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1.  Evidence from randomised controlled trials did not support the introduction of dietary fat guidelines in 1977 and 1983: a systematic review and meta-analysis 
Open Heart  2015;2(1):e000196.
National dietary guidelines were introduced in 1977 and 1983, by the US and UK governments, respectively, with the ambition of reducing coronary heart disease (CHD) by reducing fat intake. To date, no analysis of the evidence base for these recommendations has been undertaken. The present study examines the evidence from randomised controlled trials (RCTs) available to the US and UK regulatory committees at their respective points of implementation.
A systematic review and meta-analysis were undertaken of RCTs, published prior to 1983, which examined the relationship between dietary fat, serum cholesterol and the development of CHD.
2467 males participated in six dietary trials: five secondary prevention studies and one including healthy participants. There were 370 deaths from all-cause mortality in the intervention and control groups. The risk ratio (RR) from meta-analysis was 0.996 (95% CI 0.865 to 1.147). There were 207 and 216 deaths from CHD in the intervention and control groups, respectively. The RR was 0.989 (95% CI 0.784 to 1.247). There were no differences in all-cause mortality and non-significant differences in CHD mortality, resulting from the dietary interventions. The reductions in mean serum cholesterol levels were significantly higher in the intervention groups; this did not result in significant differences in CHD or all-cause mortality. Government dietary fat recommendations were untested in any trial prior to being introduced.
Dietary recommendations were introduced for 220 million US and 56 million UK citizens by 1983, in the absence of supporting evidence from RCTs.
PMCID: PMC4316589
2.  Childhood Trauma and Hippocampal and Amygdalar Volumes in First-Episode Psychosis 
Schizophrenia Bulletin  2011;38(6):1162-1169.
Objective: A history of childhood trauma is common in individuals who later develop psychosis. Similar neuroanatomical abnormalities are observed in people who have been exposed to childhood trauma and people with psychosis. However, the relationship between childhood trauma and such abnormalities in psychosis has not been investigated. This study aimed to explore the association between the experience of childhood trauma and hippocampal and amygdalar volumes in a first-episode psychosis (FEP) population. Methods: The study employed an observational retrospective design. Twenty-one individuals, who had previously undergone magnetic resonance imaging procedures as part of the longitudinal Northern Ireland First-Episode Psychosis Study, completed measures assessing traumatic experiences and were included in the analysis. Data were subject to correlation analyses (r and r pb). Potential confounding variables (age at FEP and delay to scan from recruitment) were selected a priori for inclusion in multiple regression analyses. Results: There was a high prevalence of lifetime (95%) and childhood (76%) trauma in the sample. The experience of childhood trauma was a significant predictor of left hippocampal volume, although age at FEP also significantly contributed to this model. There was no significant association between predictor variables and right hippocampal volume. The experience of childhood trauma was a significant predictor of right and total amygdalar volumes and the hippocampal/amygdalar complex volume as a whole. Conclusions: The findings indicate that childhood trauma is associated with neuroanatomical measures in FEP. Future research controlling for childhood traumatic experiences may contribute to explaining brain morphology in people with psychosis.
PMCID: PMC3494041  PMID: 21799213
psychosis; trauma; hippocampus; amygdala
3.  High intensity interval running enhances measures of physical fitness but not metabolic measures of cardiovascular disease risk in healthy adolescents 
BMC Public Health  2013;13:498.
With accumulating evidence suggesting that CVD has its origins in childhood, the purpose of this study was to examine whether a high intensity training (HIT) intervention could enhance the CVD risk profile of secondary school aged adolescents in a time efficient manner.
Participants in the study were adolescent school children (64 boys, 25 girls, 16.7 ± 0.6 years). The intervention group (30 boys, 12 girls) performed three weekly exercise sessions over 7 weeks with each session consisting of either four to six repeats of maximal sprint running within a 20 m area with 30 s recovery. The control group were instructed to continue their normal behaviour. All participants had indices of obesity, blood pressure and nine biochemical risk markers for cardiovascular disease recorded as well as four physical performance measures at baseline and post-intervention. Feedback was provided through informal discussion throughout the intervention period as well as post-intervention focus groups. Statistical differences between and within groups were determined by use of paired samples t-tests and ANCOVA.
Significant enhancements (P ≤ 0.05) in vertical jump performance, 10 m sprint speed and cardiorespiratory fitness was evident in the intervention group whereas a significant decrease in both agility and vertical jump performance was evident in the control group. Participants in the intervention group also experienced a significant decrease in systolic blood pressure post-intervention. Limited changes occurred with respect to the biochemical markers although both groups did experience a significant increase in LDL post-intervention whilst the control group experienced a significant decrease in total cholesterol. No apparent differences were evident between groups post intervention for any of the biochemical markers. Feedback indicated that participants endorsed the use of the intervention as an effective means of exercise.
Our results demonstrate that high intensity exercise interventions may be used in the school setting for adolescents as a means of improving measures of physical fitness. Further investigations involving a larger cohort of participants, taken from different schools, is recommended.
Trial registration
PMCID: PMC3666892  PMID: 23705968
4.  The Effects of a Novel High Intensity Exercise Intervention on Established Markers of Cardiovascular Disease and Health in Scottish Adolescent Youth 
This study examined the effects of high intensity exercise on physical fitness components and cardiovascular disease (CVD) risk factors in youth. Forty-one participants (15-17 years) were divided into a control and an intervention (high intensity exercise, HIT) group. The HIT group (15 boys, 2 girls) performed three weekly sessions over seven weeks consisting of either four to six repeats of maximal sprint running with 20-30 s recovery. The control group (20 boys, 4 girls) continued their normal activity patterns. All participants had indices of obesity and blood pressure (BP) recorded in addition to four physical performance measures pre-and post-intervention: cardiorespiratory fitness, muscular power, sprint speed and agility. In the HIT group, significant improvements in cardiorespiratory fitness (P<0.01) and agility (P<0.05) were noted. Participants in the control group, meanwhile, experienced a significant decrease in counter movement jump performance. These findings demonstrate that brief, intense exercise interventions are useful for improving indices of physical fitness in a short period of time.
The authors gratefully acknowledge Ms. Maini Tulokas in the Social Insurance Institution for her skilled help in preparing the figures.
this study was financially supported by the Chief Scientist Office for Scotland.
PMCID: PMC4140358  PMID: 25170459
health; youth; high intensity exercise
5.  Membrane-elution analysis of content of cyclins A, B1, and E during the unperturbed mammalian cell cycle 
Cell Division  2007;2:28.
Problems with whole-culture synchronization methods for the study of the cell cycle have led to the need for an analysis of protein content during the cell cycle of cells that have not been starved or inhibited. The membrane-elution method is a method that allows the study of the cell cycle by producing a culture of unperturbed, synchronized cells.
The Helmstetter membrane-elution method for the continuous production of newborn, unperturbed, mammalian cells has been enhanced so that the collection of cells of different cell cycle ages is automated, reproducible, and relatively inexpensive. We have applied the automated membrane-elution method to the analysis of cyclin content during the cell cycle. Cyclin E protein was invariant during the cell cycle. Cyclins B1 and A accumulated continuously during the cell cycle and were degraded at mitosis. Newborn cells had ~0.5% of the cyclin B1 content of dividing cells.
The expression patterns of cyclins A, B1, and E can be explained by constant mRNA levels during the cell cycle. Previously reported phase specific variations of the cyclins are not strictly necessary for cell-cycle progression. Cells produced by membrane-elution are available to other laboratories for analysis of the cell cycle.
PMCID: PMC2064908  PMID: 17892542
6.  Distinguishing between linear and exponential cell growth during the division cycle: Single-cell studies, cell-culture studies, and the object of cell-cycle research 
Two approaches to understanding growth during the cell cycle are single-cell studies, where growth during the cell cycle of a single cell is measured, and cell-culture studies, where growth during the cell cycle of a large number of cells as an aggregate is analyzed. Mitchison has proposed that single-cell studies, because they show variations in cell growth patterns, are more suitable for understanding cell growth during the cell cycle, and should be preferred over culture studies. Specifically, Mitchison argues that one can glean the cellular growth pattern by microscopically observing single cells during the division cycle. In contrast to Mitchison's viewpoint, it is argued here that the biological laws underlying cell growth are not to be found in single-cell studies. The cellular growth law can and should be understood by studying cells as an aggregate.
The purpose or objective of cell cycle analysis is presented and discussed. These ideas are applied to the controversy between proponents of linear growth as a possible growth pattern during the cell cycle and the proponents of exponential growth during the cell cycle. Differential (pulse) and integral (single cell) experiments are compared with regard to cell cycle analysis and it is concluded that pulse-labeling approaches are preferred over microscopic examination of cell growth for distinguishing between linear and exponential growth patterns. Even more to the point, aggregate experiments are to be preferred to single-cell studies.
The logical consistency of exponential growth – integrating and accounting for biochemistry, cell biology, and rigorous experimental analysis – leads to the conclusion that proposals of linear growth are the result of experimental perturbations and measurement limitations. It is proposed that the universal pattern of cell growth during the cell cycle is exponential.
PMCID: PMC1402260  PMID: 16504098
7.  Comment on and reply to "Analysis of variation of amplitudes in cell cycle gene expression" by Liu, Gaido and Wolfinger: On the analysis of gene expression during the normal, eukaryotic, cell cycle 
The paper of Liu, Gaido and Wolfinger on gene expression during the division cycle of HeLa cells using the data of Whitfield et al. are discussed in order to see whether their analysis is related to gene expression during the division cycle.
The results of Liu, Gaido and Wolfinger demonstrate that different inhibition methods proposed to "synchronize" cells lead to different levels of gene expression. This result, in and of itself, should be taken as evidence that the original work of Whitfield et al. is flawed and should not be used to support the notion that the cells studied were synchronized or that the microarray analyses identify cell-cycle-regulated genes. Furthermore, the DNA content evidence presented by Whitfield et al. supports the proposal that the cells described as 'synchronized' are not synchronized. A comparison of the gene expression amplitudes from two different experiments indicates that the results are not reproducible.
It is concluded that the analysis of Liu, Gaido, and Wolfinger is problematic because their work assumes that the cells they analyze are or were synchronized. The very fact that different inhibition methods lead to different degrees of gene expression should be taken as additional evidence that the experiments should be viewed skeptically rather than accepted as an approach to understanding gene expression during the cell cycle.
PMCID: PMC1298338  PMID: 16297235
8.  Control and maintenance of mammalian cell size 
BMC Cell Biology  2004;5:35.
Conlon and Raff propose that mammalian cells grow linearly during the division cycle. According to Conlon and Raff, cells growing linearly do not need a size checkpoint to maintain a constant distribution of cell sizes. If there is no cell-size-control system, then exponential growth is not allowed, as exponential growth, according to Conlon and Raff, would require a cell-size-control system.
A reexamination of the model and experiments of Conlon and Raff indicates that exponential growth is fully compatible with cell size maintenance, and that mammalian cells have a system to regulate and maintain cell size that is related to the process of S-phase initiation. Mammalian cell size control and its relationship to growth rate–faster growing cells are larger than slower growing cells–is explained by the initiation of S phase occurring at a relatively constant cell size coupled with relatively invariant S- and G2-phase times as interdivision time varies.
This view of the mammalian cell cycle, the continuum model, explains the mass growth pattern during the division cycle, size maintenance, size determination, and the kinetics of cell-size change following a shift-up from slow to rapid growth.
PMCID: PMC524481  PMID: 15456512
cell cycle; cell size; exponential growth; linear growth; shift-up; continuum model
9.  Microarray analysis of gene expression during the cell cycle 
Cell & Chromosome  2003;2:1.
Microarrays have been applied to the determination of genome-wide expression patterns during the cell cycle of a number of different cells. Both eukaryotic and prokaryotic cells have been studied using whole-culture and selective synchronization methods. The published microarray data on yeast, mammalian, and bacterial cells have been uniformly interpreted as indicating that a large number of genes are expressed in a cell-cycle-dependent manner. These conclusions are reconsidered using explicit criteria for synchronization and precise criteria for identifying gene expression patterns during the cell cycle. The conclusions regarding cell-cycle-dependent gene expression based on microarray analysis are weakened by arguably problematic choices for synchronization methodology (e.g., whole-culture methods that do not synchronize cells) and questionable statistical rigor for identifying cell-cycle-dependent gene expression. Because of the uncertainties in synchrony methodology, as well as uncertainties in microarray analysis, one should be somewhat skeptical of claims that there are a large number of genes expressed in a cell-cycle-dependent manner.
PMCID: PMC239863  PMID: 14577836
Double thymidine block; Affymetrix, cell cycle, synchronization, nocodazole, yeast, HeLa
10.  Analysis of cell-cycle gene expression in Saccharomyces cerevisiae using microarrays and multiple synchronization methods 
Nucleic Acids Research  2002;30(13):2920-2929.
Microarray analysis of gene expression during the yeast division cycle has led to the proposal that a significant number of genes in Saccharomyces cerevisiae are expressed in a cell-cycle-specific manner. Four different methods of synchronization were used for cell-cycle analysis. Randomized data exhibit periodic patterns of lesser strength than the experimental data. Thus the cyclicities in the expression measurements in the four experiments presented do not arise from chance fluctuations or noise in the data. However, when the degree of cyclicity for genes in different experiments are compared, a large degree of non-reproducibility is found. Re-examining the phase timing of peak expression, we find that three of the experiments (those using α-factor, CDC28 and CDC15 synchronization) show consistent patterns of phasing, but the elutriation synchrony results demonstrate a different pattern from the other arrest-release synchronization methods. Specific genes can show a wide range of cyclical behavior between different experiments; a gene with high cyclicity in one experiment can show essentially no cyclicity in another experiment. The elutriation experiment, possibly being the least perturbing of the four synchronization methods, may give the most accurate characterization of the state of gene expression during the normal, unperturbed cell cycle. Under this alternative explanation, the observed cyclicities in the other three experiments are a stress response to synchronization, and may not reproduce in unperturbed cells.
PMCID: PMC117069  PMID: 12087178
12.  Efficacy of Low Dose Combination Analgesics: Acetaminophen/Codeine, Aspirin/Butalbital/Caffeine/Codeine, and Placebo in Oral Surgery Pain 
Anesthesia Progress  1986;33(3):143-146.
A double-blind, randomized, single-dose study was performed to compare the efficacy and safety of two commonly prescribed combination analgesic products to placebo. The combinations were acetaminophen 300 mg/codeine 30 mg†, and aspirin 325 mg/butalbital 50 mg/caffeine 40 mg/codeine 30 mg††. One hundred twenty-three (123) oral surgery outpatients took study medications when their pain became moderate to severe and recorded the levels of pain intensity, pain relief, anxiety and relaxation at 30 minutes and hourly for 6 hours after dosing. Remedication was permitted if study medications did not provide adequate pain relief. Time to remedication, and the number of observations with 50% or better relief, were noted as were any side effects. An overall evaluation was obtained from each patient. Results of the study showed that the aspirin/butalbital/caffeine/codeine combination was significantly more effective than placebo for total pain relief, peak relief and global evaluation. While the acetaminophen/codeine combination was numerically superior to placebo, it achieved statistical significance only for global evaluation. The aspirin/butalbital/caffeine/codeine combination was numerically superior to acetaminophen/codeine for every measure of analgesic efficacy but the differences did not achieve statistical significance. Both active treatment groups experienced significantly less total anxiety than did the placebo group. Only 11 patients reported mild, transient adverse effects; the most common was drowsiness. The adverse effects occurred equally among the three treatment groups. In this study, the aspirin/butalbital/caffeine/codeine combination was significantly superior to placebo and somewhat better than acetaminophen/codeine.
PMCID: PMC2175477  PMID: 3461726
13.  Double-comparison of an Acetaminophen-Codeine-Caffeine Combination in Oral Surgery Pain 
Anesthesia Progress  1986;33(3):139-142.
The purpose of this paper was to evaluate the contribution of low dosages of codeine and caffeine when added to acetaminophen. Subjects were dental outpatients undergoing oral surgery involving bone removal. This was a single-dose, parallel group, double-blind assay evaluting 99 subjects. The treatment groups were acetaminophen 1000 mg, acetaminophen 1000 mg + codeine 16 mg + caffeine 30 mg and placebo. The results demonstrated that both active treatments were superior to placebo. Overall, the combination was slightly better than acetaminophen alone. The advantage of the combination appeared more evident in the “severe” baseline pain group.
PMCID: PMC2175476  PMID: 3461725
14.  Temperature-Sensitive Nonsense Mutations in Essential Genes of Escherichia coli 
Journal of Bacteriology  1973;116(3):1336-1342.
Cells containing nonsense mutations in essential genes have been isolated in a strain of Escherichia coli that carried the su4ts gene which specifies a temperature-sensitive tyrosine transfer ribonucleic acid. Such cells are unable to form colonies at temperatures which inactivate this suppressor transfer ribonucleic acid. A screening procedure for the identification of mutants that carry temperature-sensitive nonsense mutations in essential genes is described, and certain properties of two such mutants are reported.
PMCID: PMC246492  PMID: 4127628
15.  Replication of Deoxyribonucleic Acid During the Division Cycle of Salmonella typhimurium 
Journal of Bacteriology  1973;114(3):966-973.
The rate of thymidine incorporation into cells of Salmonella typhimurium growing in different media has been measured. In glucose-minimal medium, deoxyribonucleic acid (DNA) replication occurs during the first two-thirds of the division cycle; the final one-third of the division cycle was devoid of DNA replication. The measured doubling time of S. typhimurium in this medium is approximately 48 min, indicating that C (the time for a round of replication) and D (the time between termination and cell division) are approximately 32 and 16 min, respectively. At slower growth rates the pattern of replication is the same as glucose minimal medium. At faster growth rates the “gap” in DNA synthesis disappears. At rapid growth rates evidence for multiple forks is obtained.
PMCID: PMC285352  PMID: 4576412
16.  Comment on the Use of Chloramphenicol to Study the Initiation of Deoxyribonucleic Acid Synthesis 
Journal of Bacteriology  1971;106(2):709-711.
Chloramphenicol cannot be used to distinguish different steps in the initiation of bacterial chromosome replication.
PMCID: PMC285155  PMID: 4929877
17.  Utilization of d-Methionine by Escherichia coli 
Journal of Bacteriology  1966;92(2):328-332.
Cooper, Stephen (University Institute of Microbiology, Copenhagen, Denmark). Utilization of d-methionine by Escherichia coli. J. Bacteriol. 92:328–332. 1966.—Methionine-requiring strains of Escherichia coli grow on d-methionine. Mutants can be isolated which cannot grow on d-methionine. The d-methionine nonutilizing mutation is independent of the methionine requirement, and maps near the lac region of the E. coli genome. Growth of methionine-requiring strains on d-methionine is dependent upon aerobic conditions. Cells grown on d-methionine have a sixfold greater ability to incorporate d-methionine into protein than cells grown on l-methionine. The incorporation of d-methionine is inhibited by l-methionine.
PMCID: PMC276242  PMID: 16562114

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