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1.  Rate of first recorded diagnosis of autism and other pervasive developmental disorders in United Kingdom general practice, 1988 to 2001 
BMC Medicine  2004;2:39.
Background
There has been concern that the incidence of autism and other pervasive developmental disorders (PDDs) is increasing. Previous studies have been smaller, restricted to autism (excluding other pervasive developmental disorders such as Asperger's syndrome), included boys only, or have not been based on a national sample. We investigated time trends in the rates of diagnosis of pervasive developmental disorders.
Methods
We analysed the rates of first diagnosis of pervasive developmental disorders among people registered with a practice contributing to the United Kingdom General Practice Research Database during the period 1988 to 2001. We included 1410 cases from over 14 million person-years of observation. The main outcome measures were rates of diagnosis of pervasive developmental disorders by year of diagnosis, year of birth, gender and geographical region.
Results
The rate increased progressively from 0.40/10,000 person-years (95% CI 0.30 to 0.54) in 1991 to 2.98/10,000 (95% CI 2.56 to 3.47) in 2001. A similar change occurred in the age standardised incidence ratios, from 35 (95% CI: 26–47) in 1991 to 365 (95% CI: 314–425) in 2001. The temporal increase was not limited to children born during specific years nor to children diagnosed in a specific time period. The rate of diagnosis of PDDs other than autism rose from zero for the period 1988–1992 to 1.06/10,000 person-years in 2001. The rate of diagnosis of autism also increased but to a lesser extent. There was marked geographical variation in rates, with standardised incidence ratios varying from 66 for Wales to 141 for the South East of England.
Conclusions
Better ascertainment of diagnosis is likely to have contributed to the observed temporal increase in rates of diagnosis of PDD, but we cannot exclude a real increase.
doi:10.1186/1741-7015-2-39
PMCID: PMC533883  PMID: 15535890
2.  Acetylcysteine for prevention of contrast-induced nephropathy after intravascular angiography: A systematic review and meta-analysis 
BMC Medicine  2004;2:38.
Background
Contrast-induced nephropathy is an important cause of acute renal failure. We assess the efficacy of acetylcysteine for prevention of contrast-induced nephropathy among patients undergoing intravascular angiography.
Methods
We conducted a systematic review and meta-analysis of randomized controlled trials comparing prophylactic acetylcysteine plus hydration versus hydration alone in patients undergoing intravascular angiography. Studies were identified by searching MEDLINE, EMBASE, and CENTRAL databases. Our main outcome measures were the risk of contrast-induced nephropathy and the difference in serum creatinine between acetylcysteine and control groups at 48 h.
Results
Fourteen studies involving 1261 patients were identified and included for analysis, and findings were heterogeneous across studies. Acetylcysteine was associated with a significantly reduced incidence of contrast-induced nephropathy in five studies, and no difference in the other nine (with a trend toward a higher incidence in six of the latter studies). The pooled odds ratio for contrast-induced nephropathy with acetylcysteine relative to control was 0.54 (95% CI, 0.32–0.91, p = 0.02) and the pooled estimate of difference in 48-h serum creatinine for acetylcysteine relative to control was -7.2 μmol/L (95% CI -19.7 to 5.3, p = 0.26). These pooled values need to be interpreted cautiously because of the heterogeneity across studies, and due to evidence of publication bias. Meta-regression suggested that the heterogeneity might be partially explained by whether the angiography was performed electively or as emergency.
Conclusion
These findings indicate that published studies of acetylcysteine for prevention of contrast-induced nephropathy yield inconsistent results. The efficacy of acetylcysteine will remain uncertain unless a large well-designed multi-center trial is performed.
doi:10.1186/1741-7015-2-38
PMCID: PMC526263  PMID: 15500690
3.  Significance of MDR1 and multiple drug resistance in refractory human epileptic brain 
BMC Medicine  2004;2:37.
Background
The multiple drug resistance protein (MDR1/P-glycoprotein) is overexpressed in glia and blood-brain barrier (BBB) endothelium in drug refractory human epileptic tissue. Since various antiepileptic drugs (AEDs) can act as substrates for MDR1, the enhanced expression/function of this protein may increase their active extrusion from the brain, resulting in decreased responsiveness to AEDs.
Methods
Human drug resistant epileptic brain tissues were collected after surgical resection. Astrocyte cell cultures were established from these tissues, and commercially available normal human astrocytes were used as controls. Uptake of fluorescent doxorubicin and radioactive-labeled Phenytoin was measured in the two cell populations, and the effect of MDR1 blockers was evaluated.
Frozen human epileptic brain tissue slices were double immunostained to locate MDR1 in neurons and glia. Other slices were exposed to toxic concentrations of Phenytoin to study cell viability in the presence or absence of a specific MDR1 blocker.
Results
MDR1 was overexpressed in blood vessels, astrocytes and neurons in human epileptic drug-resistant brain. In addition, MDR1-mediated cellular drug extrusion was increased in human 'epileptic' astrocytes compared to 'normal' ones. Concomitantly, cell viability in the presence of cytotoxic compounds was increased.
Conclusions
Overexpression of MDR1 in different cell types in drug-resistant epileptic human brain leads to functional alterations, not all of which are linked to drug pharmacokinetics. In particular, the modulation of glioneuronal MDR1 function in epileptic brain in the presence of toxic concentrations of xenobiotics may constitute a novel cytoprotective mechanism.
doi:10.1186/1741-7015-2-37
PMCID: PMC524356  PMID: 15473912
4.  Exposure to malaria affects the regression of hepatosplenomegaly after treatment for Schistosoma mansoni infection in Kenyan children 
BMC Medicine  2004;2:36.
Background
Schistosoma mansoni and malaria infections are often endemic in the same communities in sub-Saharan Africa, and both have pathological effects on the liver and the spleen. Hepatosplenomegaly associated with S. mansoni is exacerbated in children with relatively high exposure to malaria. Treatment with praziquantel reduces the degree of hepatosplenomegaly, but the condition does not completely resolve in some cases. The present analysis focused on the possibility that exposure to malaria infection may have limited the resolution of hepatosplenomegaly in a cohort of Kenyan schoolchildren.
Methods
Ninety-six children aged 6–16, from one community in Makueni district, Kenya, were treated with praziquantel. At baseline, all children had hepatomegaly and most had splenomegaly. The source of S. mansoni infection, a river, was molluscicided regularly over the following three years to limit S. mansoni re-infection, whereas malaria exposure was uninterrupted. Hepatic and splenic enlargement was assessed annually outside the malaria transmission season.
Results
Children living in an area of relatively high exposure to both infections presented with the largest spleens before treatment and at each follow-up. Spleens of firm consistency were associated with proximity to the river. The regression of hepatomegaly was also affected by location, being minimal in an area with relatively low S. mansoni exposure but high exposure to malaria, and maximal in an area with relatively low exposure to both infections.
Conclusions
The outcome of treating cases of hepatosplenomegaly with praziquantel in this cohort of Kenyan children depended strongly on their level of exposure to malaria infection. Furthermore, a residual burden of hepatosplenic morbidity was observed, which was possibly attributable to the level of exposure to malaria. The results suggest that exposure to malaria infection may be a significant factor affecting the outcome of praziquantel treatment to reduce the level of hepatosplenic morbidity.
doi:10.1186/1741-7015-2-36
PMCID: PMC522803  PMID: 15450118
5.  Neoadjuvant or adjuvant therapy for resectable esophageal cancer: a systematic review and meta-analysis 
BMC Medicine  2004;2:35.
Background
Carcinoma of the esophagus is an aggressive malignancy with an increasing incidence. Its virulence, in terms of symptoms and mortality, justifies a continued search for optimal therapy. The large and growing number of patients affected, the high mortality rates, the worldwide geographic variation in practice, and the large body of good quality research warrants a systematic review with meta-analysis.
Methods
A systematic review and meta-analysis investigating the impact of neoadjuvant or adjuvant therapy on resectable thoracic esophageal cancer to inform evidence-based practice was produced.
MEDLINE, CANCERLIT, Cochrane Library, EMBASE, and abstracts from the American Society of Clinical Oncology and the American Society for Therapeutic Radiology and Oncology were searched for trial reports.
Included were randomized trials or meta-analyses of neoadjuvant or adjuvant treatments compared with surgery alone or other treatments in patients with resectable thoracic esophageal cancer. Outcomes of interest were survival, adverse effects, and quality of life. Either one- or three-year mortality data were pooled and reported as relative risk ratios.
Results
Thirty-four randomized controlled trials and six meta-analyses were obtained and grouped into 13 basic treatment approaches.
Single randomized controlled trials detected no differences in mortality between treatments for the following comparisons:
- Preoperative radiotherapy versus postoperative radiotherapy.
- Preoperative and postoperative radiotherapy versus postoperative radiotherapy. Preoperative and postoperative radiotherapy was associated with a significantly higher mortality rate.
- Postoperative chemotherapy versus postoperative radiotherapy.
- Postoperative radiotherapy versus postoperative radiotherapy plus protein-bound polysaccharide versus chemoradiation versus chemoradiation plus protein-bound polysaccharide.
Pooling one-year mortality detected no statistically significant differences in mortality between treatments for the following comparisons:
- Preoperative radiotherapy compared with surgery alone (five randomized trials).
- Postoperative radiotherapy compared with surgery alone (five randomized trials).
- Preoperative chemotherapy versus surgery alone (six randomized trials).
- Preoperative and postoperative chemotherapy versus surgery alone (two randomized trials).
- Preoperative chemoradiation therapy versus surgery alone (six randomized trials).
Single randomized controlled trials detected differences in mortality between treatments for the following comparison:
- Preoperative hyperthermia and chemoradiotherapy versus preoperative chemoradiotherapy in favour of hyperthermia.
Pooling three-year mortality detected no statistically significant difference in mortality between treatments for the following comparison:
- Postoperative chemotherapy compared with surgery alone (two randomized trials).
Pooling three-year mortality detected statistically significant differences between treatments for the following comparisons:
- Preoperative chemoradiation therapy versus surgery alone (six randomized trials) in favour of preoperative chemoradiation with surgery.
- Preoperative chemotherapy compared with preoperative radiotherapy (one randomized trial) in favour of preoperative radiotherapy.
Conclusion
For adult patients with resectable thoracic esophageal cancer for whom surgery is considered appropriate, surgery alone (i.e., without neoadjuvant or adjuvant therapy) is recommended as the standard practice.
doi:10.1186/1741-7015-2-35
PMCID: PMC529457  PMID: 15447788
6.  Delta-9 tetrahydrocannabinol (THC) inhibits lytic replication of gamma oncogenic herpesviruses in vitro 
BMC Medicine  2004;2:34.
Background
The major psychoactive cannabinoid compound of marijuana, delta-9 tetrahydrocannabinol (THC), has been shown to modulate immune responses and lymphocyte function. After primary infection the viral DNA genome of gamma herpesviruses persists in lymphoid cell nuclei in a latent episomal circular form. In response to extracellular signals, the latent virus can be activated, which leads to production of infectious virus progeny. Therefore, we evaluated the potential effects of THC on gamma herpesvirus replication.
Methods
Tissue cultures infected with various gamma herpesviruses were cultured in the presence of increasing concentrations of THC and the amount of viral DNA or infectious virus yield was compared to those of control cultures. The effect of THC on Kaposi's Sarcoma Associated Herpesvirus (KSHV) and Epstein-Barr virus (EBV) replication was measured by the Gardella method and replication of herpesvirus saimiri (HVS) of monkeys, murine gamma herpesvirus 68 (MHV 68), and herpes simplex type 1 (HSV-1) was measured by yield reduction assays. Inhibition of the immediate early ORF 50 gene promoter activity was measured by the dual luciferase method.
Results
Micromolar concentrations of THC inhibit KSHV and EBV reactivation in virus infected/immortalized B cells. THC also strongly inhibits lytic replication of MHV 68 and HVS in vitro. Importantly, concentrations of THC that inhibit virus replication of gamma herpesviruses have no effect on cell growth or HSV-1 replication, indicating selectivity. THC was shown to selectively inhibit the immediate early ORF 50 gene promoter of KSHV and MHV 68.
Conclusions
THC specifically targets viral and/or cellular mechanisms required for replication and possibly shared by these gamma herpesviruses, and the endocannabinoid system is possibly involved in regulating gamma herpesvirus latency and lytic replication. The immediate early gene ORF 50 promoter activity was specifically inhibited by THC. These studies may also provide the foundation for the development of antiviral strategies utilizing non-psychoactive derivatives of THC.
doi:10.1186/1741-7015-2-34
PMCID: PMC521080  PMID: 15369590
7.  What do evidence-based secondary journals tell us about the publication of clinically important articles in primary healthcare journals? 
BMC Medicine  2004;2:33.
Background
We conducted this analysis to determine i) which journals publish high-quality, clinically relevant studies in internal medicine, general/family practice, general practice nursing, and mental health; and ii) the proportion of clinically relevant articles in each journal.
Methods
We performed an analytic survey of a hand search of 170 general medicine, general healthcare, and specialty journals for 2000. Research staff assessed individual articles by using explicit criteria for scientific merit for healthcare application. Practitioners assessed the clinical importance of these articles. Outcome measures were the number of high-quality, clinically relevant studies published in the 170 journal titles and how many of these were published in each of four discipline-specific, secondary "evidence-based" journals (ACP Journal Club for internal medicine and its subspecialties; Evidence-Based Medicine for general/family practice; Evidence-Based Nursing for general practice nursing; and Evidence-Based Mental Health for all aspects of mental health). Original studies and review articles were classified for purpose: therapy and prevention, screening and diagnosis, prognosis, etiology and harm, economics and cost, clinical prediction guides, and qualitative studies.
Results
We evaluated 60,352 articles from 170 journal titles. The pass criteria of high-quality methods and clinically relevant material were met by 3059 original articles and 1073 review articles. For ACP Journal Club (internal medicine), four titles supplied 56.5% of the articles and 27 titles supplied the other 43.5%. For Evidence-Based Medicine (general/family practice), five titles supplied 50.7% of the articles and 40 titles supplied the remaining 49.3%. For Evidence-Based Nursing (general practice nursing), seven titles supplied 51.0% of the articles and 34 additional titles supplied 49.0%. For Evidence-Based Mental Health (mental health), nine titles supplied 53.2% of the articles and 34 additional titles supplied 46.8%. For the disciplines of internal medicine, general/family practice, and mental health (but not general practice nursing), the number of clinically important articles was correlated withScience Citation Index (SCI) Impact Factors.
Conclusions
Although many clinical journals publish high-quality, clinically relevant and important original studies and systematic reviews, the articles for each discipline studied were concentrated in a small subset of journals. This subset varied according to healthcare discipline; however, many of the important articles for all disciplines in this study were published in broad-based healthcare journals rather than subspecialty or discipline-specific journals.
doi:10.1186/1741-7015-2-33
PMCID: PMC518974  PMID: 15350200
8.  Emergence of new Salmonella Enteritidis phage types in Europe? Surveillance of infections in returning travellers 
BMC Medicine  2004;2:32.
Background
Among human Salmonella Enteritidis infections, phage type 4 has been the dominant phage type in most countries in Western Europe during the last years. This is reflected in Salmonella infections among Swedish travellers returning from abroad. However, there are differences in phage type distribution between the countries, and this has also changed over time.
Methods
We used data from the Swedish infectious disease register and the national reference laboratory to describe phage type distribution of Salmonella Enteritidis infections in Swedish travellers from 1997 to 2002, and have compared this with national studies conducted in the countries visited.
Results
Infections among Swedish travellers correlate well with national studies conducted in the countries visited. In 2001 a change in phage type distribution in S. Enteritidis infections among Swedish travellers returning from some countries in southern Europe was observed, and a previously rare phage type (PT 14b) became one of the most commonly diagnosed that year, continuing into 2002 and 2003.
Conclusions
Surveillance of infections among returning travellers can be helpful in detecting emerging infections and outbreaks in tourist destinations. The information needs to be communicated rapidly to all affected countries in order to expedite the implementation of appropriate investigations and preventive measures.
doi:10.1186/1741-7015-2-32
PMCID: PMC518973  PMID: 15345058
9.  What does my patient's coronary artery calcium score mean? Combining information from the coronary artery calcium score with information from conventional risk factors to estimate coronary heart disease risk 
BMC Medicine  2004;2:31.
Background
The coronary artery calcium (CAC) score is an independent predictor of coronary heart disease. We sought to combine information from the CAC score with information from conventional cardiac risk factors to produce post-test risk estimates, and to determine whether the score may add clinically useful information.
Methods
We measured the independent cross-sectional associations between conventional cardiac risk factors and the CAC score among asymptomatic persons referred for non-contrast electron beam computed tomography. Using the resulting multivariable models and published CAC score-specific relative risk estimates, we estimated post-test coronary heart disease risk in a number of different scenarios.
Results
Among 9341 asymptomatic study participants (age 35–88 years, 40% female), we found that conventional coronary heart disease risk factors including age, male sex, self-reported hypertension, diabetes and high cholesterol were independent predictors of the CAC score, and we used the resulting multivariable models for predicting post-test risk in a variety of scenarios. Our models predicted, for example, that a 60-year-old non-smoking non-diabetic women with hypertension and high cholesterol would have a 47% chance of having a CAC score of zero, reducing her 10-year risk estimate from 15% (per Framingham) to 6–9%; if her score were over 100, however (a 17% chance), her risk estimate would be markedly higher (25–51% in 10 years). In low risk scenarios, the CAC score is very likely to be zero or low, and unlikely to change management.
Conclusion
Combining information from the CAC score with information from conventional risk factors can change assessment of coronary heart disease risk to an extent that may be clinically important, especially when the pre-test 10-year risk estimate is intermediate. The attached spreadsheet makes these calculations easy.
doi:10.1186/1741-7015-2-31
PMCID: PMC515311  PMID: 15327691
10.  Loss of KCNJ10 protein expression abolishes endocochlear potential and causes deafness in Pendred syndrome mouse model 
BMC Medicine  2004;2:30.
Background
Pendred syndrome, a common autosomal-recessive disorder characterized by congenital deafness and goiter, is caused by mutations of SLC26A4, which codes for pendrin. We investigated the relationship between pendrin and deafness using mice that have (Slc26a4+/+) or lack a complete Slc26a4 gene (Slc26a4-/-).
Methods
Expression of pendrin and other proteins was determined by confocal immunocytochemistry. Expression of mRNA was determined by quantitative RT-PCR. The endocochlear potential and the endolymphatic K+ concentration were measured with double-barreled microelectrodes. Currents generated by the stria marginal cells were recorded with a vibrating probe. Tissue masses were evaluated by morphometric distance measurements and pigmentation was quantified by densitometry.
Results
Pendrin was found in the cochlea in apical membranes of spiral prominence cells and spindle-shaped cells of stria vascularis, in outer sulcus and root cells. Endolymph volume in Slc26a4-/- mice was increased and tissue masses in areas normally occupied by type I and II fibrocytes were reduced. Slc26a4-/- mice lacked the endocochlear potential, which is generated across the basal cell barrier by the K+ channel KCNJ10 localized in intermediate cells. Stria vascularis was hyperpigmented, suggesting unalleviated free radical damage. The basal cell barrier appeared intact; intermediate cells and KCNJ10 mRNA were present but KCNJ10 protein was absent. Endolymphatic K+ concentrations were normal and membrane proteins necessary for K+ secretion were present, including the K+ channel KCNQ1 and KCNE1, Na+/2Cl-/K+ cotransporter SLC12A2 and the gap junction GJB2.
Conclusions
These observations demonstrate that pendrin dysfunction leads to a loss of KCNJ10 protein expression and a loss of the endocochlear potential, which may be the direct cause of deafness in Pendred syndrome.
doi:10.1186/1741-7015-2-30
PMCID: PMC516044  PMID: 15320950
11.  Stress, burnout and doctors' attitudes to work are determined by personality and learning style: A twelve year longitudinal study of UK medical graduates 
BMC Medicine  2004;2:29.
Background
The study investigated the extent to which approaches to work, workplace climate, stress, burnout and satisfaction with medicine as a career in doctors aged about thirty are predicted by measures of learning style and personality measured five to twelve years earlier when the doctors were applicants to medical school or were medical students.
Methods
Prospective study of a large cohort of doctors. The participants were first studied when they applied to any of five UK medical schools in 1990. Postal questionnaires were sent to all doctors with a traceable address on the current or a previous Medical Register. The current questionnaire included measures of Approaches to Work, Workplace Climate, stress (General Health Questionnaire), burnout (Maslach Burnout Inventory), and satisfaction with medicine as a career and personality (Big Five). Previous questionnaires had included measures of learning style (Study Process Questionnaire) and personality.
Results
Doctors' approaches to work were predicted by study habits and learning styles, both at application to medical school and in the final year. How doctors perceive their workplace climate and workload is predicted both by approaches to work and by measures of stress, burnout and satisfaction with medicine. These characteristics are partially predicted by trait measures of personality taken five years earlier. Stress, burnout and satisfaction also correlate with trait measures of personality taken five years earlier.
Conclusions
Differences in approach to work and perceived workplace climate seem mainly to reflect stable, long-term individual differences in doctors themselves, reflected in measures of personality and learning style.
doi:10.1186/1741-7015-2-29
PMCID: PMC516448  PMID: 15317650
12.  Optimizing the HIV/AIDS informed consent process in India 
BMC Medicine  2004;2:28.
Background
While the basic ethical issues regarding consent may be universal to all countries, the consent procedures required by international review boards which include detailed scientific and legal information, may not be optimal when administered within certain populations. The time and the technicalities of the process itself intimidate individuals in societies where literacy and awareness about medical and legal rights is low.
Methods
In this study, we examined pregnant women's understanding of group education and counseling (GEC) about HIV/AIDS provided within an antenatal clinic in Maharashtra, India. We then enhanced the GEC process with the use of culturally appropriate visual aids and assessed the subsequent changes in women's understanding of informed consent issues.
Results
We found the use of visual aids during group counseling sessions increased women's overall understanding of key issues regarding informed consent from 38% to 72%. Moreover, if these same visuals were reinforced during individual counseling, improvements in women's overall comprehension rose to 96%.
Conclusions
This study demonstrates that complex constructs such as informed consent can be conveyed in populations with little education and within busy government hospital settings, and that the standard model may not be sufficient to ensure true informed consent.
doi:10.1186/1741-7015-2-28
PMCID: PMC509426  PMID: 15287983
13.  Assessing the determinants of stillbirths and early neonatal deaths using routinely collected data in an inner city area 
BMC Medicine  2004;2:27.
Background
Within the UK there is considerable variation in the perinatal mortality rate. The objective of this study was to assess the factors associated with stillbirths and early neonatal deaths (ENND) and the suitability of the available databases in a health authority with one of the highest rates in the country.
Methods
Two case-control studies were carried out in three hospital trusts in the Lambeth, Southwark and Lewisham Health Authority, London, using routinely collected information. In one study, 342 stillbirths and 1,368 controls were included, and in the other study, 205 ENND and 820 controls were included. In the two studies cases and controls were matched for hospital trust.
Results
A birthweight below 1.5 kg was found in 54% and 48% of the stillbirths and ENND, respectively. More than 50% of the cases, stillbirths and ENND, had a length of gestation below 32 weeks. Length of gestation, birthweight, emergency caesarean section and age of the mother were associated with stillbirths. Birthweight and Apgar score at 1 minute as a categorical variable were associated with ENND. There was no direct evidence of an effect of social deprivation on the outcomes of interest.
Conclusion
Birthweight and length of gestation are the most influential factors on an unfavourable outcome. Conception at an older age has a serious impact on stillbirth rates. In our health authority social disadvantage did not have a direct impact on stillbirth and ENND. Maternity information systems should collect routine data on fewer variables, but their quality in terms of value, standardization and completion rates must improve.
doi:10.1186/1741-7015-2-27
PMCID: PMC471578  PMID: 15238165
14.  Breastfeeding patterns and exposure to suboptimal breastfeeding among children in developing countries: review and analysis of nationally representative surveys 
BMC Medicine  2004;2:26.
Background
Suboptimal breastfeeding is associated with higher mortality among infants and young children in the developing world. We describe patterns in 'exclusive breastfeeding' and 'any breastfeeding' rates and quantify exposure to suboptimal breastfeeding among children aged two years or younger in developing countries.
Methods
We reviewed nationally representative surveys that collected data on breastfeeding rates in 94 developing countries. Surveys were categorized by completeness and comprehensiveness of data. Complete and comprehensive data were analysed with minimum chi-square regression. With a fitting procedure, estimated parameters were used to impute missing observations for incomplete or non-comprehensive surveys. Breastfeeding indicators were calculated and are reported for 135 developing countries by UN region.
Results
Amongst infants aged six months or younger in the developing world, the prevalence of exclusive breastfeeding is 39% and the prevalence of no breastfeeding is 5.6%. The prevalence of continued breastfeeding is 86% and 68% for infants and children aged 6–11 and 12–23 months, respectively, in the developing world. Imputation expands population coverage of indicators, especially for infants. Breastfeeding trends are highly linear and estimated parameters defining the age-specific attrition hazard are robust. Survey-reported rates, particularly for exclusive breastfeeding, appear to have systematic upward bias, and exposure estimates must be considered conservative.
Conclusions
Compliance with breastfeeding recommendations in developing countries is low, and more attention should be given to increasing breastfeeding – especially exclusive breastfeeding – and to monitoring trends. Although the introduction of more standardized and better validated survey instruments is desirable, since data coverage, completeness and comprehensiveness are extensive, global exposure assessment is relatively robust. Moreover, the regularity of breastfeeding patterns show existing survey data capture real biological and social phenomena. Our method for the analysis of breastfeeding rates provides a potent tool for summarizing trends, validating observations, translating and extrapolating indicators (as well as projecting and imputing estimates when necessary) and should support more effective child health monitoring.
doi:10.1186/1741-7015-2-26
PMCID: PMC455698  PMID: 15230974
15.  Clinic-based screening for domestic violence: use of a child safety questionnaire 
BMC Medicine  2004;2:25.
Background
Domestic violence affects many women during their lifetime. Children living in homes where they are or have been exposed to violence are at increased risk for adverse outcomes. The American Academy of Pediatrics, the American Academy of Family Practice, and the American College of Obstetrics/Gynecology have recently joined in recommending routine screening of all families for the presence of domestic violence. We present our experience with an office-based domestic violence screening questionnaire.
Methods
A series of four child safety questionnaires (designed for parents of infant, preschool-age, school-age, and adolescent patients), which included specific questions about domestic violence, was given to all mothers presenting to a university out-patient general pediatric clinic. The questionnaires, offered in both English and Spanish, were reviewed for the presence of domestic violence exposure, usually at the time of the clinic visit. The number of women who reported either current or past exposure to domestic violence as disclosed by this active screening process was compared to the number discovered prior to the use of these questionnaires.
Results
Prior to the use of active screening with a child safety questionnaire, five cases of domestic violence were identified in our clinic population of approximately 5000 children over a 3 month period. Active screening of this population with a parent questionnaire resulted in the identification of 69 cases of current domestic violence exposure (2% of those screened) during each of 2 years of screening. Use of the child safety questionnaire was associated with a significantly increased odds of detecting current domestic violence (OR = 3.6, 95% CI [1.4, 9.1], P = 0.007), with 72% [26–84%] of the cases identified being attributable to the use of the questionnaire. Of children screened, 2% were currently exposed to domestic violence, and 13% had been exposed to past domestic violence. Thus a total of 15% of our patient population has been exposed to domestic violence in their homes.
Conclusion
Children in our clinic population are frequently exposed to domestic violence. Active screening for the presence of current or past domestic violence through the use of a parent questionnaire resulted in a significant increase in our ability to identify such families and provide appropriate referral information.
doi:10.1186/1741-7015-2-25
PMCID: PMC455697  PMID: 15228622
16.  Evolution of somatic mutations in mammary tumors in transgenic mice is influenced by the inherited genotype 
BMC Medicine  2004;2:24.
Background
MMTV-Wnt1 transgenic mice develop mammary hyperplasia early in development, followed by the appearance of solitary mammary tumors with a high proportion of cells expressing early lineage markers and many myoepithelial cells. The occurrence of tumors is accelerated in experiments that activate FGF proto-oncogenes or remove the tumor suppressor genes Pten or P53, implying that secondary oncogenic events are required for progression from mammary hyperplasia to carcinoma. It is not known, however, which oncogenic pathways contribute to Wnt1-induced tumorigenesis – further experimental manipulation of these mice is needed. Secondary events also appear to be required for mammary tumorigenesis in MMTV-Neu transgenic mice because the transgene in the tumors usually contains an acquired mutation that activates the Neu protein-tyrosine kinase.
Methods
cDNA or DNA from the mammary glands and mammary tumors from MMTV-Wnt1, MMTV-Wnt1/p53-/-, MMTV-Neu transgenic mice, and newly generated MMTV-Wnt1/MMTV-Neu bitransgenic mice, was sequenced to seek activating mutations in H-Ras, K-Ras, and N-Ras genes, or in the MMTV-Neu transgene. In addition, tumors from bitransgenic animals were examined to determine the cellular phenotype.
Results
We found activating mutations at codons 12, 13, and 61 of H-Ras in just over half of the mammary tumors in MMTV-Wnt1 transgenic mice, and we confirmed the high frequency of activating mutations of Neu in tumors in MMTV-Neu transgenic mice. Tumors appeared earlier in bitransgenic MMTV-Wnt1/MMTV-Neu mice, but no Ras or MMTV-Neu mutations were found in these tumors, which were phenotypically similar to those arising in MMTV-Wnt1 mice. In addition, no Ras mutations were found in the mammary tumors that arise in MMTV-Wnt1 transgenic mice lacking an intact P53 gene.
Conclusions
Tumorigenic properties of cells undergoing functionally significant secondary mutations in H-Ras or the MMTV-Neu transgene allow selection of those cells in MMTV-Wnt1 and MMTV-Neu transgenic mice, respectively. Alternative sources of oncogenic potential, such as a second transgenic oncogene or deficiency of a tumor suppressor gene, can obviate the selective power of those secondary mutations. These observations are consistent with the notion that somatic evolution of mouse mammary tumors is influenced by the specific nature of the inherited cancer-promoting genotype.
doi:10.1186/1741-7015-2-24
PMCID: PMC446228  PMID: 15198801
17.  Developing optimal search strategies for detecting clinically sound prognostic studies in MEDLINE: an analytic survey 
BMC Medicine  2004;2:23.
Background
Clinical end users of MEDLINE have a difficult time retrieving articles that are both scientifically sound and directly relevant to clinical practice. Search filters have been developed to assist end users in increasing the success of their searches. Many filters have been developed for the literature on therapy and reviews but little has been done in the area of prognosis. The objective of this study is to determine how well various methodologic textwords, Medical Subject Headings, and their Boolean combinations retrieve methodologically sound literature on the prognosis of health disorders in MEDLINE.
Methods
An analytic survey was conducted, comparing hand searches of journals with retrievals from MEDLINE for candidate search terms and combinations. Six research assistants read all issues of 161 journals for the publishing year 2000. All articles were rated using purpose and quality indicators and categorized into clinically relevant original studies, review articles, general papers, or case reports. The original and review articles were then categorized as 'pass' or 'fail' for methodologic rigor in the areas of prognosis and other clinical topics. Candidate search strategies were developed for prognosis and run in MEDLINE – the retrievals being compared with the hand search data. The sensitivity, specificity, precision, and accuracy of the search strategies were calculated.
Results
12% of studies classified as prognosis met basic criteria for scientific merit for testing clinical applications. Combinations of terms reached peak sensitivities of 90%. Compared with the best single term, multiple terms increased sensitivity for sound studies by 25.2% (absolute increase), and increased specificity, but by a much smaller amount (1.1%) when sensitivity was maximized. Combining terms to optimize both sensitivity and specificity achieved sensitivities and specificities of approximately 83% for each.
Conclusion
Empirically derived search strategies combining indexing terms and textwords can achieve high sensitivity and specificity for retrieving sound prognostic studies from MEDLINE.
doi:10.1186/1741-7015-2-23
PMCID: PMC441418  PMID: 15189561
18.  War-related psychological sequelae among emergency department patients in the former Republic of Yugoslavia 
BMC Medicine  2004;2:22.
Background
Residents of the Republic of Serbia faced civil war and a NATO-led bombing campaign in 1999. We sought to assess the burden of metal health dysfunction among emergency department (ED) patients presenting for care three years post-war in Serbia.
Methods
This study was conducted during July and August 2002 at two sites: a university hospital ED in Belgrade, Serbia and an ED in a remote district hospital serving a Serbian enclave in Laplje Selo, Kosovo. Investigators collected data on a systematic sample of non-acute patients presenting to the ED. All respondents completed a structured questionnaire assessing demographics and symptoms of post-traumatic stress disorder (PTSD) (using the Harvard Trauma Questionnaire), and major depression (using the Center for Epidemiologic Studies Depression Scale).
Results
A total of 562 respondents participated (310 in Belgrade, 252 in Laplje Selo); the response rate was 83.8%, 43% were female, and mean age was 37.6 years (SD = 13.4). Overall, 73 (13.0%) participants had symptoms consistent with PTSD, and 272 (49.2%) had symptoms consistent with depression. Sixty-six respondents had both disorders (11.9%). In separate multivariable logistic regression models, predictors of PTSD were refugee status and residence in Laplje Selo, and predictors of depression were older age, current unemployment, and lower social support.
Conclusions
Three years post-war, symptoms of PTSD and major depression in Serbia remained a significant public health concern, particularly among refugees, those suffering subsequent economic instability, and persons living in rural, remote areas.
doi:10.1186/1741-7015-2-22
PMCID: PMC425605  PMID: 15171785
19.  Vasectomy surgical techniques: a systematic review 
BMC Medicine  2004;2:21.
Background
A wide variety of surgical techniques are used to perform vasectomy. The purpose of this systematic review was to assess if any surgical techniques to isolate or occlude the vas are associated with better outcomes in terms of occlusive and contraceptive effectiveness, and complications.
Methods
We searched MEDLINE (1966-June 2003), EMBASE (1980-June 2003), reference lists of retrieved articles, urology textbooks, and our own files looking for studies comparing two or more vasectomy surgical techniques and reporting on effectiveness and complications. From 2,058 titles or abstracts, two independent reviewers identified 224 as potentially relevant. Full reports of 219 articles were retrieved and final selection was made by the same two independent reviewers using the same criteria as for the initial selection. Discrepancies were resolved by involving a third reviewer. Data were extracted and methodological quality of selected studies was assessed by two independent reviewers. Studies were divided in broad categories (isolation, occlusion, and combined isolation and occlusion techniques) and sub-categories of specific surgical techniques performed. Qualitative analyses and syntheses were done.
Results
Of 31 comparative studies (37 articles), only four were randomized clinical trials, most studies were observational and retrospective. Overall methodological quality was low. From nine studies on vas isolation, there is good evidence that the no-scalpel vasectomy approach decreases the risk of surgical complications, namely hematoma/bleeding and infection, compared with incisional techniques. Five comparative studies including one high quality randomized clinical trial provided good evidence that fascial interposition (FI) increases the occlusive effectiveness of ligation and excision. Results of 11 comparative studies suggest that FI with cautery of the vas lumen provides the highest level of occlusive effectiveness, even when leaving the testicular end open. Otherwise, firm evidence to support any occlusion technique in terms of increased effectiveness or decreased risk of complications is lacking.
Conclusions
Current evidence supports no-scalpel vasectomy as the safest surgical approach to isolate the vas when performing vasectomy. Adding FI increases effectiveness beyond ligation and excision alone. Occlusive effectiveness appears to be further improved by combining FI with cautery. Methodologically sound prospective controlled studies should be conducted to evaluate specific occlusion techniques further.
doi:10.1186/1741-7015-2-21
PMCID: PMC428590  PMID: 15157272
20.  Socioeconomic disparities in intimate partner violence against Native American women: a cross-sectional study 
BMC Medicine  2004;2:20.
Background
Intimate partner violence (IPV) against women is a global public health problem, yet data on IPV against Native American women are extremely limited. We conducted a cross-sectional study of Native American women to determine prevalence of lifetime and past-year IPV and partner injury; examine IPV in relation to pregnancy; and assess demographic and socioeconomic correlates of past-year IPV.
Methods
Participants were recruited from a tribally-operated clinic serving low-income pregnant and childbearing women in southwest Oklahoma. A self-administered survey was completed by 312 Native American women (96% response rate) attending the clinic from June through August 1997. Lifetime and past-year IPV were measured using modified 18-item Conflict Tactics Scales. A socioeconomic index was created based on partner's education, public assistance receipt, and poverty level.
Results
More than half (58.7%) of participants reported lifetime physical and/or sexual IPV; 39.1% experienced severe physical IPV; 12.2% reported partner-forced sexual activity; and 40.1% reported lifetime partner-perpetrated injuries. A total of 273 women had a spouse or boyfriend during the previous 12 months (although all participants were Native American, 59.0% of partners were non-Native). Among these women, past-year prevalence was 30.1% for physical and/or sexual IPV; 15.8% for severe physical IPV; 3.3% for forced partner-perpetrated sexual activity; and 16.4% for intimate partner injury. Reported IPV prevalence during pregnancy was 9.3%. Pregnancy was not associated with past-year IPV (odds ratio = 0.9). Past-year IPV prevalence was 42.8% among women scoring low on the socioeconomic index, compared with 10.1% among the reference group. After adjusting for age, relationship status, and household size, low socioeconomic index remained strongly associated with past-year IPV (odds ratio = 5.0; 95% confidence interval: 2.4, 10.7).
Conclusions
Native American women in our sample experienced exceptionally high rates of lifetime and past-year IPV. Additionally, within this low-income sample, there was strong evidence of socioeconomic variability in IPV. Further research should determine prevalence of IPV against Native American women from diverse tribes and regions, and examine pathways through which socioeconomic disadvantage may increase their IPV risk.
doi:10.1186/1741-7015-2-20
PMCID: PMC446227  PMID: 15157273
21.  ACE2 gene expression is up-regulated in the human failing heart 
BMC Medicine  2004;2:19.
Background
ACE2 is a novel homologue of angiotensin converting enzyme (ACE). ACE2 is highly expressed in human heart and animal data suggest that ACE2 is an essential regulator of cardiac function in vivo. Since overactivity of the renin-angiotensin system contributes to the progression of heart failure, this investigation assessed changes in gene expression of ACE2, ACE, AT1 receptor and renin in the human failing heart.
Methods
The sensitive technique of quantitative reverse transcriptase polymerase chain reaction was used to determine the level of mRNA expression of ACE and ACE2 in human ventricular myocardium from donors with non-diseased hearts (n = 9), idiopathic dilated cardiomyopathy (IDC, n = 11) and ischemic cardiomyopathy (ICM, n = 12). Following logarithmic transformation of the data, a one-way analysis of variance was performed for each target gene followed by a Dunnett's test to compare the two disease groups IDC and ICM versus control.
Results
As anticipated, ACE mRNA was found to be significantly increased in the failing heart with a 3.1 and 2.4-fold up-regulation found in IDC and ICM relative to non-diseased myocardium. Expression of ACE2 mRNA was also significantly up-regulated in IDC (2.4-fold increase) and ICM (1.8-fold increase) versus non-diseased myocardium. No change in angiotensin AT1 receptor mRNA expression was found in failing myocardium and renin mRNA was not detected.
Conclusions
These data suggest that ACE2 is up-regulated in human IDC and ICM and are consistent with the hypothesis that differential regulation of this enzyme may have important functional consequences in heart failure. This strengthens the hypothesis that ACE2 may be a relevant target for the treatment of heart failure and will hopefully spur further studies to clarify the functional effects in human myocardium of ACE2 derived peptides.
doi:10.1186/1741-7015-2-19
PMCID: PMC425604  PMID: 15151696
22.  Bias associated with delayed verification in test accuracy studies: accuracy of tests for endometrial hyperplasia may be much higher than we think! 
BMC Medicine  2004;2:18.
Background
To empirically evaluate bias in estimation of accuracy associated with delay in verification of diagnosis among studies evaluating tests for predicting endometrial hyperplasia.
Methods
Systematic reviews of all published research on accuracy of miniature endometrial biopsy and endometr ial ultrasonography for diagnosing endometrial hyperplasia identified 27 test accuracy studies (2,982 subjects). Of these, 16 had immediate histological verification of diagnosis while 11 had verification delayed > 24 hrs after testing. The effect of delay in verification of diagnosis on estimates of accuracy was evaluated using meta-regression with diagnostic odds ratio (dOR) as the accuracy measure. This analysis was adjusted for study quality and type of test (miniature endometrial biopsy or endometrial ultrasound).
Results
Compared to studies with immediate verification of diagnosis (dOR 67.2, 95% CI 21.7–208.8), those with delayed verification (dOR 16.2, 95% CI 8.6–30.5) underestimated the diagnostic accuracy by 74% (95% CI 7%–99%; P value = 0.048).
Conclusion
Among studies of miniature endometrial biopsy and endometrial ultrasound, diagnostic accuracy is considerably underestimated if there is a delay in histological verification of diagnosis.
doi:10.1186/1741-7015-2-18
PMCID: PMC419332  PMID: 15137911
23.  Long-term clinical, immunologic and virologic impact of glucocorticoids on the chronic phase of HIV infection 
BMC Medicine  2004;2:17.
Background
To test the hypothesis of down-regulating the increased immune system activation/destruction process associated with chronic HIV infection, we focused our interest on prednisolone (PDN), because we had showed that, in vitro, PDN had a strong anti-apoptotic activity on activated T cells of HIV-infected patients and no effect on viral replication. We thus designed in 1992 a pilot study to evaluate the clinical, immunologic and virologic effects of PDN. The drug was given to a group of 44 patients with CD4 T cells over 200/μl. After one year, no patient had developed clinical AIDS and the mean CD4 T cell count of the group had increased from 441 ± 21 cells/μl to 553 ± 43 cells/μl. Moreover, markers of immune activation had dropped back to normal levels while the mean viral load of the group had remained unchanged. Here we explore the long-term clinical, immunologic, and virologic impact of prednisolone on the chronic phase of HIV infection.
Methods
Retrospective study over 10 years starting between July 1992 and February 1993. A total of 44 patients with CD4 cells/μl ranging from 207 to 775 were treated with prednisolone, 0.5 mg/kg/d, over 6 months and 0.3 mg/kg/d thereafter.
Results
No clinical AIDS developed under prednisolone; side effects of the drug were mild. CD4 cells which increased from 421 cells/μl at entry to 625 cells/μl at day 15, slowly decreased to reach 426 cells/μl after two years; T cell apoptosis and activation markers dropped within 15 days to normal levels and reincreased slowly thereafter. Serum viral loads remained stable. The percentage of patients maintaining CD4 cells over entry was 43.2% at two years, 11.4% at five years and 4.6% at 10 years. Initial viral load was highly predictive of the rate of CD4 decrease under prednisolone.
Conclusions
Prednisolone postponed CD4 cell decrease in a viral load dependent manner for a median of two years and for up to 10 years in a fraction of the patients with a low viral load. These findings might stimulate clinical trials as well as biological research on the role of antiapoptotic drugs in HIV infection.
doi:10.1186/1741-7015-2-17
PMCID: PMC411065  PMID: 15128452
24.  Membrane transport of camptothecin: facilitation by human P-glycoprotein (ABCB1) and multidrug resistance protein 2 (ABCC2) 
BMC Medicine  2004;2:16.
Background
The purpose of the present study was to continue the investigation of the membrane transport mechanisms of 20-(S)-camptothecin (CPT) in order to understand the possible role of membrane transporters on its oral bioavailability and disposition.
Methods
The intestinal transport kinetics of CPT were characterized using Caco-2 cells, MDCKII wild-type cells and MDCKII cells transfected with human P-glycoprotein (PGP) (ABCB1) or human multidrug resistance protein 2 (MRP2) (ABCC2). The effects of drug concentration, inhibitors and temperature on CPT directional permeability were determined.
Results
The absorptive (apical to basolateral) and secretory (basolateral to apical) permeabilities of CPT were found to be saturable. Reduced secretory CPT permeabilities with decreasing temperatures suggests the involvement of an active, transporter-mediated secretory pathway. In the presence of etoposide, the CPT secretory permeability decreased 25.6%. However, inhibition was greater in the presence of PGP and of the breast cancer resistant protein inhibitor, GF120918 (52.5%). The involvement of additional secretory transporters was suggested since the basolateral to apical permeability of CPT was not further reduced in the presence of increasing concentrations of GF120918. To investigate the involvement of specific apically-located secretory membrane transporters, CPT transport studies were conducted using MDCKII/PGP cells and MDCKII/MRP2 cells. CPT carrier-mediated permeability was approximately twofold greater in MDCKII/PGP cells and MDCKII/MRP2 cells than in MDCKII/wild-type cells, while the apparent Km values were comparable in all three cell lines. The efflux ratio of CPT in MDCKII/PGP in the presence of 0.2 μM GF120918 was not completely reversed (3.36 to 1.49). However, the decrease in the efflux ratio of CPT in MDCKII/MRP2 cells (2.31 to 1.03) suggests that CPT efflux was completely inhibited by MK571, a potent inhibitor of the Multidrug Resistance Protein transporter family.
Conclusions
The current results provide evidence that PGP and MRP2 mediate the secretory transport of CPT in vitro. However, the involvement of other transporters cannot be ruled out based on these studies. Since these transporters are expressed in the intestine, liver and kidney variations in their expression levels and/or regulation may be responsible for the erratic oral absorption and biliary excretion of CPT observed in human subjects.
doi:10.1186/1741-7015-2-16
PMCID: PMC411064  PMID: 15125776
Caco-2 cells; camptothecin; efflux; MDCK II cells; Multidrug Resistance Protein 2; membrane transport; P-glycoprotein; secretion
25.  A systematic review of the incidence of schizophrenia: the distribution of rates and the influence of sex, urbanicity, migrant status and methodology 
BMC Medicine  2004;2:13.
Background
Understanding variations in the incidence of schizophrenia is a crucial step in unravelling the aetiology of this group of disorders. The aims of this review are to systematically identify studies related to the incidence of schizophrenia, to describe the key features of these studies, and to explore the distribution of rates derived from these studies.
Methods
Studies with original data related to the incidence of schizophrenia (published 1965–2001) were identified via searching electronic databases, reviewing citations and writing to authors. These studies were divided into core studies, migrant studies, cohort studies and studies based on Other Special Groups. Between- and within-study filters were applied in order to identify discrete rates. Cumulative plots of these rates were made and these distributions were compared when the underlying rates were sorted according to sex, urbanicity, migrant status and various methodological features.
Results
We identified 100 core studies, 24 migrant studies, 23 cohort studies and 14 studies based on Other Special Groups. These studies, which were drawn from 33 countries, generated a total of 1,458 rates. Based on discrete core data for persons (55 studies and 170 rates), the distribution of rates was asymmetric and had a median value (10%–90% quantile) of 15.2 (7.7–43.0) per 100,000. The distribution of rates was significantly higher in males compared to females; the male/female rate ratio median (10%–90% quantile) was 1.40 (0.9–2.4). Those studies conducted in urban versus mixed urban-rural catchment areas generated significantly higher rate distributions. The distribution of rates in migrants was significantly higher compared to native-born; the migrant/native-born rate ratio median (10%–90% quantile) was 4.6 (1.0–12.8). Apart from the finding that older studies reported higher rates, other study features were not associated with significantly different rate distributions (e.g. overall quality, methods related to case finding, diagnostic confirmation and criteria, the use of age-standardization and age range).
Conclusions
There is a wealth of data available on the incidence of schizophrenia. The width and skew of the rate distribution, and the significant impact of sex, urbanicity and migrant status on these distributions, indicate substantial variations in the incidence of schizophrenia.
doi:10.1186/1741-7015-2-13
PMCID: PMC421751  PMID: 15115547

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