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1.  Childbirth and consequent atopic disease: emerging evidence on epigenetic effects based on the hygiene and EPIIC hypotheses 
In most high and middle income countries across the world, at least 1:4 women give birth by cesarean section. Rates of labour induction and augmentation are rising steeply; and in some countries up to 50 % of laboring women and newborns are given antibiotics. Governments and international agencies are increasingly concerned about the clinical, economic and psychosocial effects of these interventions.
There is emerging evidence that certain intrapartum and early neonatal interventions might affect the neonatal immune response in the longer term, and perhaps trans-generationally. Two theories lead the debate in this area. Those aligned with the hygiene (or ‘Old Friends’) hypothesis have examined the effect of gut microbiome colonization secondary to mode of birth and intrapartum/neonatal pharmacological interventions on immune response and epigenetic phenomena. Those working with the EPIIC (Epigenetic Impact of Childbirth) hypothesis are concerned with the effects of eustress and dys-stress on the epigenome, secondary to mode of birth and labour interventions.
This paper examines the current and emerging findings relating to childbirth and atopic/autoimmune disease from the perspective of both theories, and proposes an alliance of research effort. This is likely to accelerate the discovery of important findings arising from both approaches, and to maximize the timely understanding of the longer-term consequences of childbirth practices.
PMCID: PMC4712556  PMID: 26762406
Epigenetics; Birth; Caesarean section; Syntocinon; Microbiome; Antibiotics
3.  International standards for early fetal size and pregnancy dating based on ultrasound measurement of crown–rump length in the first trimester of pregnancy 
There are no international standards for relating fetal crown–rump length (CRL) to gestational age (GA), and most existing charts have considerable methodological limitations. The INTERGROWTH-21st Project aimed to produce the first international standards for early fetal size and ultrasound dating of pregnancy based on CRL measurement.
Urban areas in eight geographically diverse countries that met strict eligibility criteria were selected for the prospective, population-based recruitment, between 9 + 0 and 13 + 6 weeks' gestation, of healthy well-nourished women with singleton pregnancies at low risk of fetal growth impairment. GA was calculated on the basis of a certain last menstrual period, regular menstrual cycle and lack of hormonal medication or breastfeeding in the preceding 2 months. CRL was measured using strict protocols and quality-control measures. All women were followed up throughout pregnancy until delivery and hospital discharge. Cases of neonatal and fetal death, severe pregnancy complications and congenital abnormalities were excluded from the study.
A total of 4607 women were enrolled in the Fetal Growth Longitudinal Study, one of the three main components of the INTERGROWTH-21st Project, of whom 4321 had a live singleton birth in the absence of severe maternal conditions or congenital abnormalities detected by ultrasound or at birth. The CRL was measured in 56 women at < 9 + 0 weeks' gestation; these were excluded, resulting in 4265 women who contributed data to the final analysis. The mean CRL and SD increased with GA almost linearly, and their relationship to GA is given by the following two equations (in which GA is in days and CRL in mm): mean CRL = −50.6562 + (0.815118 × GA) + (0.00535302 × GA2); and SD of CRL = −2.21626 + (0.0984894 × GA). GA estimation is carried out according to the two equations: GA = 40.9041 + (3.21585 × CRL0.5) + (0.348956 × CRL); and SD of GA = 2.39102 + (0.0193474 × CRL).
We have produced international prescriptive standards for early fetal linear size and ultrasound dating of pregnancy in the first trimester that can be used throughout the world. © 2014 Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
PMCID: PMC4286014  PMID: 25044000
crown–rump length; dating; gestational age; global health; growth; pregnancy
4.  Regulation of alternative VEGF-A mRNA splicing is a therapeutic target for analgesia☆ 
Neurobiology of Disease  2014;71:245-259.
Vascular endothelial growth factor-A (VEGF-A) is best known as a key regulator of the formation of new blood vessels. Neutralization of VEGF-A with anti-VEGF therapy e.g. bevacizumab, can be painful, and this is hypothesized to result from a loss of VEGF-A-mediated neuroprotection. The multiple vegf-a gene products consist of two alternatively spliced families, typified by VEGF-A165a and VEGF-A165b (both contain 165 amino acids), both of which are neuroprotective. Under pathological conditions, such as in inflammation and cancer, the pro-angiogenic VEGF-A165a is upregulated and predominates over the VEGF-A165b isoform.
We show here that in rats and mice VEGF-A165a and VEGF-A165b have opposing effects on pain, and that blocking the proximal splicing event – leading to the preferential expression of VEGF-A165b over VEGF165a – prevents pain in vivo. VEGF-A165a sensitizes peripheral nociceptive neurons through actions on VEGFR2 and a TRPV1-dependent mechanism, thus enhancing nociceptive signaling. VEGF-A165b blocks the effect of VEGF-A165a.
After nerve injury, the endogenous balance of VEGF-A isoforms switches to greater expression of VEGF-Axxxa compared to VEGF-Axxxb, through an SRPK1-dependent pre-mRNA splicing mechanism. Pharmacological inhibition of SRPK1 after traumatic nerve injury selectively reduced VEGF-Axxxa expression and reversed associated neuropathic pain. Exogenous VEGF-A165b also ameliorated neuropathic pain.
We conclude that the relative levels of alternatively spliced VEGF-A isoforms are critical for pain modulation under both normal conditions and in sensory neuropathy. Altering VEGF-Axxxa/VEGF-Axxxb balance by targeting alternative RNA splicing may be a new analgesic strategy.
Graphical abstract
•The different vegf-a splice variants, VEGF-A165a and VEGF-A165b have pro- and anti-nociceptive actions respectively.•Pro-nociceptive actions of VEGF-A165a are dependent on TRPV1.•Alternative pre-mRNA splicing underpins peripheral sensitization by VEGF-A isoforms in normal and neuropathic animals.
PMCID: PMC4194316  PMID: 25151644
VEGF-A, vascular endothelial growth factor-A; SRPK1, serine arginine protein kinase 1; SRSF1, serine arginine splice factor 1; VEGFR2, vascular endothelial growth factor receptor 2; IB4, isolectin B4; TRPV1, transient receptor potential vanilloid 1; CV, conduction velocity; PSNI, partial saphenous nerve ligation injury; DRG, dorsal root ganglia; Vascular endothelial growth factor A; Alternative mRNA splicing; Neuropathy; Nociceptors
5.  Phytochemistry, Pharmacology and Ethnomedicinal Uses of Ficus Thonningii (Blume Moraceae): A Review 
The common wild fig, Ficus thonningii, is extensively used in African ethnomedicine for treating a number of disease conditions which include diarrhoea, urinary tract infections, diabetes mellitus, gonorrhoea, respiratory infections, and mental illnesses. This review aims to present a logical analysis of the nutritional, phytochemical and pharmacological properties of F. thonningii in relation to its therapeutic applications. A bibliographic analysis of the uses, phytochemical constituents and phytophamacological properties of Ficus thonningii was carried out using published papers, medicinal plant databases and various ethnobotanical and ethnopharmacological books. Ficus thonningii contains various bioactive compounds which include alkaloids, terpenoids, flavonoids, tannins and active proteins, all of which contribute to its curative properties. In vitro and in vivo pharmacological studies revealed that F. thonningii possesses antimicrobial, antidiarrhoeal, antihelmintic, antioxidant, anti-inflammatory and analgesic properties. Acute and sub-chronic toxicity studies have shown that Ficus thonningii is non-toxic if administered orally in low doses. Scientific research has validated the ethnomedicinal claims that Ficus thonningii is useful in disease management. However, there is need to continue identifying, isolating and quantifying the active principles and possibly determine the mechanisms underlying its curative properties.
PMCID: PMC3746567  PMID: 24146443
Ficus thonningii; phytochemical; toxicity; nutraceutical
6.  The Effects of Crude Aqueous and Alcohol Extracts of Aloe Vera on Growth and Abdominal Viscera of Suckling Rats 
The gastrointestinal tract of neonates is sensitive to dietary manipulations. When nursing mothers use Aloe vera, their babies are at risk of indirect exposure to Aloe vera via breast feeding or directly as health supplements. The effects of orally administered extracts of Aloe vera in unweaned rats were investigated. Six day old Sprague-Dawley rats were gavaged with aqueous or alcohol extracts of Aloe vera (low dose 50mg. kg−1 or high dose 500mg. kg−1) daily for eight days. All data were expressed as mean ± SD and analyzed by one way ANOVA. Pups receiving high doses of either extract had a significantly higher body mass gain than the group receiving lower dose (p < 0.05). Tibial length was significantly increased in the high dose aqueous extract group (15–26 %). The differences in growth could not be attributed to circulating insulin-like growth factor-1 as the levels were not significantly different. The caecum was significantly enlarged in the rats that received the high doses of both extracts. Although, there was no significant difference in the non-fasting plasma concentration of glucose and triglycerides, the hepatic lipid and glycogen content were significantly higher (p < 0.001) for the high dose aqueous extract group. The plasma alanine transaminase was not affected by the treatments, however the high doses of the extracts significantly increased plasma alkaline phosphatase activity. Short term administration of Aloe vera extracts resulted in growth promotion, enhanced hepatic storage of metabolic substrates, increased ALP possibly in relation to bone growth and caused hypertrophy of the caecum of neonatal rats. These effects need to be explored further to enhance animal production and health.
PMCID: PMC3746647  PMID: 23983392
Aloe vera; neonate; growth; gastrointestinal tract; metabolism
7.  The EPIIC hypothesis: Intrapartum effects on the neonatal epigenome and consequent health outcomes 
Medical hypotheses  2013;80(5):656-662.
There are many published studies about the epigenetic effects of the prenatal and infant periods on health outcomes. However, there is very little knowledge regarding the effects of the intrapartum period (labor and birth) on health and epigenetic remodeling. Although the intrapartum period is relatively short compared to the complete perinatal period, there is emerging evidence that this time frame may be a critical formative phase for the human genome. Given the debates from the National Institutes of Health and World Health Organization regarding routine childbirth procedures, it is essential to establish the state of the science concerning normal intrapartum epigenetic physiology. EPIIC (Epigenetic Impact of Childbirth) is an international, interdisciplinary research collaboration with expertise in the fields of genetics, physiology, developmental biology, epidemiology, medicine, midwifery, and nursing. We hypothesize that events during the intrapartum period – specifically the use of synthetic oxytocin, antibiotics, and cesarean section – affect the epigenetic remodeling processes and subsequent health of the mother and offspring. The rationale for this hypothesis is based on recent evidence and current best practice.
PMCID: PMC3612361  PMID: 23414680
8.  Phylogeny and taxonomic revision of the Planistromellaceae including its coelomycetous anamorphs: contributions towards a monograph of the genus Kellermania 
The core species of the family Planistromellaceae are included in the teleomorphic genera Planistroma and Planistromella and the connected anamorphic, coelomycetous genera Alpakesa, Kellermania, and Piptarthron. These genera have been defined primarily on the basis of ascospore septation or number of conidial appendages. Due to a lack of DNA sequence data, phylogenetic placement of these genera within the Dothideomycetes, evaluation of monophyly, and questions about generic boundaries could not be adequately addressed in the past. Isolates of nearly all of the known species in these genera were studied genetically and morphologically. DNA sequence data were generated for the nSSU, ITS, nLSU, and RPB1 markers and analysed phylogenetically. These results placed the Planistromellaceae, herein recognised as a distinct family, in an unresolved position relative to other genera within the order Botryosphaeriales. Species representing the core genera of the Planistromellaceae formed a clade and evaluation of its topology revealed that previous morphology-based definitions of genera resulted in an artificial classification system. Alpakesa, Kellermania, Piptarthron, Planistroma, and Planistromella are herein recognised as belonging to the single genus Kellermania. The following new combinations are proposed: Kellermania crassispora, K. dasylirionis, K. macrospora, K. plurilocularis, and K. unilocularis. Five new species are described, namely K. con- fusa, K. dasylirionicola, K. micranthae, K. ramaleyae, and K. rostratae. Descriptions of species in vitro and a key to species known from culture are provided.
PMCID: PMC3589788  PMID: 23606762
Agavaceae; Ascomycota; Asparagaceae; Botryosphaeriaceae; Botryosphaeriales; coelomycetes; Dothideomycetes; molecular phylogeny; Planistromellaceae; Septoplaca; taxonomy
9.  Coding regions of INHBA, SFRP4 and HOXA10 are not implicated in familial endometriosis linked to chromosome 7p13–15 
Molecular Human Reproduction  2011;17(10):605-611.
Endometriosis is a common, chronic gynaecological disease affecting up to 10% of women in their reproductive years. Its aetiology still remains unclear, but evidence indicates genetic factors play a role. We previously identified a region of significant linkage on chromosome 7 in 52 families comprising at least three affected women, stretching ∼6.4 Mb. We screened coding regions and parts of the regulatory regions of three candidate genes with a known role in endometrial development and function—INHBA, SFRP4 and HOXA10—located under or very near the linkage peak, for potential causal mutations using Sanger sequencing. Sequencing was conducted in 47 cases from the 15 families contributing most to the linkage signal (Zmean ≥ 1). Minor allele frequencies (MAFs) of observed variants were compared with MAFs from two publicly available reference populations of European ancestry: 60 individuals in HapMap and 150 individuals in the 1000 Genomes Project. A total of 11 variants were found, 5 (45%) of which were common (MAF > 0.05) among the 15 case families and the reference populations (P-values for MAF difference: 0.88–1.00). The remaining six were rare and unlikely to be individually or cumulatively responsible for the linkage signal. The results indicate that the coding regions of these three genes do not harbour mutations responsible for linkage to endometriosis in these families.
PMCID: PMC3172037  PMID: 21576276
endometriosis; aetiology; PCR sequencing; candidate gene; coding region
10.  A Weighted and Directed Interareal Connectivity Matrix for Macaque Cerebral Cortex 
Cerebral Cortex (New York, NY)  2012;24(1):17-36.
Retrograde tracer injections in 29 of the 91 areas of the macaque cerebral cortex revealed 1,615 interareal pathways, a third of which have not previously been reported. A weight index (extrinsic fraction of labeled neurons [FLNe]) was determined for each area-to-area pathway. Newly found projections were weaker on average compared with the known projections; nevertheless, the 2 sets of pathways had extensively overlapping weight distributions. Repeat injections across individuals revealed modest FLNe variability given the range of FLNe values (standard deviation <1 log unit, range 5 log units). The connectivity profile for each area conformed to a lognormal distribution, where a majority of projections are moderate or weak in strength. In the G29 × 29 interareal subgraph, two-thirds of the connections that can exist do exist. Analysis of the smallest set of areas that collects links from all 91 nodes of the G29 × 91 subgraph (dominating set analysis) confirms the dense (66%) structure of the cortical matrix. The G29 × 29 subgraph suggests an unexpectedly high incidence of unidirectional links. The directed and weighted G29 × 91 connectivity matrix for the macaque will be valuable for comparison with connectivity analyses in other species, including humans. It will also inform future modeling studies that explore the regularities of cortical networks.
PMCID: PMC3862262  PMID: 23010748
connection; cortex; graph; monkey; network
11.  Obstetric ultrasound scanning by local health workers in a refugee camp on the Thai–Burmese border 
Ultrasound examination of the fetus is a powerful tool for assessing gestational age and detecting obstetric problems but is rarely available in developing countries. The aim of this study was to assess the intraobserver and interobserver agreement of fetal biometry by locally trained health workers in a refugee camp on the Thai–Burmese border.
One expatriate doctor and four local health workers participated in the study, which included examinations performed on every fifth pregnant woman with a singleton pregnancy between 16 and 40 weeks’ gestation, and who had undergone an early dating ultrasound scan, attending the antenatal clinic in Maela refugee camp. At each examination, two examiners independently measured biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC) and femur length (FL), with one of the examiners obtaining duplicate measurements of each parameter. Intraobserver measurement error was assessed using the intraclass correlation coefficient (ICC) and interobserver error was assessed by the Bland and Altman 95% limits of agreement method.
A total of 4188 ultrasound measurements (12 per woman) were obtained in 349 pregnancies at a median gestational age of 27 (range, 16–40) weeks in 2008. The ICC for BPD, HC, AC and FL was greater than 0.99 for all four trainees and the doctor (range, 0.996–0.998). For gestational ages between 18 and 24 weeks, interobserver 95% limits of agreement corresponding to differences in estimated gestational age of less than ± 1 week were calculated for BPD, HC, AC and FL. Measurements by local health workers showed high levels of agreement with those of the expatriate doctor.
Locally trained health workers working in a well organized unit with ongoing quality control can obtain accurate fetal biometry measurements for gestational age estimation. This experience suggests that training of local health workers in developing countries is possible and could allow effective use of obstetric ultrasound imaging.
PMCID: PMC3438883  PMID: 19790099
accuracy; developing country; fetal biometry; reproducibility; ultrasound
12.  Nutraceutical values of natural honey and its contribution to human health and wealth 
The use of natural honey (NH) as a nutraceutical agent is associated with nutritional benefits and therapeutic promises. NH is widely accepted as food and medicine by all generations, traditions and civilizations, both ancient and modern. The nutritional profiles, including its use in infant and children feeding reported in different literatures as well as health indices and biomarkers observed by various researchers are illustrated in this manuscript. The review documents folk medicine, experimentation with animal models, and orthodox medical practices shown by clinical trials. This covers virtually all human organs and body systems extensively studied by different workers. The sources and adverse effects of NH contamination, as well as the preventive methods are identified. This could promote the availability of residue free honey and a wholesome natural product for domestic consumption and international market. This could also help to prevent health problems associated with NH poisoning. In addition, apicultural practices and the economic importance of honey are well documented. This report also includes information about a relatively unknown and uncommon South American stingless bee species. We concluded this review by identifying important roles for Ethno-entomologists, other Scientists and Apiculturists in the development of stingless bees to boost honey production, consumption and economic earnings.
PMCID: PMC3583289  PMID: 22716101
Apiculture; Economic importance; Ethno-entomologist; Folk medicine; Health indices; Honey; Metabolic syndrome; Nutraceutics; Stingless bee
14.  Long-term clinical outcome of oestrogen receptor-positive operable primary breast cancer in older women: a large series from a single centre 
British Journal of Cancer  2011;104(9):1393-1400.
A Cochrane review of seven randomised trials (N=1571) comparing surgery and primary endocrine therapy (PET) (oestrogen receptor (ER) unselected) shows no difference in overall survival (OS). We report outcome of a large series with ER-positive (ER+) early invasive primary breast cancer.
Between 1973 and 2009, 1065 older (⩾70 years) women (median age 78 years (70–99)) had either surgery (N=449) or PET (N=616) as initial treatment.
At 49-month median follow-up (longest 230 months), the 5-year breast cancer-specific survival (BCSS) and OS were 90 and 62%, respectively. Majority (74.2%) died from causes other than breast cancer. The rates (per annum) of local/regional recurrence (<1%) (following surgery), contralateral tumour (<1%) and metastases (<3%) were low. For patients on PET, 97.9% achieved clinical benefit (CB) at 6 months, with median time to progression of 49 months (longest 132 months) and significantly longer BCSS when compared with those who progressed (P<0.001). All patients with strongly ER+ (H-score >250) tumours achieved CB and had better BCSS (P<0.01). Patients with tumours having an H-score >250 were found to have equivalent BCSS regardless of treatment (surgery or PET; P=0.175), whereas for those with H-score ⩽250, surgery produced better outcome (P<0.001).
Older women with ER+ breast cancer appear to have excellent long-term outcome regardless of initial treatment. Majority also die from non-breast cancer causes. Although surgery remains the treatment of choice, patients with ER-rich (H-score >250) tumours tend to do equally well when treated by PET. This should be taken into account when therapies are considered.
PMCID: PMC3101924  PMID: 21448163
elderly; ER; primary breast cancer; endocrine therapy; surgery
15.  Asperisporium and Pantospora (Mycosphaerellaceae): epitypifications and phylogenetic placement 
The species-rich family Mycosphaerellaceae contains considerable morphological diversity and includes numerous anamorphic genera, many of which are economically important plant pathogens. Recent revisions and phylogenetic research have resulted in taxonomic instability. Ameliorating this problem requires phylogenetic placement of type species of key genera. We present an examination of the type species of the anamorphic Asperisporium and Pantospora. Cultures isolated from recent port interceptions were studied and described, and morphological studies were made of historical and new herbarium specimens. DNA sequence data from the ITS region and nLSU were generated from these type species, analysed phylogenetically, placed into an evolutionary context within Mycosphaerellaceae, and compared to existing phylogenies. Epitype specimens associated with living cultures and DNA sequence data are designated herein. Asperisporium caricae, the type of Asperisporium and cause of a leaf and fruit spot disease of papaya, is closely related to several species of Passalora including P. brachycarpa. The status of Asperisporium as a potential generic synonym of Passalora remains unclear. The monotypic genus Pantospora, typified by the synnematous Pantospora guazumae, is not included in Pseudocercospora sensu stricto or sensu lato. Rather, it represents a distinct lineage in the Mycosphaerellaceae in an unresolved position near Mycosphaerella microsora.
PMCID: PMC3251325  PMID: 22403473
Ascomycota; Capnodiales; Dothideomycetes; lectotype; pawpaw; Pseudocercospora ulmifoliae
16.  Peripheral biomarkers of endometriosis: a systematic review 
Human Reproduction Update  2010;16(6):651-674.
Endometriosis is estimated to affect 1 in 10 women during the reproductive years. There is often delay in making the diagnosis, mainly due to the non-specific nature of the associated symptoms and the need to verify the disease surgically. A biomarker that is simple to measure could help clinicians to diagnose (or at least exclude) endometriosis; it might also allow the effects of treatment to be monitored. If effective, such a marker or panel of markers could prevent unnecessary diagnostic procedures and/or recognize treatment failure at an early stage.
We used QUADAS (Quality Assessment of Diagnostic Accuracy Studies) criteria to perform a systematic review of the literature over the last 25 years to assess critically the clinical value of all proposed biomarkers for endometriosis in serum, plasma and urine.
We identified over 100 putative biomarkers in publications that met the selection criteria. We were unable to identify a single biomarker or panel of biomarkers that have unequivocally been shown to be clinically useful.
Peripheral biomarkers show promise as diagnostic aids, but further research is necessary before they can be recommended in routine clinical care. Panels of markers may allow increased sensitivity and specificity of any diagnostic test.
PMCID: PMC2953938  PMID: 20462942
endometriosis; infertility; laparoscopy
17.  Weight Consistency Specifies Regularities of Macaque Cortical Networks 
Cerebral Cortex (New York, NY)  2010;21(6):1254-1272.
To what extent cortical pathways show significant weight differences and whether these differences are consistent across animals (thereby comprising robust connectivity profiles) is an important and unresolved neuroanatomical issue. Here we report a quantitative retrograde tracer analysis in the cynomolgus macaque monkey of the weight consistency of the afferents of cortical areas across brains via calculation of a weight index (fraction of labeled neurons, FLN). Injection in 8 cortical areas (3 occipital plus 5 in the other lobes) revealed a consistent pattern: small subcortical input (1.3% cumulative FLN), high local intrinsic connectivity (80% FLN), high-input form neighboring areas (15% cumulative FLN), and weak long-range corticocortical connectivity (3% cumulative FLN). Corticocortical FLN values of projections to areas V1, V2, and V4 showed heavy-tailed, lognormal distributions spanning 5 orders of magnitude that were consistent, demonstrating significant connectivity profiles. These results indicate that 1) connection weight heterogeneity plays an important role in determining cortical network specificity, 2) high investment in local projections highlights the importance of local processing, and 3) transmission of information across multiple hierarchy levels mainly involves pathways having low FLN values.
PMCID: PMC3097985  PMID: 21045004
amygdala; area 17; macaque; network; primate; thalamus
18.  Do calcium channel blockers and antimuscarinics protect against perforated colonic diverticular disease? A case control study 
Gut  2003;52(12):1734-1737.
Background: The aetiology of perforated colonic diverticular disease (PCDD) remains largely unknown. Perforation may result from a combination of high intracolonic pressures, secondary to excessive colonic segmentation, and impairment of the mucosal barrier. Calcium channel blockers and antimuscarinic drugs, which reduce colonic contractility and tone, could potentially protect against perforation. The aim of this study was to test this hypothesis using a case control design.
Methods: All cases of acute PCDD were identified over a five year period in two hospitals in Norfolk, UK. Each case was matched for age, sex, and date of admission to two controls groups: (1) patients undergoing cataract surgery and (2) patients with basal cell carcinoma. Data on drug use prior to hospital admission were obtained from medical and nursing records and compared between cases and controls.
Results: A total of 120 cases of PCDD were identified and matched to 240 controls in each group. A statistically significant protective association was seen between calcium channel blocker use and PCDD using both control groups. The odds ratios were 0.41 (95% confidence interval (CI) 0.18–0.93) using the ophthalmology control group and 0.36 (95% CI 0.16–0.82) using the dermatology control group.
Conclusions: This study has shown for the first time that a protective association exists between calcium channel blockers and PCDD. The validity of this association is supported by the consistent finding in both control groups and the plausible biological mechanisms. Further studies are required to confirm this association but calcium channel blockers may represent a potential preventive therapy in PCDD.
PMCID: PMC1773902  PMID: 14633952
aetiology; calcium channel blockers; perforated colonic diverticular disease
19.  Epidemiology of perforated colonic diverticular disease 
Postgraduate Medical Journal  2002;78(925):654-658.
Perforated colonic diverticular disease results in considerable mortality and morbidity. This review appraises existing evidence on the epidemiology and mechanisms of perforation, highlights areas of further study, and suggests an epidemiological approach towards preventing the condition. Computerised searches were used to identify published articles relating to the epidemiology, pathophysiology, and clinical features of perforated colonic diverticular disease. Several drug and dietary exposures have potential biological mechanisms for causing perforation. Of these only non-steroidal anti-inflammatory drugs have been consistently identified as risk factors in aetiological studies. The causes of perforated colonic diverticular disease remain largely unknown. Further aetiological studies, looking specifically at perforation, are required to investigate whether cause-effect relationships exist for both drug and dietary exposures. The identification of risk factors for perforation would allow primary public health prevention, secondary risk factor modification, and early prophylactic surgery to be aimed at people at high risk.
PMCID: PMC1742564  PMID: 12496319
20.  Beyond Burkitt—is diverticular disease more than just cereal fibre deficiency? 
Postgraduate Medical Journal  2000;76(895):257-258.
PMCID: PMC1741585  PMID: 10775276
21.  The community prevalence of chronic pelvic pain in women and associated illness behaviour. 
BACKGROUND: Chronic pelvic pain has often been described as a major women's health issue, but no information exists on the extent of the problem in the United Kingdom. AIM: To investigate the community prevalence of chronic pelvic pain and its effect on the lives of consulting and non-consulting women. DESIGN OF STUDY: Postal questionnaire survey. SETTING: Women aged 18 to 49 (n = 3916) randomly selected from the Oxfordshire Health Authority Register. METHOD: The questionnaire response rate (adjusted for non-deliveries) was 74% (2304/3106). Chronic pelvic pain was defined as recurrent or constant pelvic pain of at least six months' duration, unrelated to periods, intercourse, or pregnancy. Case subgroups comprised recent consulters, past consulters, and non-consulters. Women who reported dysmenorrhoea alone formed a comparison group. RESULTS: The three-month prevalence of chronic pelvic pain was 24.0% (95% CI = 22.1% to 25.8%). One-third of women reported pain that started more than five years ago. Recent consulters (32% of cases) were most affected by their symptoms in terms of pain severity, use of health care, physical and mental health scores, sleep quality, and pain-related absence from work. Non-consulters (41% of cases) did not differ from women with dysmenorrhoea in terms of symptom-related impairment. Irrespective of consulting behaviour, a high rate of symptom-related anxiety was found in women with chronic pelvic pain (31%) compared with women with dysmenorrhoea (7%). CONCLUSIONS: This study showed a high community prevalence of chronic pelvic pain in women of reproductive age. Cases varied substantially in the degree to which they were affected by their symptoms. The high symptom-related anxiety in these women emphasises the need for more information about chronic pelvic pain and its possible causes.
PMCID: PMC1314045  PMID: 11462313
22.  Quality of life: an important dimension in assessing the treatment of depression? 
Quality of life is used to assess the overall impact of medical treatments from the patient's perspective. Because depression affects a person's ability to function at work and at home, the evaluation of various treatments must include an assessment of patients' physical, social and psychological status. This paper classifies and evaluates a variety of widely used health-related quality-of-life questionnaires that have potential value as outcome measures in the treatment of depression. The paper also outlines how these measures have been beneficial in the assessment of depressed patients. They reveal differences between patients with depression and control groups, are sensitive to change in status during treatment, have predictive value for outcome measures and provide additional information about timelines for improvement in psychosocial functioning, which may occur at a different rate than changes in other depressive symptoms. Despite the limitations of these questionnaires, they provide an important additional dimension to the evaluation of treatment with antidepressant medications.
PMCID: PMC2553258  PMID: 11590966
23.  Preliminary randomized double-blind placebo-controlled trial of tryptophan combined with fluoxetine to treat major depressive disorder: antidepressant and hypnotic effects. 
OBJECTIVE: Because the initial phase of treatment of depression with a selective serotonin reuptake inhibitor is often complicated by a delayed onset of action of the antidepressant or severe insomnia or both, we investigated whether tryptophan, an amino acid with both antidepressant-augmenting and hypnotic effects, would benefit patients with depression at the beginning of treatment with fluoxetine. DESIGN: Randomized, double-blind, placebo-controlled trial. PATIENTS: Thirty individuals with major depressive disorder. INTERVENTIONS: Treatment over 8 weeks with 20 mg of fluoxetine per day and either tryptophan (2 to 4 g per day) or placebo. OUTCOME MEASURES: Mood was assessed using the 29-item Hamilton Depression Rating Scale (HDRS-29) and the Beck Depression Inventory (BDI). Laboratory sleep studies were done at baseline and after 4 and 8 weeks of treatment using standard procedures. RESULTS: During the first week of treatment, there was a significantly greater decrease in HDRS-29 depression scores, and a similar trend in BDI scores, in the tryptophan/fluoxetine group than in the placebo/fluoxetine group. No significant differences were noted at later time points. With respect to sleep measures, there was a significant group-by-time interaction for slow-wave sleep at week 4. Further analysis revealed a significant decrease in slow-wave sleep after 4 weeks of treatment in the placebo/fluoxetine group, but not in the tryptophan/fluoxetine group. No cases of serotonin syndrome occurred, and the combination was well tolerated, although the 4 g per day dosage of tryptophan produced daytime drowsiness. CONCLUSIONS: Combining 20 mg of fluoxetine with 2 g of tryptophan daily at the outset of treatment for major depressive disorder appears to be a safe protocol that may have both a rapid antidepressant effect and a protective effect on slow-wave sleep. Further large-scale studies are needed to confirm these initial findings.
PMCID: PMC1407729  PMID: 11022398
24.  Citalopram--a review of pharmacological and clinical effects. 
OBJECTIVE: To provide clinicians with a critical evaluation of citalopram, a selective serotonin reuptake inhibitor (SSRI) that has been available in Canada since March 1999. DATA SOURCES: Commercial searches (MEDLINE and BiblioTech) and an "in-house" search (InfoDrug) were used to find published English-language references for clinical and preclinical publications. There was no restriction of publication dates. Primary index terms used were: pharmacological properties, receptors, pharmacological selectivity, pharmacokinetics, age-related pharmacokinetics, sex-related pharmacokinetics, renal dysfunction, hepatic dysfunction, cytochrome activity, drug interactions, adverse reactions, antidepressant switching, precautions, overdose, drug discontinuation, children, geriatric, depression, combination therapy, placebo control, refractory depression, anxiety disorders and medical disorders. STUDY SELECTION: A total of 74 studies were reviewed. Twenty-one of these studies specifically examined the clinical efficacy and tolerability of citalopram in depressive disorders as well as other disorders. In depressive disorders, clinical studies were required to have either placebo or active comparison controls for a minimum of 3 weeks. For other disorders, in the absence of double-blind trials, open-label studies were included. Pharmacological studies were limited to animal studies focusing on citalopram's selectivity and receptor specificity, and positron emission tomography studies were incorporated to include human pharmacological data. Pharmacokinetic studies focused on the metabolism, safety and tolerability of citalopram, specifically with reference to adverse reactions, drug interactions and overdose in addition to citalopram's effect on vulnerable populations, such as children, the elderly and patients with metabolic diseases. DATA EXTRACTION: Data on clinical studies were summarized according to test measures, study duration and outcome of study. Pharmacokinetic and pharmacodynamic studies were summarized according to properties and interactions. Adverse reactions were extracted to outline citalopram's safety profile. DATA SYNTHESIS: Citalopram is an SSRI antidepressant with a more specific and selective pharmacological profile than other antidepressants of its class. It is well tolerated, and drug interactions are not a significant concern. It is also reasonably safe for populations vulnerable to pharmacokinetic effects, such as the elderly and patients with metabolic diseases. In addition to its tolerability, citalopram is effective in the treatment of major depression, other depressive disorders and panic disorder. It has the potential to effectively treat other anxiety disorders and substance-use disorders; in addition, it may be useful in several medical conditions. CONCLUSIONS: There is evidence to support the role of citalopram as a well-tolerated and effective SSRI antidepressant. There is a need for further evaluation of its role in psychiatric disorders other than major depressive disorder.
PMCID: PMC1407724  PMID: 10863884
25.  Use of slow-release melatonin in treatment-resistant depression. 
OBJECTIVE: To examine antidepressant augmentation with and hypnotic effects of slow-release melatonin (SR-melatonin) in patients with treatment-resistant depression. DESIGN: Open-label trial. SETTING: Tertiary care outpatient depression clinic. PATIENTS: Nine outpatients who had failed to respond to 2 or more 8-week trials of antidepressant medication. INTERVENTIONS: Patients received SR-melatonin 5 mg per day for the first 2 weeks and 10 mg per day for the final 2 weeks, in addition to their antidepressant medication. OUTCOME MEASURES: Structured Clinical Interview for DSM-IV, Axis 1 Disorders, Hamilton Rating Scale for Depression (HRSD), Beck Depression Inventory, Response Style Questionnaire, sleep and fatigue measures. RESULTS: One patient was excluded after 1 week because of the development of a mixed affective state. In the remaining 8 patients there was a 20% mean decrease in HRSD scores after 4 weeks of treatment, with no individual achieving an improvement of 50% or more. There was a 36% decrease on the 3-item HRSD related to insomnia, with 4 of 8 patients showing at least a 50% improvement on this measure. The greatest decrease in insomnia occurred during the last 2 weeks of the study, following the increase in dosage to 10 mg per day of SR-melatonin. Patients also reported significantly lower levels of fatigue post-treatment. CONCLUSIONS: SR-melatonin may be a useful adjunct for sleep, but does not substantially augment existing antidepressant therapies in some patients with treatment-resistant depression.
PMCID: PMC1407707  PMID: 10721684

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