DNA vaccines for biodefence

The advantages associated with DNA vaccines include the speed with which they may be constructed and produced at large-scale, the ability to produce a broad spectrum of immune responses, and the ability for delivery using non-invasive means. In addition, DNA vaccines may be manipulated to express multiple antigens and may be tailored for the induction of appropriate immune responses. These advantages make DNA vaccination a promising approach for the development of vaccines for biodefence. In this review, the potential of DNA vaccines for biodefence is discussed.     

Fixed dose-rate gemcitabine infusion as first-line treatment for advanced-stage carcinoma of the pancreas and biliary tree

BACKGROUND: Gemcitabine infusion at the fixed dose rate of 10 mg/m(2) per minute (FDR-gemcitabine) has pharmacokinetic advantages and may result in improved therapeutic efficacy. METHODS: Between April 2002 and September 2003, 40 patients with advanced-stage pancreatic adenocarcinoma (PDAC; n = 27) or biliary tree carcinoma (BTC; n = 13) were treated with weekly FDR-gemcitabine (1000 mg/m(2)). The primary end point was the response rate. The secondary end points were progression-free and overall survival (PFS and OS), tumor marker response, and clinical benefit response (CBR). RESULTS: The overall response rate (ORR) on an intent-to-treat basis was 15% (95% confidence interval [95% CI], 4-26%). A positive CBR was obtained in 14 of 29 (48%) patients. Seventeen of 25 (68%) patients had a reduction in carbohydrate antigen 19-9 (CA 19-9) of > 25%. The median time to treatment failure and the median PFS were 17 weeks (95% CI, 13-22 weeks) and 19 weeks (95% CI, 15-23 weeks), respectively. The median OS was 40 weeks (95% CI, 36-45 weeks) and the 1-year actuarial survival rate was 25.8%. Multivariate analysis showed that a performance status score of 0-1 at study entry and locally advanced disease were the only independent predictors of longer PFS and OS, whereas a reduction in CA 19-9 serum levels > 75% was an independent predictor of longer PFS, but had no impact on OS. Toxicity was mild with Grade 3-4 neutropenia (according to the National Cancer Institute-Common Toxicity Criteria [version 2.0]) in 18 of 427 treatment weeks (4.2%), and Grade 3 anemia and thrombocytopenia in 6 of 427 treatment weeks (1.4%) and 9 of 427 treatment weeks (2.1%), respectively, and asymptomatic Grade 3-4 transaminase elevation in 21 of 427 treatment weeks (4.9%). CONCLUSIONS: FDR-gemcitabine at the weekly dose of 1000 mg/m(2) demonstrated promising activity, despite negligible toxicity, in patients with advanced-stage PDAC and BTC.     

Risk of breast cancer after miscarriage or induced abortion: a Scottish record linkage case-control study

STUDY OBJECTIVE: To assess the risk of breast cancer in patients with a previous history of miscarriage or induced abortion. DESIGN: Case-control study relating "exposure" to outcome by linkage of national hospital discharge and maternity records, the national cancer registry, and death records. SETTING: Scotland. PARTICIPANTS: Miscarriage analysis-2828 women with breast cancer and 9781 matched controls; induced abortion analysis-2833 women with breast cancer and 9888 matched controls. MAIN RESULTS: After stratification for age at diagnosis, parity, and age at first birth, the odds ratio (95% confidence intervals) of breast cancer was 1.02 (0.88 to 1.18) in women with a previous miscarriage, and 0.80 (0.72 to 0.89) in women with a previous induced abortion. Further adjustments for age at bilateral oophorectomy, socioeconomic status (based on small area of residence), and health board area of residence had only minor effects on these odds ratios. CONCLUSION: These data do not support the hypothesis that miscarriage or induced abortion represent substantive risk factors for the future development of breast cancer.     

Economic evaluation of ultrasonography in the diagnosis and management of developmental hip dysplasia in the United Kingdom and Ireland

BACKGROUND: Clinical neonatal hip screening is performed to identify hip instability and the increased risk of later hip subluxation and dislocation. However, there is minimal information regarding the costs of such screening to parents and health services. The aim of this study was to assess these costs in association with the use of ultrasonography for the diagnosis and management of neonatal hip instability. METHODS: We conducted a prospective economic analysis in conjunction with a randomized clinical trial (the Hip Trial), for which 629 patients were recruited from thirty-three centers in the United Kingdom and Ireland to be randomized to undergo either ultrasonographic hip examination (314 patients) or clinical assessment alone (315 patients). Information on clinical outcomes was obtained from hospital records and records from the Hip Trial. Resource information was obtained from hospital records and from repeated periodic cross-sectional surveys of the families. Typical unit costs were applied to resource information to obtain a cost per patient, and the mean costs in the two study groups were calculated and compared. RESULTS: The average overall health-service cost per patient (and standard deviation) was $1298 +/- $2168 in the ultrasonography group and $1488 +/- $2912 in the group that underwent clinical assessment alone, a net difference of -$190 (95% confidence interval, -$630 to $250). Families in which the infant was examined with ultrasonography had significantly lower costs associated with splinting: $92 compared with $118 in the group that underwent clinical assessment alone, a mean difference of -$26 (95% confidence interval, -$46 to -$6). Costs associated with surgery and total costs to the family were also slightly, but not significantly, lower in the ultrasonography group. CONCLUSIONS: Our results suggest that use of ultrasonography in the management of neonates with clinical hip instability is unlikely to impose an increased cost burden and may reduce costs to health services and families.     

Survival of severe congenital diaphragmatic hernia has morbid consequences

Background/Purpose

Fetal tracheal occlusion (TO) was developed in an attempt to enhance prenatal lung growth and improve survival in fetuses with severe congenital diaphragmatic hernia (CDH). We conducted a randomized, controlled clinical trial in 24 fetuses with severe left CDH (liver herniated into the thorax and low lung-to-head ratio) to compare survival after endoscopic fetal TO vs standard perinatal care (control) and prospectively followed up the 16 survivors (9 control, 7 TO) to compare neurodevelopmental, respiratory, surgical, growth, and nutritional outcomes.

Methods

At 1 and 2 years old, subjects underwent evaluation consisting of medical and neurological history and physical, developmental testing, nutritional assessment, oxygen saturation and pulmonary function testing, chest radiograph, and echocardiogram. Growth and developmental measures were corrected for prematurity. Data were analyzed by Mann-Whitney rank sum test, Fisher's Exact test, and logistic and linear regression.

Results

Infants with TO were significantly more premature at birth (control vs TO, 37.4 ± 1.0 vs 31.1 ± 1.7 weeks; P < .01). Growth failure (z score for weight <2 SDs below mean) was severe in both groups at 1 year of age (control vs TO, 56% vs 86%; P = .31). There was considerable catch-up growth by age 2 years (growth failure: control vs TO, 22% vs 33%; P = .19). There were no differences in other growth parameters. There were also no differences in neurodevelopmental outcome at 1 and 2 years. Supplemental oxygen at hospital discharge was a significant predictor of worse neurodevelopmental outcome at 1 and 2 years old (P = .05 and P = .02, respectively). Hearing loss requiring amplification has been diagnosed in 44% of the group (control vs TO, 44% vs 43%; P = 1.0).

Conclusions

In this group of infants with severe CDH, there were no differences in outcome at 2 years old despite significant prematurity in the TO group. Oxygen supplementation at hospital discharge identified the most vulnerable group with respect to neurodevelopmental outcome, but all infants had significant growth failure, and hearing impairment is a substantial problem in this population. Severe CDH carries significant risk of chronic morbidity.     

Subcutaneous endoscopically assisted ligation (SEAL) of the internal ring for repair of inguinal hernias in children: a novel technique

Subcutaneous endoscopically assisted ligation (SEAL) is a technique for high ligation of the patent processus at the internal ring without a groin incision or dissection of the vas and vessels. Under endoscopic visualization through a single umbilical port, a suture is guided extraperitoneally around the internal ring, avoiding the vas and vessels. The safety, efficacy (recurrence risk), and cost-effectiveness of this unproven procedure must be tested against standard open repair in a trial.     

Heat shock inhibits NF-kB activation in a dose- and time-dependent manner

BACKGROUND: The heat shock response (HSR) attenuates NF-kappaB mediated activation of the acute inflammatory response by inhibiting IkB degradation. The HSR also confers a protective phenotype upon cells through production of heat shock proteins (HSP). However, the exact conditions that induce the HSR and stimulate the production of protective HSP are poorly defined. Consequently, we hypothesized that the inhibition of NF-kappaB activation through the HSR is dependent both on the degree of cellular injury and the length of the recovery period from the heat shock. METHODS: RAW 264.7 murine macrophages were heated to 43 degrees C for 15 (mild heat shock), 45 (moderate heat shock), or 90 min (severe heat shock), allowed to recover at 37 degrees C for 0 to 24 h, and then exposed to 100 ng/ml of Escherichia coli (055:B5) lipopolysaccharide (LPS). Cellular viability, HSP expression, and the activation of NF-kappaB after LPS exposure were determined by alamarBlue assay, immunoblot, and electrophoretic mobility shift assay, respectively. RESULTS: Transient attenuation of NF-kappaB activation and IkappaB preservation was observed only with moderate heat shock and 1 h of recovery. Mild heat shock had no effect on LPS-induced NF-kappaB activation or IkappaB degradation. Severe heat shock completely inhibited NF-kappaB activation and preserved IkappaB protein levels. Heat shock proteins were detectable 30 min after moderate heat shock, with maximal and sustained levels 2 to 24 h after heat shock. CONCLUSION: The attenuation of NF-kappaB activation after heat shock is both dose- and time-dependent.     

Importance of magnesium in absorption and excretion of oxalate

INTRODUCTION: Magnesium treatment for calcium oxalate urolithiasis is discussed controversially. The aim of this study was to investigate the influence of magnesium supplementation on the oxalate absorption. MATERIALS AND METHODS: The [13C2]oxalate absorption test was always performed three times in 6 healthy volunteers under standardized conditions, with one 10-mmol magnesium supplement together with the labeled oxalate and with two 10-mmol magnesium supplements given in 12-hour intervals. RESULTS: The mean intestinal oxalate absorption under standard conditions was 8.6 +/- 2.83%. The oxalate absorption with one 10-mmol magnesium supplement was 5.2 +/- 1.40% and with two supplements 5.5 +/- 1.62%. Both decreases were statistically significant relative to the standard test, however, not significantly different from each other. CONCLUSIONS: The results show that magnesium administration decreases the oxalate absorption, when magnesium is taken together with oxalate. However, magnesium administration does not decrease the oxalate absorption, when magnesium and oxalate intake differ by 12 h.