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1.  Population Genetic Analyses of Helicobacter pylori Isolates from Gambian Adults and Children 
PLoS ONE  2014;9(10):e109466.
The gastric pathogen Helicobacter pylori is one of the most genetically diverse of bacterial species. Much of its diversity stems from frequent mutation and recombination, preferential transmission within families and local communities, and selection during persistent gastric mucosal infection. MLST of seven housekeeping genes had identified multiple distinct H. pylori populations, including three from Africa: hpNEAfrica, hpAfrica1 and hpAfrica2, which consists of three subpopulations (hspWAfrica, hspCAfrica and hspSAfrica). Most detailed H. pylori population analyses have used strains from non-African countries, despite Africa's high importance in the emergence and evolution of humans and their pathogens. Our concatenated sequences from seven H. pylori housekeeping genes from 44 Gambian patients (MLST) identified 42 distinct sequence types (or haplotypes), and no clustering with age or disease. STRUCTURE analysis of the sequence data indicated that Gambian H. pylori strains belong to the hspWAfrica subpopulation of hpAfrica1, in accord with Gambia's West African location. Despite Gambia's history of invasion and colonisation by Europeans and North Africans during the last millennium, no traces of Ancestral Europe1 (AE1) population carried by those people were found. Instead, admixture of 17% from Ancestral Europe2 (AE2) was detected in Gambian strains; this population predominates in Nilo-Saharan speakers of North-East Africa, and might have been derived from admixture of hpNEAfrica strains these people carried when they migrated across the Sahara during the Holocene humid period 6,000–9,000 years ago. Alternatively, shared AE2 ancestry might have resulted from shared ancestral polymorphisms already present in the common ancestor of sister populations hpAfrica1 and hpNEAfrica.
doi:10.1371/journal.pone.0109466
PMCID: PMC4195673  PMID: 25310300
2.  Inactive alleles of cytochrome P450 2C19 may be positively selected in human evolution 
Background
Cytochrome P450 CYP2C19 metabolizes a wide range of pharmacologically active substances and a relatively small number of naturally occurring environmental toxins. Poor activity alleles of CYP2C19 are very frequent worldwide, particularly in Asia, raising the possibility that reduced metabolism could be advantageous in some circumstances. The evolutionary selective forces acting on this gene have not previously been investigated.
We analyzed CYP2C19 genetic markers from 127 Gambians and on 120 chromosomes from Yoruba, Europeans and Asians (Japanese + Han Chinese) in the Hapmap database. Haplotype breakdown was explored using bifurcation plots and relative extended haplotype homozygosity (REHH). Allele frequency differentiation across populations was estimated using the fixation index (FST) and haplotype diversity with coalescent models.
Results
Bifurcation plots suggested conservation of alleles conferring slow metabolism (CYP2C19*2 and *3). REHH was high around CYP2C19*2 in Yoruba (REHH 8.3, at 133.3 kb from the core) and to a lesser extent in Europeans (3.5, at 37.7 kb) and Asians (2.8, at −29.7 kb). FST at the CYP2C19 locus was low overall (0.098). CYP2C19*3 was an FST outlier in Asians (0.293), CYP2C19 haplotype diversity < = 0.037, p <0.001.
Conclusions
We found some evidence that the slow metabolizing allele CYP2C19*2 is subject to positive selective forces worldwide. Similar evidence was also found for CYP2C19*3 which is frequent only in Asia. FST is low at the CYP2C19 locus, suggesting balancing selection overall. The biological factors responsible for these selective pressures are currently unknown. One possible explanation is that early humans were exposed to a ubiquitous novel toxin activated by CYP2C19. The genetic adaptation took place within the last 10,000 years which coincides with the development of systematic agricultural practices.
doi:10.1186/1471-2148-14-71
PMCID: PMC4036532  PMID: 24690327
Positive selection; Cytochrome P450 2C19; Xenobiotics; Drug metabolism; Extended haplotype homozygosity; Bifurcation plots
3.  Effects of genetic variation at the CYP2C19/CYP2C9 locus on pharmacokinetics of chlorcycloguanil in adult Gambians 
Pharmacogenomics  2009;10(9):10.2217/pgs.09.72.
Aims
Antimalarial biguanides are metabolized by CYP2C19, thus genetic variation at the CYP2C locus might affect pharmacokinetics and so treatment outcome for malaria.
Materials & methods
Polymorphisms in CYP2C19 and CYP2C9 in 43 adult Gambians treated with chlorproguanil/dapsone for uncomplicated malaria were assessed. Chlorcycloguanil pharmacokinetics were measured and associations with CYP2C19 and CYP2C9 alleles and CYP2C19 metabolizer groups investigated.
Results
All CYP2C19/CYP2C9 alleles obeyed Hardy–Weinberg equilibrium. There were 15 CYP2C19/2C9 haplotypes with a common haplotype frequency of 0.23. Participants with the CYP2C19*17 allele had higher chlorcycloguanil area under the concentration versus time curve at 24 h (AUC0-24) than those without (geometric means: 317 vs 216 ng.h/ml; ratio of geometric means: 1.46; 95% CI: 1.03 to 2.09; p = 0.0363) and higher Cmax (geometric mean ratio: 1.52; 95% CI: 1.13 to 2.05; p = 0.0071).
Conclusion
CYP2C19*17 determines antimalarial biguanide metabolic profile at the CYP2C19/CYP2C9 locus.
doi:10.2217/pgs.09.72
PMCID: PMC3870622  PMID: 19761366
chlorcycloguanil; CYP2C19; CYP2C9; drug metabolism; pharmacokinetics; polymorphisms
4.  Antimicrobial Susceptibility and Resistance Patterns among Helicobacter pylori Strains from The Gambia, West Africa 
Helicobacter pylori is a globally important and genetically diverse gastric pathogen that infects most people in developing countries. Eradication efforts are complicated by antibiotic resistance, which varies in frequency geographically. There are very few data on resistance in African strains. Sixty-four Gambian H. pylori strains were tested for antibiotic susceptibility. The role of rdxA in metronidazole (Mtz) susceptibility was tested by DNA transformation and sequencing; RdxA protein variants were interpreted in terms of RdxA structure. Forty-four strains (69%) were resistant to at least 8 μg of Mtz/ml. All six strains from infants, but only 24% of strains from adults, were sensitive (P = 0.0031). Representative Mtz-resistant (Mtzr) strains were rendered Mtz susceptible (Mtzs) by transformation with a functional rdxA gene; conversely, Mtzs strains were rendered Mtzr by rdxA inactivation. Many mutations were found by Gambian H. pylori rdxA sequencing; mutations that probably inactivated rdxA in Mtzr strains were identified and explained using RdxA protein's structure. All of the strains were sensitive to clarithromycin and erythromycin. Amoxicillin and tetracycline resistance was rare. Sequence analysis indicated that most tetracycline resistance, when found, was not due to 16S rRNA gene mutations. These data suggest caution in the use of Mtz-based therapies in The Gambia. The increasing use of macrolides against respiratory infections in The Gambia calls for continued antibiotic susceptibility monitoring. The rich variety of rdxA mutations that we found will be useful in further structure-function studies of RdxA, the enzyme responsible for Mtz susceptibility in this important pathogen.
doi:10.1128/AAC.00517-12
PMCID: PMC3591906  PMID: 23263004
5.  DHCR7 mutations linked to higher vitamin D status allowed early human migration to Northern latitudes 
Background
Vitamin D is essential for a wide range of physiological processes including immune function and calcium homeostasis. Recent investigations have identified candidate genes which are strongly linked to concentrations of 25-hydroxyvitamin D. Since there is insufficient UVB radiation to induce year-round cutaneous synthesis of vitamin D at latitudes distant from the equator it is likely that these genes were subject to forces of natural selection. We used the fixation index (FST) to measure differences in allele frequencies in 993 individuals from ten populations to identify the presence of evolutionary selection in genes in the vitamin D pathway. We then explored the length of haplotypes in chromosomes to confirm recent positive selection.
Results
We find evidence of positive selection for DHCR7, which governs availability of 7-dehydrocholesterol for conversion to vitamin D3 by the action of sunlight on the skin. We show that extended haplotypes related to vitamin D status are highly prevalent at Northern latitudes (Europe 0.72, Northeast Asia 0.41). The common DHCR7 haplotype underwent a recent selective sweep in Northeast Asia, with relative extended haplotype homozygosity of 5.03 (99th percentile). In contrast, CYP2R1, which 25-hydroxylates vitamin D, is under balancing selection and we found no evidence of recent selection pressure on GC, which is responsible for vitamin D transport.
Conclusions
Our results suggest that genetic variation in DHCR7 is the major adaptation affecting vitamin D metabolism in recent evolutionary history which helped early humans to avoid severe vitamin D deficiency and enabled them to inhabit areas further from the equator.
doi:10.1186/1471-2148-13-144
PMCID: PMC3708787  PMID: 23837623
Evolutionary selection; Vitamin D; DHCR7; Fixation index; Long range haplotype test
6.  The role of zebrafish (Danio rerio) in dissecting the genetics and neural circuits of executive function 
Zebrafish have great potential to contribute to our understanding of behavioral genetics and thus to contribute to our understanding of the etiology of psychiatric disease. However, progress is dependent upon the rate at which behavioral assays addressing complex behavioral phenotypes are designed, reported and validated. Here we critically review existing behavioral assays with particular focus on the use of adult zebrafish to explore executive processes and phenotypes associated with human psychiatric disease. We outline the case for using zebrafish as models to study impulse control and attention, discussing the validity of applying extant rodent assays to zebrafish and evidence for the conservation of relevant neural circuits.
doi:10.3389/fncir.2013.00063
PMCID: PMC3619107  PMID: 23580329
zebrafish; attention; impulsivity; behavioral flexibility; psychiatric disorder; neural circuits
7.  HMOX1 Gene Promoter Alleles and High HO-1 Levels Are Associated with Severe Malaria in Gambian Children 
PLoS Pathogens  2012;8(3):e1002579.
Heme oxygenase 1 (HO-1) is an essential enzyme induced by heme and multiple stimuli associated with critical illness. In humans, polymorphisms in the HMOX1 gene promoter may influence the magnitude of HO-1 expression. In many diseases including murine malaria, HO-1 induction produces protective anti-inflammatory effects, but observations from patients suggest these may be limited to a narrow range of HO-1 induction, prompting us to investigate the role of HO-1 in malaria infection. In 307 Gambian children with either severe or uncomplicated P. falciparum malaria, we characterized the associations of HMOX1 promoter polymorphisms, HMOX1 mRNA inducibility, HO-1 protein levels in leucocytes (flow cytometry), and plasma (ELISA) with disease severity. The (GT)n repeat polymorphism in the HMOX1 promoter was associated with HMOX1 mRNA expression in white blood cells in vitro, and with severe disease and death, while high HO-1 levels were associated with severe disease. Neutrophils were the main HO-1-expressing cells in peripheral blood, and HMOX1 mRNA expression was upregulated by heme-moieties of lysed erythrocytes. We provide mechanistic evidence that induction of HMOX1 expression in neutrophils potentiates the respiratory burst, and propose this may be part of the causal pathway explaining the association between short (GT)n repeats and increased disease severity in malaria and other critical illnesses. Our findings suggest a genetic predisposition to higher levels of HO-1 is associated with severe illness, and enhances the neutrophil burst leading to oxidative damage of endothelial cells. These add important information to the discussion about possible therapeutic manipulation of HO-1 in critically ill patients.
Author Summary
HO-1 is an important anti-inflammatory enzyme induced by several stimuli associated with critical illness. In humans, the amount of HO-1 produced is influenced by a genetic polymorphism in the gene promoter region. Using Plasmodium falciparum malaria that can cause a sepsis-like syndrome as an example, we characterize the associations between the (GT)n polymorphism, HO-1 protein levels and HMOX1-mRNA expression with severity of malaria in 307 Gambian children. Our results support the functionality of this polymorphism, demonstrate that P. falciparum infections increase HO-1 levels, and indicate that a genetic predisposition to strongly upregulate HO-1 is associated with severe forms of malaria and increased risk of dying. We identify neutrophils as the main HO-1-producing blood cells, and provide evidence that hemin-mediated induction of HMOX1 in neutrophils in vitro enhances the oxidative burst. In this way sequestered neutrophils may contribute to oxidative damage of endothelial cells, which may be part of a causal pathway explaining the association between short (GT)n repeats and increased disease severity. Our findings imply that the beneficial effects of HO-1 may be limited to a narrow window of concentrations, which should be born in mind when considering the therapeutic potential of manipulating HO-1 induction in critically ill patients.
doi:10.1371/journal.ppat.1002579
PMCID: PMC3305414  PMID: 22438807
8.  Mixed Infection with cagA Positive and cagA Negative Strains of Helicobacter pylori Lowers Disease Burden in The Gambia 
PLoS ONE  2011;6(11):e27954.
Background
The prevalence of Helicobacter pylori including strains with putatively virulent genotypes is high, whereas the H. pylori-associated disease burden is low, in Africa compared to developed countries. In this study, we investigated the prevalence of virulence-related H. pylori genotypes and their association with gastroduodenal diseases in The Gambia.
Methods and Findings
DNA extracted from biopsies and H. pylori cultures from 169 subjects with abdominal pain, dyspepsia or other gastroduodenal diseases were tested by PCR for H. pylori. The H. pylori positive samples were further tested for the cagA oncogene and vacA toxin gene.
One hundred and twenty one subjects (71.6%) were H. pylori positive. The cagA gene and more toxigenic s1 and m1 alleles of the vacA gene were found in 61.2%, 76.9% and 45.5% respectively of Gambian patients harbouring H. pylori. There was a high prevalence of cagA positive strains in patients with overt gastric diseases than those with non-ulcerative dyspepsia (NUD) (p = 0.05); however, mixed infection by cagA positive and cagA negative strains was more common in patients with NUD compared to patients with gastric disease (24.5% versus 0%; p = 0.002).
Conclusion
This study shows that the prevalence of H. pylori is high in dyspeptic patients in The Gambia and that many strains are of the putatively more virulent cagA+, vacAs1 and vacAm1 genotypes. This study has also shown significantly lower disease burden in Gambians infected with a mixture of cag-positive and cag-negative strains, relative to those containing only cag-positive or only cag-negative strains, which suggests that harbouring both cag-positive and cag-negative strains is protective.
doi:10.1371/journal.pone.0027954
PMCID: PMC3226634  PMID: 22140492
9.  Randomized Trial of Safety and Effectiveness of Chlorproguanil-Dapsone and Lumefantrine-Artemether for Uncomplicated Malaria in Children in The Gambia 
PLoS ONE  2011;6(6):e17371.
Background
Chlorproguanil-dapsone (Lapdap), developed as a low-cost antimalarial, was withdrawn in 2008 after concerns about safety in G6PD deficient patients. This trial was conducted in 2004 to evaluate the safety and effectiveness of CD and comparison with artemether-lumefantrine (AL) under conditions of routine use in G6PD normal and G6PD deficient patients with uncomplicated malaria in The Gambia. We also examined the effects of a common genetic variant that affects chlorproguanil metabolism on risk of treatment failure.
Methods
1238 children aged 6 months to 10 years with uncomplicated malaria were randomized to receive CD or artemether-lumefantrine (AL) and followed for 28 days. The first dose was supervised, subsequent doses given unsupervised at home. G6PD genotype was determined to assess the interaction between treatment and G6PD status in their effects on anaemia. The main endpoints were clinical treatment failure by day 28, incidence of severe anaemia (Hb<5 g/dL), and haemoglobin concentration on day 3.
Findings
One third of patients treated with AL, and 6% of patients treated with CD, did not complete their course of medication. 18% (109/595) of children treated with CD and 6.1% (36/587) with AL required rescue medication within 4 weeks, risk difference 12% (95%CI 8.9%–16%). 23 children developed severe anaemia (17 (2.9%) treated with CD and 6 (1.0%) with AL, risk difference 1.8%, 95%CI 0.3%–3.4%, P = 0.02). Haemoglobin concentration on day 3 was lower among children treated with CD than AL (difference 0.43 g/dL, 95% CI 0.24 to 0.62), and within the CD group was lower among those children who had higher parasite density at enrolment. Only 17 out of 1069 children who were typed were G6PD A- deficient, of these 2/9 treated with CD and 1/8 treated with AL developed severe anaemia. 5/9 treated with CD had a fall of 2 g/dL or more in haemoglobin concentration by day 3.
Interpretation
AL was well tolerated and highly effective and when given under operational conditions despite poor adherence to the six-dose regimen. There were more cases of severe malaria and anaemia after CD treatment although G6PD deficiency was uncommon.
Trial Registration
Clinicaltrials.gov NCT00118794
doi:10.1371/journal.pone.0017371
PMCID: PMC3110183  PMID: 21666744
10.  PCR-based genotyping of Helicobacter pylori of Gambian children and adults directly from biopsy specimens and bacterial cultures 
Gut Pathogens  2011;3:5.
Background
Helicobacter pylori is an important agent of gastroduodenal disease in Africa and throughout the world. We sought to determine an optimum method for genotyping H. pylori strains from children and adults in The Gambia, West Africa.
Results
Virulence genes were amplified in 127 of 190 cases tested (121 adults and 6 children); each of 60 bacterial cultures, and 116 from DNA extracted directly from biopsies. The proportion of biopsies that were cagA+, the ratio of vacAs1/s2, and vacAm1/m2, and the proportion of mixed strain populations in individual subjects changed with age. Strains lacking virulence cagA and vacA genes and with apparently homogeneous (one predominant strain) infections were more common among infants than adults.
Conclusions
In order to detect the range of bacterial genotypes harbored by individual patients, direct PCR proved slightly superior to isolation of H. pylori by biopsy culture, but the techniques were complementary, and the combination of both culture and direct PCR produced the most complete picture. The seemingly higher virulence of strains from adult than infant infections in The Gambia merits further analysis.
doi:10.1186/1757-4749-3-5
PMCID: PMC3107793  PMID: 21507253
Genotyping; Helicobacter pylori; biopsy specimens; bacterial cultures
11.  Influence of HLA Class I and HLA-KIR Compound Genotypes on HIV-2 Infection and Markers of Disease Progression in a Manjako Community in West Africa ▿  
Journal of Virology  2010;84(16):8202-8208.
Overall, the time to AIDS after HIV-2 infection is longer than with HIV-1, and many individuals infected with HIV-2 virus remain healthy throughout their lives. Multiple HLA and KIR gene products have been implicated in the control of HIV-1, but the effect of variation at these loci on HIV-2 disease is unknown. We show here for the first time that HLA-B*1503 is associated significantly with poor prognosis after HIV-2 infection and that HLA-B*0801 is associated with susceptibility to infection. Interestingly, previous data indicate that HLA-B*1503 is associated with low viral loads in HIV-1 clade B infection but has no significant effect on viral load in clade C infection. In general, alleles strongly associated with HIV-1 disease showed no effect in HIV-2 disease. These data emphasize the unique nature of the effects of HLA and HLA/KIR combinations on HIV-2 immune responses relative to HIV-1, which could be related to their distinct clinical course.
doi:10.1128/JVI.00116-10
PMCID: PMC2916551  PMID: 20519398
12.  Effects of Acute Nicotine Abstinence on Cue-elicited Ventral Striatum/Nucleus Accumbens Activation in Female Cigarette Smokers: A Functional Magnetic Resonance Imaging Study 
Brain imaging and behavior  2007;1(3-4):43-57.
To achieve greater understanding of the brain mechanisms underlying nicotine craving in female smokers, we examined the influence of nicotine non-abstinence vs. acute nicotine abstinence on cue-elicited activation of the ventral striatum. Eight female smokers underwent an event-related functional magnetic resonance imaging (fMRI) paradigm presenting randomized sequences of smoking-related and non-smoking related pictures. Participants were asked to indicate by a key press the gender of individuals in smoking-related and non-smoking related pictures (gender discrimination task), to maintain and evaluate attention to the pictures. There was a significant effect of smoking condition on reaction times (RT) for a gender discrimination task intended to assess and maintain attention to the photographs—suggesting a deprivation effect of acute nicotine abstinence and a statistical trend indicating greater RTs for smoking cues than neutral cues. BOLD contrast (smoking vs. non-smoking cues) was greater in the non-abstinent vs. acutely abstinent conditions in the ventral striatum including the nucleus accumbens (VS/NAc). Moreover, a significant positive correlation was observed between baseline cigarette craving prior to scanning and VS/NAc activation (r=0.84, p=0.009), but only in the non-abstinent condition. These results may either be explained by ceiling effects of nicotine withdrawal in the abstinent condition or, may indicate reduced relative activation (smoking vs. neutral contrast) in the VS/NAc in the abstinent vs. non-abstinent conditions in this group of female smokers.
doi:10.1007/s11682-007-9004-1
PMCID: PMC2367252  PMID: 18458752
fMRI; Smoking; Tobacco; Cue reactivity; Ventral striatum; Nucleus accumbens
13.  The serotonin transporter 5-HTTLPR polymorphism and treatment response to nicotine patch: Follow-up of a randomized controlled trial 
In this follow-up of a randomized placebo-controlled clinical trial of nicotine replacement transdermal patch for smoking cessation, 741 smokers of European ancestry who were randomized to receive active patch or placebo patch were genotyped for the serotonin transporter gene-linked polymorphic region. The study setting was a primary care research network in Oxfordshire, United Kingdom. The primary outcome measures were biochemically verified sustained abstinence from cigarette smoking at end of treatment and 24-week follow-up. The main effect of genotype was not associated with sustained abstinence from smoking at either end of treatment (SL: p=.33; SS: p=.81) or 24-week follow-up (SL: p=.05; SS: p=.21), and we found no evidence for a genotype×treatment interaction effect. In summary, despite the theoretically important contribution of serotonin neurotransmission to smoking cessation, the serotonin transporter gene was not associated with treatment response to nicotine patch for smoking cessation in this primary care–based trial.
doi:10.1080/14622200601078566
PMCID: PMC2031912  PMID: 17365753
14.  Association of COMT Val108/158Met Genotype with Smoking Cessation in a Nicotine Replacement Therapy Randomized Trial 
We investigated the association of catechol O-methyltransferase (COMT) genotype with abstinence following a smoking cessation attempt among a large cohort of smokers who attempted to quit using either the nicotine transdermal patch or placebo and were followed up over an 8-year period following their initial cessation attempt. In addition, we examined the possible moderating influence of sex on any association. The genotype × treatment interaction effect at 12-week follow-up indicated a greater benefit of active nicotine replacement treatment compared with placebo on likelihood of abstinence in the COMT Met/Met genotype group (33% versus 12%), in comparison to the Met/Val + Val/Val group (22% versus 16%). Our results indicate that COMT genotype may moderate the effect of active transdermal nicotine patch compared with placebo, with reduced relative benefit of nicotine replacement therapy in individuals with Met/Val or Val/Val genotype. Our data follow an emerging pattern of results suggesting that genetic variation in the dopamine pathway may provide a future basis for tailored smoking cessation therapies, but indicate that different genes influencing various components of this pathway may have different effects on response to smoking cessation pharmacotherapy.
doi:10.1158/1055-9965.EPI-06-0936
PMCID: PMC2031911  PMID: 17548664
15.  A Functional Genetic Variation of the Serotonin (5-HT) Transporter Affects 5-HT1A Receptor Binding in Humans 
In humans, 5-HT1A receptors are implicated in anxiety and depressive disorders and their treatment. However, the physiological and genetic factors controlling 5-HT1A receptor expression are undetermined in health and disease. In this study, the influence of two genetic factors on 5-HT1A receptor expression in the living human brain was assessed using the 5-HT1A-selective positron emission tomography (PET) ligand [ 11C]WAY 100635. After the genotyping of 140 healthy volunteers to study population frequencies of known single nucleotide polymorphisms (SNPs) in the 5-HT1A receptor gene, the influence of the common SNP [(−1018) C>G] on 5-HT1A receptor expression was examined in a group of 35 healthy individuals scanned with [ 11C]WAY 100635. In the PET group, we also studied the influence of a common variable number tandem repeat polymorphism [short (S) and long (L) alleles] of the 5-HT transporter (5-HTT) gene on 5-HT1A receptor density. Whereas, the 5-HT1A receptor genotype did not show any significant effects on [ 11C]WAY 100635 binding, 5-HT1A receptor binding potential values were lower in all brain regions in subjects with 5-HTTLPR short (SS or SL) genotypes than those with long (LL) genotypes. Although the PET groups are necessarily a small sample size for a genetic association study, our results demonstrate for the first time that a functional polymorphism in the 5-HTT gene, but not the 5-HT1A receptor gene, affects 5-HT1A receptor availability in man. The results may offer a plausible physiological mechanism underlying the association between 5-HTTLPR genotype, behavioral traits, and mood states.
doi:10.1523/JNEUROSCI.3769-04.2005
PMCID: PMC1942077  PMID: 15758168
serotonin; 5-HT1A receptor; serotonin transporter; genetics; polymorphisms; positron emission tomography
18.  Computer support for interpreting family histories of breast and ovarian cancer in primary care: comparative study with simulated cases 
BMJ : British Medical Journal  2000;321(7252):28-32.
Objectives
To evaluate the potential effect of computer support on general practitioners' management of familial breast and ovarian cancer, and to compare the effectiveness of two different types of computer program.
Design
Crossover experiment with balanced block design.
Participants
Of a random sample of 100 general practitioners from Buckinghamshire who were invited, 41 agreed to participate. From these, 36 were selected for a fully balanced study.
Interventions
Doctors managed 18 simulated cases: 6 with computerised decision support system Risk Assessment in Genetics (RAGs), 6 with Cyrillic (an established pedigree drawing program designed for clinical geneticists), and 6 with pen and paper.
Main outcome measures
Number of appropriate management decisions made (maximum 6), mean time taken to reach a decision, number of pedigrees accurately drawn (maximum 6). Secondary measures were method of support preferred for particular aspects of managing family histories of cancer; importance of specific information on cancer genetics that might be provided by an “ideal computer program.”
Results
RAGs resulted in significantly more appropriate management decisions (median 6) than either Cyrillic (median 3) or pen and paper (median 3); median difference between RAGs and Cyrillic 2.5 (95% confidence interval 2.0 to 3.0; P<0.0001). RAGs also resulted in significantly more accurate pedigrees (median 5) than both Cyrillic (median 3.5) and pen and paper (median 2); median difference between RAGs and Cyrillic 1.5 (1.0 to 2.0; P<0.0001). The time taken to use RAGs (median 178 seconds) was 51 seconds longer per case (95% confidence interval 36 to 65; P<0.0001) than pen and paper (median 124 seconds) but was less than Cyrillic (median 203 seconds; difference 23. (5 to 43; P=0.02)). 33 doctors (92% (78% to 98%)) preferred using RAGs overall. The most important elements of an “ideal computer program” for genetic advice in primary care were referral advice, the capacity to create pedigrees, and provision of evidence and explanations to support advice.
Conclusions
RAGs could enable general practitioners to be more effective gatekeepers to genetics services, empowering them to reassure the majority of patients with a family history of breast and ovarian cancer who are not at increased genetic risk.
PMCID: PMC27423  PMID: 10875832
19.  Computer support for recording and interpreting family histories of breast and ovarian cancer in primary care (RAGs): qualitative evaluation with simulated patients 
BMJ : British Medical Journal  1999;319(7201):32-36.
Objectives
To explore general practitioners’ attitudes towards and use of a computer program for assessing genetic risk of cancer in primary care.
Design
Qualitative analysis of semistructured interviews and video recordings of simulated consultations.
Participants
Purposive sample of 15 general practitioners covering a range of computer literacy, interest in genetics, age, and sex.
Interventions
Each doctor used the program in two consultations in which an actor played a woman concerned about her family history of cancer. Consultations were videotaped and followed by interviews with the video as a prompt to questioning.
Main outcome measures
Use of computer program in the consultation.
Results
The program was viewed as an appropriate application of information technology because of the complexity of cancer genetics and a sense of “guideline chaos” in primary care. Doctors found the program easy to use, but it often affected their control of the consultation. They needed to balance their desire to share the computer screen with the patient, driven by their concerns about the effect of the computer on doctor-patient communication, against the risk of premature disclosure of bad news.
Conclusions
This computer program could provide the necessary support to assist assessment of genetic risk of cancer in primary care. The potential impact of computer software on the consultation should not be underestimated. This study highlights the need for careful evaluation when developing medical information systems.
Key messagesGeneral practitioners are under increasing pressure to advise their patients about genetic predisposition to various diseasesComputers could help doctors to give genetic advice by simplifying the construction and assessment of family trees and implementing referral guidelinesThis qualitative evaluation explored the context in which a computer program for assessing genetic risk of cancer would be used in general practice and issues surrounding its integration into a consultationMost of the doctors found the program easy to use, but it affected their control of the consultation—because of their desire to share the computer screen with the patient and their inability to anticipate the information that would be displayedThe study identified important issues relating to the use of computers in consultations which may be of use in testing software for primary care in the future
PMCID: PMC28153  PMID: 10390458
20.  Computer support for determining drug dose: systematic review and meta-analysis 
BMJ : British Medical Journal  1999;318(7189):984-990.
Objective
To review the effectiveness of computer support for determining optimum drug dose.
Design
Systematic review of comparative studies where computers gave advice to clinicians on the most appropriate drug dose. Search methods used were standard for the Cochrane Collaboration on Effective Professional Practice.
Subjects
Comparative studies conducted worldwide and published between 1966 and 1996.
Main outcome measures
For qualitative review, relative percentage differences were calculated to compare effects of computer support in different settings. For quantitative data, effect sizes were calculated and combined in meta-analyses.
Results
Eighteen studies met the inclusion criteria. The drugs studied were theophylline, warfarin, heparin, aminoglycosides, nitroprusside, lignocaine, oxytocin, fentanyl, and midazolam. The computer programs used individualised pharmacokinetic models to calculate the most appropriate dose. Meta-analysis of data from 671 patients showed higher blood concentrations of drug with computer support (effect size 0.69, 95% confidence interval 0.36 to 1.02) and reduced time to achieve therapeutic control (0.44, 0.17 to 0.71). The total dose of drug used was unchanged, and there were fewer unwanted effects of treatment. Five of six studies measuring outcomes of care showed benefit from computer assistance.
Conclusions
This review suggests that using computers to determine the correct dose of certain drugs in acute hospital settings is beneficial. Computers may give doctors the confidence to use higher doses when necessary, adjusting the drug dose more accurately to individual patients. Further research is necessary to evaluate the benefits in general use.
Key messages This systematic review of studies examining computer support for determining optimum drug dose showed benefits from computer use Computer support led to patients having increased blood concentrations of drug, reduced time to achieve therapeutic benefits, and fewer unwanted effects of treatment Computer support helps doctors to tailor drug doses more closely to the needs of individual patients All the studies took place in hospitals, and further research is needed to determine the risks and benefits of widespread use of computer support, particularly in general practice, where most prescribing takes place
PMCID: PMC27828  PMID: 10195972
23.  Pigmented Nevi—Induced Changes in the Junctional Component 
California Medicine  1966;104(1):32-34.
The pigmented nevus represents a potentially more dynamic lesion than has been indicated by most published studies. New nevus cell clusters frequently appear in the epidermis over the residual portion of a nevus that remains after partial surgical excision. Even in relatively inactive nevi in adults, new junctional nevus cells may be induced by surgical trauma. This stimulated growth usually regresses by the time one year or more has elapsed. The growth of nevus cells is probably comparable to that induced in other cells by traumatic injury. There is no evidence to suggest that it is related to the development of melanoma in pigmented nevi.
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PMCID: PMC1516182  PMID: 5909250
24.  REVERSAL OF THE ANTIBIOTIC, BACILLIN, BY N-ACETYLGLUCOSAMINE 
Journal of Bacteriology  1962;84(6):1148-1151.
Walton, Robert B. (Merck Sharp & Dohme Research Laboratories, Rahway, N.J.) and Edward L. Rickes. Reversal of the antibiotic, bacillin, by N-acetylglucosamine. J. Bacteriol. 84:1148–1151. 1962.—Antibacillin, previously shown to reverse the antibiotic action of bacillin, was isolated from powdered milk and identified as N-acetylglucosamine, a substance that is present in almost all microbial and animal cells.
PMCID: PMC278038  PMID: 13998745
25.  SYSTEMIC USE OF CORTICOSTEROIDS IN DERMATOLOGY 
California Medicine  1961;94(4):209-210.
The use of corticosteroids systemically in dermatology has benefited patients with pemphigus and systemic lupus erythematosus in that they now have a better chance to carry on a productive life. These hormones, used cautiously, can alleviate some of the tremendous suffering during the explosive exacerbations and acute crises of atopic and neurodermatitis. Corticosteroids are useful in the widespread and acute contact dermatitis and drug eruptions; they are contraindicated in the treatment of ordinary psoriasis.
Every attempt should be made by history-taking, clinical examination and necessary laboratory studies to reach an accurate diagnosis before corticosteroids are used. If use of them is indicated, then total patient care is required to avoid complications, and a very careful follow-up is mandatory.
PMCID: PMC1574635  PMID: 13783009

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