Occult upper gastrointestinal mucosal abnormalities in critically ill patients.

BACKGROUND: The objectives of this study were to estimate the frequency of occult upper gastrointestinal abnormalities, presence of gastric acid as a contributing factor, and associations with clinical outcomes. METHODS: Data were extracted for study participants at a single centre who had an endoscopy performed purely for research purposes and in whom treating physicians were not suspecting gastrointestinal bleeding. Endoscopic data were independently adjudicated by two gastroenterologists who rated the likelihood that observed pathological abnormalities were related to gastric acid secretion using a 3-point ordinal scale (unlikely, possible or probable). RESULTS: Endoscopy reports were extracted for 74 patients [age 52 (37, 65) years] undergoing endoscopy on day 5 [3, 9] of ICU admission. Abnormalities were found in 25 (34%) subjects: gastritis/erosions in 10 (14%), nasogastric tube trauma in 8 (11%), oesophagitis in 4 (5%) and non-bleeding duodenal ulceration in 3 (4%). The contribution of acid secretion to observed pathology was rated 'probable' in six subjects (rater #1) and five subjects (rater #2). Prior to endoscopy, 39 (53%) patients were receiving acid-suppressive therapy. The use of acid-suppressive therapy was not associated with the presence of an endoscopic abnormality (present 15/25 (60%) vs. absent 24/49 (49%); P = 0.46). Haemoglobin concentrations, packed red cells transfused and mortality were not associated with mucosal abnormalities (P = 0.83, P > 0.9 and P > 0.9 respectively). CONCLUSIONS: Occult mucosal abnormalities were observed in one-third of subjects. The presence of mucosal abnormalities appeared to be independent of prior acid-suppressive therapy and was not associated with reduced haemoglobin concentrations, increased transfusion requirements, or mortality.

Infection transmission and chronic disease models in the study of infection-associated cancers.

In the last three decades, the appreciation of the role of infections in cancer aetiology has greatly expanded. Among the 13 million new cancer cases that occurred worldwide in 2008, around 2 million (16%) were attributable to infections. Concurrently, the approach to prevention of infection-related cancers is shifting from cancer control to infection control, for example, vaccination and the detection of infected individuals. In support of this change, the use of infection transmission models has entered the field of infection-related cancer epidemiology. These models are useful to understand the infection transmission processes, to estimate the key parameters that govern the spread of infection, and to project the potential impact of different preventive measures. However, the concepts, terminology, and methods used to study infection transmission are not yet well known in the domain of cancer epidemiology. This review aims to concisely illustrate the main principles of transmission dynamics, the basic structure of infection transmission models, and their use in combination with empirical data. We also briefly summarise models of carcinogenesis and discuss their specificities and possible integration with models of infection natural history.

Cholangiocarcinoma: descriptive epidemiology and risk factors.

In theory, the term of cholangiocarcinoma is reserved for the tumours originating from the intrahepatic bile ducts. The problems of classification of the most frequent hilar tumours and the absence of histopathological confirmation in a large percentage of cases in cancer registries from many countries show the difficulty of establishing the specific epidemiologic behaviour of intrahepatic cholangiocarcinoma (ICC). There are clearly two types of ICC: the first one is the consequence of the recurrent infection of the biliary ducts by the parasites Opisthorchis viverrini and Clonorchis sinensis, and is only seen in the areas of Southeast Asia where liver flukes are endemic. In these areas, incidence and mortality rates of ICC are extremely high. Both parasites have been classified class I carcinogens by the International Agency for Research on Cancer. The other type of ICC is a cancer much rarer but present in the whole world. Some risk factors have been well-established (chronic inflammation of biliary ducts, hepatitis, thorotrast, etc) but many patients do not have any of these factors. An increase in incidence and mortality of this second type of ICC has been seen in recent years, mostly in developed countries. There is an ongoing discussion in the literature about its authenticity and potential causes.

Differences in the risk of cervical cancer and human papillomavirus infection by education level.

BACKGROUND: Cervical cancer risk is associated with low education even in an unscreened population, but it is not clear whether human papillomavirus (HPV) infection follows the same pattern. METHODS: Two large multicentric studies (case-control studies of cervical cancer and HPV prevalence survey) including nearly 20 000 women. GP5+/GP6+ PCR was used to detect HPV. RESULTS: Education level was consistently associated with cervical cancer risk (odds ratio (OR) for 0 and >5 years vs 1-5 years=1.50, 95% confidence interval (CI): 1.25-1.80 and 0.69, 95% CI: 0.57-0.82, respectively, P for trend <0.0001). In contrast, no association emerged between education level and HPV infection in either of the two IARC studies. A majority of the women studied had never had a Pap smear. The association between low education level and cervical cancer was most strongly attenuated by adjustment for age at first sexual intercourse and first pregnancy. Parity and screening history (but not lifetime number of sexual partners, husband's extramarital sexual relationships, and smoking) also seemed to be important confounding factors. CONCLUSION: The excess of cervical cancer found in women with a low socio-economic status seems, therefore, not to be explained by a concomitant excess of HPV prevalence, but rather by early events in a woman's sexually active life that may modify the cancer-causing potential of HPV infection.

Different cervical cancer screening approaches in a Chinese multicentre study.

To evaluate alternative cervical cancer screening methods, digital colposcopy and collection of cervical exfoliated cells for liquid-based cytology (LBC) and hybrid capture 2 (HC2) testing were performed among 2562 women aged 15-59 years in three study sites in the People's Republic of China (rural Shanxi province, Shenyang city in Liaoning province and Shenzhen city in Guangdong province). Visual inspection with acetic acid (VIA) was also evaluated independently from colposcopy. A total of 74 cases of histologically confirmed cervical intraepithelial neoplasia grade 2 or worse (CIN2+) were identified, and 16 CIN2+ cases were imputed among unbiopsied women to correct for verification bias. Corrected sensitivity for CIN2+ was 37% for VIA, 54% for colposcopy, 87% for LBC with a threshold of atypical cells of undetermined significance (LBC>or=ASCUS), 90% for HC2, 84% for LBC using HC2 to triage ASCUS and 96% for positivity to LBC>or=ASCUS or HC2. For VIA, sensitivity was much lower among women >or=40 years (12%) than those aged or=ASCUS or HC2, up to 94% for LBC using HC2 to triage ASCUS. In conclusion, LBC, HC2 and their combinations performed well, whereas VIA missed a majority of CIN2+, particularly in older women. Digital colposcopy performed better than VIA, but still missed nearly half of CIN2+ in this study.

Helicobacter species in cancers of the gallbladder and extrahepatic biliary tract.

Helicobacter species have been found in human bile and biliary tract (BT) tissue and are suspected to cause BT diseases, including gallbladder and extrahepatic cancers, collectively referred to in this work as BT cancers. We conducted a literature review of the epidemiological evidence linking the presence of Helicobacter species in bile or BT biopsies to BT cancers and benign diseases. Reports showed great variability with respect to study methods. Nine studies of BT cancers were identified, all with 30 or fewer BT cancers; eight included cancer-free control subjects and used polymerase chain reaction (PCR) as a means of Helicobacter species detection. In four of these studies, Helicobacter species were detected in patients with BT cancer significantly more frequently than in controls, at least when controls without BT diseases were used. In two studies, no Helicobacter species were detected in either cases or controls. Helicobacter species were also often detected in benign BT diseases such as gallstone disease or chronic cholecystitis. As our current knowledge relies on a few small studies that showed substantial differences, larger studies and more standardised protocols for detecting DNA and antibodies against Helicobacter species are needed to investigate a potential association with BT cancer.

Rationale and design of the MEMA kwa Vijana adolescent sexual and reproductive health intervention in Mwanza Region, Tanzania.

Large-scale innovative, integrated, multifaceted adolescent sexual and reproductive health (ASRH) interventions are urgently needed in sub-Saharan Africa. Implementation through schools and health facilities may maximize intervention coverage and sustainability, however the impact of the use of these structures on intervention content and delivery is not well documented. This paper describes the rationale and design of a large-scale multifaceted ASRH intervention, which was developed and evaluated over three years in rural communities in Mwanza Region, North West Tanzania. The intervention comprised community mobilization, participatory reproductive health education in primary schools, youth-friendly reproductive health services and community-based condom provision for youth. We examine the effect of socioeconomic, cultural and infrastructural factors on intervention content and implementation. This paper demonstrates the means by which such interventions can be feasibly and sustainably implemented to a high standard through existing government health and school structures. However, the use of these structures involves compromise on some key aspects of intervention design and requires the development of complementary strategies to access out-of-school youth and the wider community.

Carcinoma of the cervix and tobacco smoking: collaborative reanalysis of individual data on 13,541 women with carcinoma of the cervix and 23,017 women without carcinoma of the cervix from 23 epidemiological studies.

Tobacco smoking has been classified as a cause of cervical cancer, but the effect of different patterns of smoking on risk is unclear. The International Collaboration of Epidemiological Studies of Cervical Cancer has brought together and combined individual data on 13,541 women with and 23,017 women without cervical carcinoma, from 23 epidemiological studies. Relative risks (RRs) and 95% confidence intervals (CIs) of carcinoma of the cervix in relation to tobacco smoking were calculated with stratification by study, age, sexual partners, age at first intercourse, oral contraceptive use and parity. Current smokers had a significantly increased risk of squamous cell carcinoma of the cervix compared to never smokers (RR = 1.60 (95% CI: 1.48-1.73), p<0.001). There was increased risk for past smokers also, though to a lesser extent (RR = 1.12 (1.01-1.25)), and there was no clear trend with time since stopping smoking (p-trend = 0.6). There was no association between smoking and adenocarcinoma of the cervix (RR = 0.89 (0.74-1.06) and 0.89 (0.72-1.10) for current and past smokers respectively), and the differences between the RRs for smoking and squamous cell and adenocarcinoma were statistically significant (current smoking p<0.001 and past smoking p = 0.01). In current smokers, the RR of squamous cell carcinoma increased with increasing number of cigarettes smoked per day and also with younger age at starting smoking (p<0.001 for each trend), but not with duration of smoking (p-trend = 0.3). Eight of the studies had tested women for cervical HPV-DNA, and in analyses restricted to women who tested positive, there was a significantly increased risk in current compared to never smokers for squamous cell carcinoma (RR = 1.95 (1.43-2.65)), but not for adenocarcinoma (RR = 1.06 (0.14-7.96)). In summary, smokers are at an increased risk of squamous cell but not of adenocarcinoma of the cervix. The risk of squamous cell carcinoma increases in current smokers with the number of cigarettes smoked per day and with younger age at starting smoking.

Papillomavirus infection in rural women in southern India.

To investigate the prevalence of, and the risk factors for, cervical infection with 44 types of human papillomavirus (HPV) in a rural area in the Dindigul District, Tamil Nadu, India, we interviewed and obtained cervical cell samples from 1891 married women aged 16-59 years. HPV prevalence was 16.9% overall and 14.0% among women without cervical abnormalities, or 17.7 and 15.2%, respectively, age-standardised to the world standard population. In all, 21.9% of infections involved more than one HPV type. High-risk HPV types predominated, particularly HPV 16 (22.5% of women infected), followed by HPV 56, HPV 31, HPV 33 and HPV 18. Unlike most populations studied in developed countries, HPV prevalence was constant across the age groups. HPV positivity was inversely associated with education level (odds ratio (OR) among women with high school vs no education=0.6) and positively associated with widowhood and divorce (OR=1.7), nulligravidity (OR=2.3), and condom use (OR=2.6). It is unclear how much low clearance of, or frequent reinfection with HPV accounted for the study prevalence of infection in different age groups.

"A bit more truthful": the validity of adolescent sexual behaviour data collected in rural northern Tanzania using five methods.

OBJECTIVE: To assess the validity of sexual behaviour data collected from African adolescents using five methods. METHODS: 9280 Tanzanian adolescents participated in a biological marker and face to face questionnaire survey and 6079 in an assisted self-completion questionnaire survey; 74 participated in in-depth interviews and 56 person weeks of participant observation were conducted. RESULTS: 38% of males and 59% of females reporting sexual activity did so in only one of the two 1998 questionnaires. Only 58% of males and 29% of females with biological markers consistently reported sexual activity in both questionnaires. Nine of 11 (82%) in-depth interview respondents who had had biological markers provided an invalid series of responses about sex in the survey and in-depth interview series. Only one of six female in-depth interview respondents with an STI reported sex in any of the four surveys, but five reported it in the in-depth interviews. CONCLUSION: In this low prevalence population, biological markers on their own revealed that a few adolescents had had sex, but in combination with in-depth interviews they may be useful in identifying risk factors for STIs. Self-reported sexual behaviour data were fraught with inconsistencies. In-depth interviews seem to be more effective than assisted self-completion questionnaires and face to face questionnaires in promoting honest responses among females with STIs. Participant observation was the most useful method for understanding the nature, complexity, and extent of sexual behaviour.

The sexual health of pupils in years 4 to 6 of primary schools in rural Tanzania.

BACKGROUND/OBJECTIVES: There is an urgent need for effective interventions to improve the sexual and reproductive health of adolescents. Reliable data on the sexual health of adolescents are needed to guide the development of such interventions. The aim was to describe the sexual health of pupils in years 4 to 6 of 121 rural primary schools in north western Tanzania, before the implementation of an innovative sexual health intervention in 58 of the schools. METHODS: A cross sectional survey of primary school pupils in rural Tanzania was carried out. The study population comprised pupils registered in years 4 to 6 of 121 primary schools in 20 rural communities in 1998. Basic demographic information was collected from all pupils seen. Those born before 1 January 1985 (aged approximately 14 years and over) were invited to participate in the survey, and asked about their knowledge and attitudes towards sexual health issues, and their sexual experience. A urine specimen was requested and tested for HIV, Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG) and, for females, pregnancy. RESULTS: 9283 pupils born before 1 January 1985 were enrolled and provided demographic information and a urine sample. Male pupils were significantly older than females (mean age 15.5 years v 14.8 years, p<0.001), but all other demographic characteristics were similar between the sexes. 14 (0.2%) of the enrolled pupils (four male and 10 female) were HIV positive, 83 (0.9%) were positive for CT, and 12 (0.1%) for NG. 32 female pupils (0.8%) were positive by pregnancy test. Sexual experience was reported by one fifth of primary school girls, and by almost half of boys. Only 45/114 (39%) girls with biological markers of sexual activity reported having had sex. CONCLUSIONS: HIV, CT, NG, and pregnancy were present though at relatively low levels among pupils in years 4 to 6 of primary school. A high proportion of pupils with a biological marker of sexual activity denied ever having had sex. Alternative ways of collecting sensitive data about the sexual behaviour of school pupils should be explored.

Human papillomavirus infection and use of oral contraceptives.

Human papillomavirus (HPV) infection is thought to be a necessary but not sufficient cause of most cases of cervical cancer. Since oral contraceptive use for long durations is associated with an increased risk of cervical cancer, it is important to know whether HPV infection is more common in oral contraceptive users. We present a systematic review of 19 epidemiological studies of the risk of genital HPV infection and oral contraceptive use. There was no evidence for a strong positive or negative association between HPV positivity and ever use or long duration use of oral contraceptives. The limited data available, the presence of heterogeneity between studies and the possibility of bias and confounding mean, however, that these results must be interpreted cautiously. Further studies are needed to confirm these findings and to investigate possible relations between oral contraceptive use and the persistence and detectability of cervical HPV infection.

Human papillomavirus types in invasive cervical cancer worldwide: a meta-analysis.

This study investigated regional variations in the contribution made by different human papilloma (HPV) types to invasive cervical cancer (ICC). A total of 85 studies using polymerase chain reaction to estimate HPV prevalence in ICC were identified. Data on HPV prevalence were extracted separately for squamous cell carcinoma (SCC) and for adeno- and adenosquamous-carcinoma (ADC). A total of 10 058 cases (8550 SCC, 1508 ADC) were included in pooled analyses. The most common HPV types in ICC were, in order of decreasing prevalence, HPV16, 18, 45, 31, 33, 58, 52, 35, 59, 56, 6, 51, 68, 39, 82, 73, 66 and 70. In SCC, HPV16 was the predominant type (46-63%) followed by HPV18 (10-14%), 45 (2-8%), 31 (2-7%) and 33 (3-5%) in all regions except Asia, where HPV types 58 (6%) and 52 (4%) were more frequently identified. In ADC, HPV prevalence was significantly lower (76.4%) than in SCC (87.3%), and HPV18 was the predominant type in every region (37-41%), followed by 16 (26-36%) and 45 (5-7%). The overall detection of HPV DNA was similar in different regions (83-89%). A majority of ICC was associated with HPV16 or 18 in all regions, but approximately a quarter of all ICC cases were associated with one of 16 other HPV types, their distribution varying by region.

Hepatitis B-associated nephrotic syndrome in Jamaican children.

Between December 1984 and November 1996, 171 children under 12 years old presented to the University Hospital of the West Indies with nephrotic syndrome. Hepatitis B surface antigen (HBsAg) was found in ten (6%) of these children, eight of whom had membranous nephropathy (MN), and one each had mesangial proliferative glomerulonephritis (MesN) and minimal change nephrotic syndrome (MCNS). Only those children with MesN and MCNS were steroid-sensitive. The HBsAg-positive status was identified incidentally on screening. At a mean follow-up of 34 months, seven of ten children had experienced complete or partial remission and three had persistent nephrotic syndrome, although none was in renal failure. Six of the ten had biochemical hepatitis. All the children were still HBsAg-positive. Hepatitis B virus (HBV) is a factor contributory to nephrotic syndrome in Jamaican children. As diagnostic clinical markers for HBV-associated nephropathy are usually absent, all children presenting with nephrotic syndrome should be screened for HBsAg. A policy should be implemented in Jamaica for screening pregnant women and at-risk groups for HBsAg, as well as for immunising susceptible neonates, in order to reduce the incidence of HBV-associated pathology.

Prevalence and determinants of human papillomavirus genital infection in men.

Four-hundred-forty-five husbands of women with invasive cervical carcinoma, 165 of women with in situ cervical cancer, and 717 of control women (age range 19-82 years) were interviewed and a sample of exfoliated cells from the penis obtained in seven case-control studies conducted by the International Agency for Research on Cancer. The characteristics of human papillomavirus-positive and human papillomavirus-negative husbands were compared using odds ratios and 95% confidence intervals. Thirteen per cent of the husbands of control women, 18% of the husbands of women with invasive cervical carcinoma, and 21% of the husbands of in situ cervical carcinoma women were positive for penile human papillomavirus DNA. Human papillomavirus 16 was detected in 45 husbands, human papillomavirus 18, 31 or 33 in 19, and human papillomavirus 6/11 in 6, but the majority of human papillomavirus infection (158) was with other or unspecified human papillomavirus types. The same human papillomavirus type was seldom identified in both husband and wife. The strongest variation in penile human papillomavirus infection was by country, with percentages among the husbands of control women ranging between 3% in Spain and 39% in Brazil. Having had over 50 lifetime sexual partners, compared with only one, was associated with an odds ratio of 2.3.

Structure-based design of caspase-1 inhibitor containing a diphenyl ether sulfonamide.

A series of compounds was designed and prepared as inhibitors of interleukin-1beta converting enzyme (ICE), also known as caspase-1. These inhibitors, which employ a diphenyl ether sulfonamide, were designed to improve potency by forming favorable interactions between the diphenyl ether rings and the prime side hydrophobic region. An X-ray crystal structure of a representative member of the diphenyl ether sulfonamide series bound to the active site of caspase-1 was obtained.

Rab3A is required for brain-derived neurotrophic factor-induced synaptic plasticity: transcriptional analysis at the population and single-cell levels.

Brain-derived neurotrophic factor (BDNF) modulates synaptic strength in hippocampal neurons, in addition to promoting survival and differentiation. To identify genes involved in trophic regulation of synaptic plasticity, we have used a multidisciplinary approach of differential display and family-specific slot blots in combination with whole-cell patch-clamp recordings of dissociated hippocampal neurons. Three hour exposure to BDNF elicited a 2.6-fold increase in synaptic charge and a concomitant induction of 11 genes as revealed by differential display, including the small GTP-binding vesicular trafficking protein Rab3A and the enzyme guanylate cyclase (GC). Slot blot analysis on a population of neurons confirmed an average of 3.1-fold induction of these clones. In contrast, individual pyramidal-like neurons that were first characterized electrophysiologically in the presence of BDNF and subjected to transcriptional analysis displayed more robust increases (4.8-fold), emphasizing the neuronal heterogeneity. Transcriptional changes of Rab3A and GC were accompanied by translational regulation, shown by Western blot analysis. Furthermore, a number of GC-associated and Rab3A effector molecules were induced by BDNF at either the gene or protein levels. The functional role of Rab3A in BDNF-induced synaptic plasticity was assessed using cells derived from Rab3A knock-out mice. These neurons failed to show an increase in synaptic charge in response to BDNF at 10 min; however a late response to BDNF was detected at 20 min. This late response was similar in time course to that induced by postsynaptic activation of glutamate receptors. Our results demonstrate a requirement for Rab3A and may reveal a temporal distinction between presynaptic and postsynaptic mechanisms of BDNF-induced synaptic plasticity associated with learning and memory.

A case-control study of gastric cancer in Venezuela.

A case-control study to evaluate risk factors for gastric cancer was carried out among 292 cases of gastric cancer and 485 controls in a high-risk area of Venezuela. Subjects were interviewed using a structured questionnaire, which elicited information on residential history, socio-economic status, family history of gastric diseases, smoking, drinking and dietary habits. Habitual diet was estimated from a meal-structured food frequency questionnaire on 75 food items. There was a strong inverse association with social class, as measured by education and by indicators of poverty. The results of the dietary analysis suggest that a diet high in starch and low in meat, fish and fresh vegetables increases risk of gastric cancer. A protective effect was observed for frequent consumption of allium vegetables. Inverse associations were found with height, which may reflect nutritional status in childhood, and with refrigerator use in the first two decades of life. Alcohol and tobacco consumption was investigated among males only, since the prevalence of alcohol and tobacco use was very low in females. Alcohol drinkers were at higher risk than non-drinkers and there was a small excess risk for current smokers compared with never smokers. There was some evidence of familial aggregation of gastric cancer. These findings will have important implications in planning preventive strategies for gastric cancer in Venezuela.