine selected large-bowel, serum cholesterol and triacylglycerol, and calcium balance responses to 3 amounts of fiber provided by a mixture of fruit, vegetables, and grains. The diets, each consumed for 1 mo, contained 16, 30, and 42 g total fiber/d, of which 2.9, 4.8, and 7.7 g, respectively, was soluble. Mean daily wet and dry stool weights increased with each fiber addition. The first fiber addition increased defecation frequency and decreased fecal pH, bile acid concentration, and neutral steroid concentration; the second addition had no further effect. Mean weight of each defecation and stool moisture did not increase and serum cholesterol and triacylglycerol concentrations, calcium balance, and gastrointestinal transit time did not decrease as fiber intake increased. We conclude that 1) fiber provided by a mixed-food diet increases stool weight as effectively as does wheat or oat bran; 2) even high amounts of dietary fiber do not change transit time or defecation frequency if they are already approximately 1 and 2-3 d, respectively; 3) food patterns consistent with the food pyramid and incorporating legumes and whole grains are necessary to achieve recommended fiber intakes of 20-35 g/d, even if energy intake is > 12.55 MJ (3000 kcal); 4) soluble fiber provided by a mixture of whole foods has no effect on serum cholesterol concentrations or output of fecal bile acids; and 5) mixed-food fiber has little effect on calcium balance when calcium intakes are high (> or = 1.5 g/d).

Adult↗

PubMed1998

Controlling confounding when studying large pharmacoepidemiologic databases: a case study of the two-stage sampling design.

Large drug databases have been the source of interesting developments for pharmacoepidemiologic research, because they provide relatively accurate drug exposure histories. An important limitation of these databases is the lack of information on potential confounders. One solution, developed more than a decade ago but not widely used, is "two-stage sampling," in which stage 1 is the collection of information on drug exposure and outcomes, and stage 2 is the collection of confounder data on a subset of the stage 1 sample. The balanced design, wherein an equal number of individuals is selected from each drug exposure/disease category, is usually the most efficient strategy by which to select the stage 2 sample. We illustrate the efficiency of the balanced design in two-stage sampling using data from a provincial health organization and a simulation. We also evaluate the relative importance of factors affecting the precision of the effect estimate of the exposure of interest.

Case-Control Studies↗

PubMed2025

Universal versus targeted chlorhexidine and mupirocin decolonisation and clinical and molecular epidemiology of Staphylococcus epidermidis bloodstream infections in patients in intensive care in Scotland, UK: a controlled time-series and longitudinal genotypic study.

BACKGROUND: There are concerns that biocide skin and mucous membrane decolonisation, which is widely used to prevent health-care-associated infections in intensive care units (ICUs), might select for multidrug-resistant pathogens. We aimed to evaluate the effects of de-escalating from universal to targeted skin and nasal decolonisation on Staphylococcus epidermidis bloodstream infections (SE-BSI). METHODS: We did a retrospective, before-after-control-impact time-series analysis and longitudinal genotypic study in two ICUs with divergent decolonisation practice in tertiary care hospitals of adjacent health boards in Scotland, UK. Participants were aged at least 16 years and admitted between July 1, 2009, and Feb 28, 2022. There were no exclusion criteria for the study. In ICU one (intervention site) universal decolonisation in all admissions was de-escalated to targeted decolonisation of meticillin-resistant Staphylococcus aureus (MRSA) carriers on Feb 1, 2019, while in ICU two (control site) targeted decolonisation was applied throughout. We collected bloodstream infection data from all causes, including clinically significant SE-BSI. Antimicrobial susceptibility testing was used to define meticillin-resistant S epidermidis (MRSE) and chlorhexidine susceptibility. We used multilocus sequence typing to identify sequence types from archived SE-BSI isolates. Whole-genome sequencing was applied to a sample from ICU one. The primary outcomes were incidence densities of all bloodstream infections, SE-BSI, and meticillin-resistant S epidermidis bloodstream infections (MRSE-BSI), and the percentage probability that SE-BSI were MRSE-BSI. The effects of de-escalation on primary outcomes were estimated by differences between the intervention and control sites, before and after de-escalation, using a before-after-control-impact time-series design. Secondary outcomes included the proportion of multidrug resistant sequence types, carriage of mobile genetic elements and genes for multidrug resistance and biofilm production. FINDINGS: Between July 1, 2009, and Feb 28, 2022, S epidermidis was identified in 334 (45%) of 735 bloodstream infections in ICU one, of which 197 occurred before the de-escalation intervention in Feb 1, 2019, and S epidermidis was identified in 167 (60%) of 278 bloodstream infections in ICU two. There was no increase in all bloodstream infection incidence coinciding with de-escalation in ICU one, whereas MRSE-BSI incidence declined significantly from 10·4 cases per 1000 occupied bed days (OBDs; 95% credible interval [CrI] 7·2-15·4) to 4·3 cases per 1000 OBDs (2·5-6·7), as did the percentage probability of MRSE (from 89·2%, 95% CrI 77·8-96·5 to 56·7%, 34·3-77·5%). No significant changes in the primary outcomes were seen in ICU two. MRSE-BSI incidence density was positively associated with chlorhexidine use, but not mupirocin use. De-escalation was associated with a reduced proportion of SE-BSI due to multidrug-resistant sequence types and reduced carriage of mobile genetic elements and genes for multidrug resistance and biofilm production, as observed by multi-locus sequence typing and whole genome sequencing. INTERPRETATION: In ICU settings with low MRSA incidence, the benefits of universal decolonisation should be balanced against the risks of selecting MRSE sequence types adapted for invasive and device-associated infection. FUNDING: National Health Service Grampian Charity.

Humans↗