The BMP pathway either enhances or inhibits the Wnt pathway depending on the SMAD4 and p53 status in CRC.

BACKGROUND: Constitutive Wnt activation is essential for colorectal cancer (CRC) initiation but also underlies the cancer stem cell phenotype, metastasis and chemosensitivity. Importantly Wnt activity is still modulated as evidenced by higher Wnt activity at the invasive front of clonal tumours termed the ß-catenin paradox. SMAD4 and p53 mutation status and the bone morphogenetic protein (BMP) pathway are known to affect Wnt activity. The combination of SMAD4 loss, p53 mutations and BMP signalling may integrate to influence Wnt signalling and explain the ß-catenin paradox. METHODS: We analysed the expression patterns of SMAD4, p53 and ß-catenin at the invasive front of CRCs using immunohistochemistry. We activated BMP signalling in CRC cells in vitro and measured BMP/Wnt activity using luciferase reporters. MTT assays were performed to study the effect of BMP signalling on CRC chemosensitivity. RESULTS: Eighty-four percent of CRCs with high nuclear ß-catenin staining are SMAD4 negative and/or p53 aberrant. BMP signalling inhibits Wnt signalling in CRC only when p53 and SMAD4 are unaffected. In the absence of SMAD4, BMP signalling activates Wnt signalling. When p53 is lost or mutated, BMP signalling no longer influences Wnt signalling. The cytotoxic effects of 5-FU are influenced in a similar manner. CONCLUSIONS: The BMP signalling pathway differentially modulates Wnt signalling dependent on the SMAD4 and p53 status. The use of BMPs in cancer therapy, as has been proposed by previous studies, should be targeted to individual cancers based on the mutational status of p53 and SMAD4.

Reduced expression of bone morphogenetic protein receptor IA in pancreatic cancer is associated with a poor prognosis.

BACKGROUND: The expression of SMAD4, the central component of the transforming growth factor-ß (TGF-ß) and bone morphogenetic protein (BMP) signalling pathways, is lost in 50% of pancreatic cancers and is associated with a poor survival. Although the TGF-ß pathway has been extensively studied and characterised in pancreatic cancer, there is very limited data on BMP signalling, a well-known tumour-suppressor pathway. BMP signalling can be lost not only at the level of SMAD4 but also at the level of BMP receptors (BMPRs), as has been described in colorectal cancer. METHODS: We performed immunohistochemical analysis of the expression levels of BMP signalling components in pancreatic cancer and correlated these with survival. We also manipulated the activity of BMP signalling in vitro. RESULTS: Reduced expression of BMPRIA is associated with a significantly worse survival, primarily in a subset of SMAD4-positive cancers. In vitro inactivation of SMAD4-dependent BMP signalling increases proliferation and invasion of pancreatic cancer cells, whereas inactivation of BMP signalling in SMAD4-negative cells does not change the proliferation and invasion or leads to an opposite effect. CONCLUSION: Our data suggest that BMPRIA expression is a good prognostic marker and that the BMP pathway is a potential target for future therapeutic interventions in pancreatic cancer.

An assessment of the iPad as a testing platform for distance visual acuity in adults.

OBJECTIVES: Visual acuity is a common measurement in general practice, and the advent of new technology such as tablet computers offers a change in the way in which these tests are delivered. The aim of this study was to assess whether measurements of distance visual acuity using LogMAR letter charts displayed on an iPad tablet computer were in agreement with standard clinical tests of visual acuity in adults with normal vision. DESIGN: Blinded, diagnostic test study. SETTING: Single centre (University) in Auckland, New Zealand. PARTICIPANTS: University staff and students (n=85). Participants were required to have visual acuity better than 6/60 and wear habitual refractive correction during testing. Participants were excluded if there was any history of ocular pathology. PRIMARY AND SECONDARY OUTCOME MEASURES: Visual acuity measured under a number of conditions. RESULTS: The iPad tablet with its glossy screen was highly susceptible to glare resulting in acuity measurements that were significantly poorer (approximately 2 LogMAR lines) than those made using an ETDRS chart and a standard computerised testing system (n=56). However, fitting the iPad with an antiglare screen and positioning the device away from sources creating reflected (veiling) glare resulted in acuity measurements that were equivalent those made using gold standard charts (n=29). CONCLUSIONS: Tablet computers are an attractive option for visual acuity measurement due to portability, the ability to randomise letters, automated scoring of acuity and the ability to select from a range of charts. However, these devices are only suitable for use in situations where sources of glare can be eliminated.

Key elements of the BMP/SMAD pathway co-localize with CDX2 in intestinal metaplasia and regulate CDX2 expression in human gastric cell lines.

Helicobacter pylori infection induces intestinal metaplasia of the stomach, a preneoplastic lesion associated with an increased risk for gastric cancer development. Intestinal metaplasia is induced by the intestine-specific transcription factor CDX2 but the mechanisms responsible for this ectopic expression have never been described. We hypothesized that the BMP/SMAD pathway has a role in CDX2 regulation, in this context, for the following reasons: (1) the BMP pathway is crucial for normal intestinal differentiation and (2) there is an influx of BMP2 and BMP4-producing cells to the stomach upon Helicobacter pylori infection. We evaluated the expression of key elements of the BMP pathway in human stomach specimens with IM. Growth factor treatments, with BMP2 and BMP4, were performed in cultured cells and a knock-down experiment of SMAD4 was done using RNAi. We showed overexpression in IM of BMP2/4, BMPR1A, and SMAD4 in 56% of IM foci, and pSMAD1/5/8 in 100% of IM foci as compared to adjacent mucosa. In vitro, treatment of AGS cells with BMP2 and BMP4 increased endogenous CDX2 expression as well as the intestinal differentiation markers MUC2 and LI-cadherin. On the other hand, SMAD4 knock-down led to decreased endogenous CDX2, MUC2, and LI-cadherin in AGS. Treatment of the SMAD4 knock-down cells had no influence on CDX2 expression as opposed to wild-type cells. A 9.3 kb CDX2 promoter could be transactivated by SMAD4 and SMAD1 in a cell-dependent manner. In conclusion, we identified for the first time that the BMP pathway is active in intestinal metaplasia and that BMP2 and BMP4 regulate CDX2 expression and promote intestinal differentiation through the canonical signal transducers.

Do too many shots due lead to missed vaccination opportunities? Does it matter?

BACKGROUND: Missed childhood vaccination opportunities have been generally described, yet not since the immunization schedule's recent rapid expansion. Little is known about the relationship between the number of vaccine doses due and whether all scheduled doses are administered, and the effect of dose deferral on immunization coverage. METHODS: 32 private pediatrics centers reviewed medical records covering the first 2 years of life for 858 patients. For each visit during ages 2-8 months, we determined the numbers of vaccine doses due versus administered. Logistic regression was used to assess the effect of dose deferral on immunization coverage at ages 1 and 2 years. RESULTS: Of 2224 visits during ages 2-8 months at which > or =1 dose was administered, > or =1 due dose was deferred at 26%, 34%, and 48% of the visits at which < or =3, 4, and 5 doses were due, respectively. Absence of a deferred dose visit predicted increased coverage at age 1 (adjusted odds ratio: 2.4, 95% confidence interval: 1.8-3.2) and 2 years (2.1, 1.4-3.0). CONCLUSIONS: Administering some but not all vaccine doses at visits during ages 2-8 months impairs immunization coverage through age 2 years.

Clinician satisfaction with vaccination visits and the role of multiple injections, results from the COVISE Study (Combination Vaccines Impact on Satisfaction and Epidemiology).

Because little is known about clinician satisfaction with infant vaccination visits, we measured satistaction and the effects of the number of injections on satisfaction. Clinicians from 35 pediatric centers self-administered a questionnaire using visual analog scales augmented by a Likert scale. All 95 pediatricians and 137 nonphysician vaccinators responded. In both populations, increased injections predicted decreased overall satisfaction, and decreased satisfaction with obtaining consent, time to prepare/administer, getting upset during administration, and time to update records (each p<0.01). Satisfaction decreased markedly, on each measure, at 4-injection visits, 5-injection visits, or both.

Economic value to parents of reducing the pain and emotional distress of childhood vaccine injections.

BACKGROUND: One reason that recommended childhood immunizations due at child health visits are deferred is to avoid the pain and emotional distress associated with the increasing number of injections required. This deferral leads to additional visits and costs and reduced immunoprotection against vaccine-preventable illnesses. To assess the economic value of combination vaccines that address this problem, we surveyed parents to determine the amount they would be willing to pay to avoid the pain and emotional distress experienced by their infants from injections. METHODS: A self-administered questionnaire was completed within 24 h of the vaccinations by 294 parents of children ages 11/2 to 7 months receiving vaccine injections at 26 outpatient child health centers. The willingness-to-pay (WTP) method was used to estimate the intangible cost of the pain and emotional distress of the 1 to 4 injections their child had received. Parents were asked how much of their own money they would have paid to avoid these injections, without any compromise in the safety and efficacy of the vaccinations. RESULTS: Wide variations in WTP amounts were observed, ranging from median values of $10 to $25 and average values of $57.06 to $79.28 to avoid the pain and emotional distress associated with eliminating all injections at visits in which one to four injections were administered. Parents placed greater value on reductions that avoided all injections than on reductions that avoided only some injections. Overall the median cost per injection avoided was $8.14, and the mean was $30.28. CONCLUSIONS: Parents have strong preferences for limiting vaccine injections. The economic cost of the pain and distress associated with such injections, reflected in the amounts they report they would be willing to pay to avoid them, represents a substantial component of the cost of disease control through immunization.

Transmission of hepatitis A through household contact.

In the USA, cost effectiveness assessments support childhood hepatitis A vaccination in geographical areas with elevated disease rates, but not nationally. However, these studies do not address the reduction in disease transmission which may result from routine childhood vaccination. Using decision analysis, we estimated the number and age distribution of secondary hepatitis A cases occurring within households with an index case. Based on the age of the index case, we determined household size and age composition, the proportion of household members susceptible to hepatitis A, the probability of disease transmission, and the likelihood secondarily infected household members would exhibit symptoms. Our model indicates that for every 100 index cases age 6-11 years, 47.2 secondary infections would occur within households, with 23.1 causing overt disease. Lower transmission rates for older index cases reflect smaller household sizes and a higher proportion of household contacts with hepatitis A immunity. When disease transmission rates are applied to a model simulating lifetime risks of hepatitis A, universal vaccination of an annual USA birth cohort is estimated to prevent 24 100 cases of overt disease among household contacts in addition to 71 000 cases among vaccinees. Sensitivity analysis provides a wide range of estimates, but even conservative assumptions suggest routine vaccination would yield an important reduction in secondary cases. Evaluations of hepatitis A prevention should consider the ability of immunization to protect household and other personal contacts.

Comparative cost effectiveness of varicella, hepatitis A, and pneumococcal conjugate vaccines.

BACKGROUND: Several state and local U.S. governments are considering making varicella, hepatitis A, and/or pneumococcal conjugate vaccination conditions of day care or school entry. These requirements will likely be issued sequentially, because simultaneous mandates exacerbate budget constraints and complicate communication with parents and providers. Cost-effectiveness assessments should aid the establishment of vaccination priorities, but comparing results of published studies is confounded by their dissimilar methods. METHODS: We reviewed U.S. cost-effectiveness studies of childhood varicella, hepatitis A, and pneumococcal conjugate vaccines and identified four providing data required to standardize methods. Vaccination, disease treatment, and work-loss costs were estimated from original study results and current prices. Estimated life-years saved were derived from original study results, epidemiological evidence, and alternative procedures for discounting to present values. RESULTS: Hepatitis A vaccine would have the lowest health system costs per life-year saved. Varicella vaccine would provide the greatest reduction in societal costs, mainly through reduced parent work loss. Pneumococcal conjugate vaccine would cost twice the amount of varicella and hepatitis A vaccines combined and be less cost effective than the other vaccines. CONCLUSIONS: Hepatitis A and varicella vaccines, but not pneumococcal conjugate vaccine, meet or exceed conventional standards of cost effectiveness.

Comparative safety of filgrastim versus sargramostim in patients receiving myelosuppressive chemotherapy.

STUDY OBJECTIVE: To compare rates of adverse events with filgrastim versus sargramostim when given prophylactically to patients receiving myelosuppressive chemotherapy. DESIGN: Retrospective review with center crossover. SETTING: Ten United States outpatient chemotherapy centers. PATIENTS: Four hundred ninety patients treated for lung, breast, lymphatic system, or ovarian tumors. INTERVENTION: Prophylactic use of filgrastim or sargramostim, with dosages at investigator discretion. MEASUREMENTS AND MAIN RESULTS: The frequency and severity of adverse events and the frequency of switching to the alternative CSF were assessed. There was no difference in infectious fever. Fever unexplained by infection was more common with sargramostim (7% vs 1%, p<0.001), as were fatigue, diarrhea, injection site reactions, other dermatologic disorders, and edema (all p<0.05). Skeletal pain was more frequent with filgrastim (p=0.06). Patients treated with sargramostim switched to the alternative agent more often (p<0.001). CONCLUSION: Adverse events were less frequent with filgrastim than with sargramostim, suggesting that quality of life and treatment costs also may differ.

The cost-effectiveness of adolescent hepatitis A vaccination in states with the highest disease rates.

BACKGROUND: The Advisory Committee on Immunization Practices has recommended routine childhood hepatitis A vaccination in states and communities where the incidence of disease exceeds the national average, but most adolescents are currently unprotected from infection. OBJECTIVE: To estimate clinical and economic consequences of vaccinating adolescents against hepatitis A in the 10 states with the highest disease rates. DESIGN: Decision analysis was used to assess cost-effectiveness from societal and health system perspectives. Parameter estimates were obtained from national surveillance data, a study of hepatitis A cases, and an expert panel. MAIN OUTCOME MEASURES: Reduction in disease incidence; costs of vaccination, treatment, and work loss; years of life saved (YOLS); and costs per YOLS. RESULTS: In states with the highest disease rates, vaccination of adolescents against hepatitis A would reduce the lifetime risk of symptomatic infection from 3.3% to 0.7% and prevent loss of 2117 years of life. Vaccination of a single birth cohort would cost $30.9 million, yet treatment and work loss costs would decline $14.2 million and $23.8 million, respectively. Hepatitis A vaccination would cost the health system $7902 per YOLS or $13,722 per discounted YOLS. Results are most sensitive to variation in the discount rate and assumptions regarding long-term vaccine protective efficacy. CONCLUSIONS: Hepatitis A vaccination of adolescents in states with high disease rates would reduce costs to society. Although health system costs would increase, cost-effectiveness is comparable to other recommended vaccines and superior to many commonly used medical interventions. Arch Pediatr Adolesc Med. 2000;154:763-770

Cost effectiveness of vaccinating food service workers against hepatitis A infection.

Foodborne transmission is an important means of hepatitis A infection that may be reduced through vaccination of food service workers (FSWs). Several states are considering actions to encourage or mandate FSW vaccination, but the cost effectiveness of such policies has not been assessed. We estimated the clinical and economic consequences of vaccinating FSWs from the 10 states with the highest reported rates of hepatitis A. A decision analytic model was used to predict the effects of vaccinating FSWs at age 20 years. It was assumed all FSWs would receive one dose of inactivated hepatitis A vaccine, and 50% would receive the second recommended dose. Parameter estimates were obtained from published reports and Centers for Disease Control and Prevention databases. The primary endpoint was cost per year of life saved (YOLS). Secondary endpoints were symptomatic infections, days of illness, deaths, and costs of hepatitis A treatment, public health intervention, and work loss. Each endpoint was considered separately for FSWs and patrons. We estimate vaccination of 100,000 FSWs would cost $8.1 million but reduce the costs of hepatitis A treatment, public health intervention, and work loss by $3.0 million, $2.3 million, and $3.1 million, respectively. Vaccination would prevent approximately 2,500 symptomatic infections, 93,000 days of illness, and 8 deaths. A vaccination policy would reduce societal costs while costing the health system $13,969 per YOLS, a ratio that exceeds generally accepted standards of cost effectiveness.

The cost of hepatitis A infections in American adolescents and adults in 1997.

The incidence of hepatitis A has declined in the United States for several decades, leading to an increased number of susceptible adolescents and adults. Because clinical severity increases with age, hepatitis A infections in older individuals cause greater morbidity, mortality, and treatment costs. Because the economic burden of hepatitis A has not been well described, we estimated its costs, from the societal perspective, for patients infected at distinct ages. A case-series study described treatment patterns, work loss, and symptom duration. Disease outcomes were estimated by an expert panel. Economic losses were calculated by applying normative data reflecting treatment charges, employee compensation, and the value of housekeeping services. In the case-series study, mean treatment charges were $740 for nonhospitalized patients versus $6,914 for hospitalized patients (P <.001). Symptom duration (67.8 vs. 34.4 days, P <.001) and work loss (33.2 vs. 15.5 days, P <.01) were also greater for those hospitalized. Nationally, we estimate 63,363 symptomatic hepatitis A infections occurred among adolescents and adults during 1997, resulting in 8,403 hospital admissions and 255 deaths. Nearly 2.5 million days of symptomatic illness and 829,000 work-loss days resulted, and 7,466 years of life were lost. Under base-case assumptions, annual hepatitis A costs were estimated at $488.8 million. In sensitivity analyses, this estimate varied from $332.4 to $579.9 million. These costs may be reduced by regionally targeted vaccination of children, as recommended by the Advisory Committee on Immunization Practices, although the cost effectiveness of this policy has not yet been established.

Evaluation of office-based intervention to improve prevention counseling for patients at risk for sexually acquired hepatitis B virus infection. Hepatitis B-WARE Study Group.

The aim of this study was to determine the effectiveness of tools to identify and counsel patients at risk for sexually transmitted hepatitis B virus infection. Physicians were randomly assigned to either an intervention group or a control group. The intervention group was provided with materials intended to encourage patients to return for counseling and to guide counseling concerning prevention of hepatitis B virus infection. Baseline data on 457 patients at risk for hepatitis B virus infection showed that 7% had received prevention counseling and 2% had begun hepatitis B vaccination. Counseling was least likely to occur in obstetric-gynecologic practices, among uninsured patients, and among patients whose only risk factor was a diagnosis of a sexually transmitted disease. After a 6-month intervention period 26% of the intervention group patients and 7% of the control group patients had been counseled (P <.01). Vaccination was more likely among intervention group patients (8% vs <1%; P <.001). The use of tools to identify and counsel patients at risk for sexually transmitted hepatitis B virus infection resulted in increased office-based prevention activities.

Study of luminance effects on pinhole test results for visually impaired patients.

PURPOSE: The visual acuity of visually impaired patients has been reported to improve after a refraction, despite pinhole test results that show a decline or no change in acuity. Our aim was to investigate whether the pinhole-induced reduction in retinal illuminance accounted for these unreliable predictions of best-corrected acuity. METHODS: Participants were 64 adult patients referred for low-vision rehabilitation. Neutral density filters reproduced the pinhole-induced luminance loss, allowing pinhole test and postrefraction acuities to be measured at essentially equivalent levels of retinal illuminance. The following data were collected in random order from each subject's better eye: (1) habitual visual acuity, (2) habitual visual acuity with filter, (3) habitual visual acuity with pinhole, (4) best-corrected/postrefraction visual acuity, (5) postrefraction visual acuity with filter. RESULTS: On average, the pinhole test under-estimated postrefraction visual acuity by six letters (95% confidence limits = +/- 20). The pinhole test underestimated postrefraction visual acuity with the filter by two letters (95% confidence limits = +/- 16). Among subjects whose acuity improved with the pinhole test (N = 24), 83% experienced better postrefraction visual acuity. Among subjects whose acuity declined or remained unchanged with the pinhole test (N = 40), 50% achieved better postrefraction visual acuity. CONCLUSIONS: The pinhole-induced luminance loss contributed to inadequate predictions of postrefraction visual acuity. Pinhole test results were enormously variable, underestimating and overestimating postrefraction visual acuity. The pinhole test was less reliable when improvements in postrefraction visual acuity were small. Visually impaired patients deserve periodic refractions, and the pinhole test result should not be used as a dichotomizer for clinical decisions regarding the need for a refraction.

Influence of age on the multifocal electroretinography.

The influence of age on the amplitude density (nV/sq deg) of the multifocal electroretinogram (ERG) was studied in 90 healthy subjects aged 18-52 years. Subjects were divided into three separate age groups; (i) 18-22 years (ii) 33-37 years and (iii) 48-52 years. Amplitude density of first order kernel of the multifocal ERG was measured for the three different age groups. When the whole response of the retina is considered, analysis of variance showed no significant differences in amplitude density between the three age groups. (ANOVA, df. 2, 87 F = 2.29, p = 0.11. However if the responses were segregated into a central area and concentric rings around the central area, analysis of variance showed that there were significant differences in responses between rings at different eccentricities and between different age groups (Anova F = 76.19, df. 17, 522, p = 0.00001). Post hoc analysis showed that the responses from the centre and the second ring around the centre of fixation for 48-52 year olds were significantly lower than those responses from the 33-37 year old and the 18-22 year old age groups. The decline in the multifocal ERG in the central retina of the 48-52 year olds could be associated with the decline of the number of photoreceptors as the eye ages. Student t test revealed no significant differences in amplitude density between males and females.