A prospective clinical trial of tumor hypoxia imaging with 18F-fluoromisonidazole positron emission tomography and computed tomography (F-MISO PET/CT) before and during radiation therapy

To visualize intratumoral hypoxic areas and their reoxygenation before and during fractionated radiation therapy (RT), ¹⁸F-fluoromisonidazole positron emission tomography and computed tomography (F-MISO PET/CT) were performed. A total of 10 patients, consisting of four with head and neck cancers, four with gastrointestinal cancers, one with lung cancer, and one with uterine cancer, were included. F-MISO PET/CT was performed twice, before RT and during fractionated RT of approximately 20 Gy/10 fractions, for eight of the 10 patients. F-MISO maximum standardized uptake values (SUVmax) of normal muscles and tumors were measured. The tumor-to-muscle (T/M) ratios of F-MISO SUVmax were also calculated. Mean SUVmax ± standard deviation (SD) of normal muscles was 1.25 ± 0.17, and SUVmax above the mean + 2 SD (≥1.60 SUV) was regarded as a hypoxic area. Nine of the 10 tumors had an F-MISO SUVmax of ≥1.60. All eight tumors examined twice showed a decrease in the SUVmax, T/M ratio, or percentage of hypoxic volume (F-MISO ≥1.60) at approximately 20 Gy, indicating reoxygenation. In conclusion, accumulation of F-MISO of ≥1.60 SUV was regarded as an intratumoral hypoxic area in our F-MISO PET/CT system. Most human tumors (90%) in this small series had hypoxic areas before RT, although hypoxic volume was minimal (0.0–0.3%) for four of the 10 tumors. In addition, reoxygenation was observed in most tumors at two weeks of fractionated RT.     

The clinical application of 4D 18F-FDG PET/CT on gross tumor volume delineation for radiotherapy planning in esophageal squamous cell cancer

A combination of four-dimensional computed tomography with ¹⁸F-fluorodeoxyglucose positron emission tomography (4D CT-FDG PET) was used to delineate gross tumor volume (GTV) in esophageal cancer (EC). Eighteen patients with EC were prospectively enrolled. Using 4D images taken during the respiratory cycle, the average CT image phase was fused with the average FDG PET phase in order to analyze the optimal standardized uptake values (SUV) or threshold. PET-based GTV (GTV_PET) was determined with eight different threshold methods using the auto-contouring function on the PET workstation. The difference in volume ratio (VR) and conformality index (CI) between GTV_PET and CT-based GTV (GTV_CT) was investigated. The image sets via automatic co-registrations of 4D CT-FDG PET were available for 12 patients with 13 GTV_CT values. The decision coefficient (R²) of tumor length difference at the threshold levels of SUV 2.5, SUV 20% and SUV 25% were 0.79, 0.65 and 0.54, respectively. The mean volume of GTV_CT was 29.41 ± 19.14 ml. The mean VR ranged from 0.30 to 1.48. The optimal VR of 0.98, close to 1, was at SUV 20% or SUV 2.5. The mean CI ranged from 0.28 to 0.58. The best CI was at SUV 20% (0.58) or SUV 2.5 (0.57). The auto-contouring function of the SUV threshold has the potential to assist in contouring the GTV. The SUV threshold setting of SUV 20% or SUV 2.5 achieves the optimal correlation of tumor length, VR, and CI using 4D-PET/CT images.     

Chronic exposure to fine particles and mortality: an extended follow-up of the Harvard Six Cities study from 1974 to 2009

Background: Epidemiologic studies have reported associations between fine particles (aerodynamic diameter ≤ 2.5 µm; PM_2.5) and mortality. However, concerns have been raised regarding the sensitivity of the results to model specifications, lower exposures, and averaging time.Objective: We addressed these issues using 11 additional years of follow-up of the Harvard Six Cities study, incorporating recent lower exposures.Methods: We replicated the previously applied Cox regression, and examined different time lags, the shape of the concentration–response relationship using penalized splines, and changes in the slope of the relation over time. We then conducted Poisson survival analysis with time-varying effects for smoking, sex, and education.Results: Since 2001, average PM_2.5 levels, for all six cities, were < 18 µg/m³. Each increase in PM_2.5 (10 µg/m³) was associated with an adjusted increased risk of all-cause mortality (PM_2.5 average on previous year) of 14% [95% confidence interval (CI): 7, 22], and with 26% (95% CI: 14, 40) and 37% (95% CI: 7, 75) increases in cardiovascular and lung-cancer mortality (PM_2.5 average of three previous years), respectively. The concentration–response relationship was linear down to PM_2.5 concentrations of 8 µg/m³. Mortality rate ratios for PM_2.5 fluctuated over time, but without clear trends despite a substantial drop in the sulfate fraction. Poisson models produced similar results.Conclusions: These results suggest that further public policy efforts that reduce fine particulate matter air pollution are likely to have continuing public health benefits.     

Dose reduction trial from 60 Gy in 10 fractions to 54 Gy in 9 fractions schedule in high-dose-rate interstitial brachytherapy for early oral tongue cancer

To compare the effects of 60 Gy/10 fractions (twice a day) with those of 54 Gy/9 fractions in high-dose-rate interstitial brachytherapy (HDR-ISBT) for early tongue cancer, we performed a matched-pair analysis of patients with early tongue cancer (T1-2N0M0), who were treated with 60 or 54 Gy of radiation between 1996 and 2004. Seventeen patients treated with 54 Gy and 34 matched-pair patients treated with 60 Gy were extracted and analyzed. Local recurrence occurred in two patients in the 54-Gy arm and five patients in the 60-Gy arm. The 2-year local control rates were 88% for both the 54-Gy arm and 60-Gy arm (not significant). The 2-year overall survival rates were 88% in the 60-Gy arm and 82% in the 54-Gy arm. Two-year actuarial complication-free rates were 91% in the 60-Gy arm and 83% in the 54-Gy arm (not significant), respectively. There was no significant association between the total dose and local control rate and late complications. The outcome of 54 Gy/ 9 fractions was similar to that of 60 Gy/ 10 fractions in patients with early tongue cancer.     

P.R4810K, a polymorphism of RNF213, the susceptibility gene for moyamoya disease, is associated with blood pressure

Background

Moyamoya disease—an idiopathic vascular disorder of intracranial arteries—is often accompanied by hypertension. RNF213 has been identified as a susceptibility gene for moyamoya disease. In the present study, the association of p.R4810K (G>A) with blood pressure (BP) was investigated in a Japanese population.

Methodology/principal findings

Three independent study populations, the Nyukawa (n = 984), Noshiro (n = 2,443) and Field (n = 881) studies, joined this study. BP, body weight and height were measured. Past and present symptoms and disease and medication histories were assessed by interview. Associations of p.R4810K (rs112735431, ss179362673) of RNF213 with BP were investigated. Two linkage disequilibrium blocks were constructed for moyamoya patients with p.R4810K (n = 140) and the general population (n = 384) using 39 single nucleotide polymorphisms (SNPs) spanning 390 kb around RNF213. A total of 60 carriers (3 for AA genotype and 57 for GA genotype) were found in these samples, and the minor allele frequencies were 1.4 % in the Nyukawa and Field studies and 0.2 % in the Noshiro study. Regression analyses adjusted for age, sex and body mass index based on an additive model demonstrated significant associations with systolic BP (mmHg/allele): β (standard error) was 8.2 (2.9) in the Nyukawa study (P = 4.7 × 10⁻³), 18.7 (5.4) in the Noshiro study (P = 4.6 × 10⁻⁴) and 8.9 (2.0) (P = 1.0 × 10⁻⁵) in the three populations. In contrast, diastolic BP showed significant associations only in the Noshiro study. Linkage disequilibrium blocks contained none of the BP-associated proxy SNPs reported by previous studies.

Conclusions/significance

Our study suggests that p.R4810K of RNF213 is associated strongly with systolic BP.

Electronic supplementary material

The online version of this article (doi:10.1007/s12199-012-0299-1) contains supplementary material, which is available to authorized users.     

Characteristics of human CD34+ cells exposed to ionizing radiation under cytokine-free conditions

To clarify the mechanisms underlying radiation-induced hematopoietic stem cell death, we investigated the effects of excessive ionizing radiation on the clonogenic potential of CD34⁺ cells obtained from human umbilical cord blood under cytokine-free conditions. The CD34⁺ cells were X-ray–irradiated (up to 2 Gy) and were cultured for 0–48 h under cytokine-free conditions. At various time-points, the CD34⁺ cells were investigated for survival, clonogenic potential and the generation of mitochondrial superoxide. At 12 h after X-ray irradiation, the number of viable cells had decreased to ∼70–80% compared with the 0-h non-irradiated control, whereas the clonogenic potential in the X-ray–irradiated cells had decreased to ∼50%–60% compared with the 0-h non-irradiated control. Furthermore, significant generation of mitochondrial superoxide was observed at 6 h, and reached a maximum value between 12 and 24 h after X-ray irradiation. However, no significant differences were observed between non-irradiated and X-ray–irradiated cells in terms of the generation of reactive oxygen species or in the intracellular mitochondrial contents. In addition, a cDNA microarray analysis showed that the majority of the altered genes in the CD34⁺ cells at 6 h after X-ray irradiation were apoptosis-related genes. These results suggest the possibility that the elimination of the clonogenic potentials of CD34⁺ cells involves the generation of mitochondrial superoxide induced by ionizing radiation.     

Seasonal Variation in TP53 R249S-Mutated Serum DNA with Aflatoxin Exposure and Hepatitis B Virus Infection

Background: Chronic hepatitis B virus (HBV) infection and dietary aflatoxin B₁ (AFB₁) exposure are etiological factors for hepatocellular carcinoma (HCC) in countries with hot, humid climates. HCC often harbors a TP53 (tumor protein p53) mutation at codon 249 (R249S). In chronic carriers, 1762^T/1764^A mutations in the HBV X gene are associated with increased HCC risk. Both mutations have been detected in circulating cell-free DNA (CFDNA) from asymptomatic HBV carriers.Objective: We evaluated seasonal variation in R249S and HBV in relation to AFB₁ exposure.Methods: R249S was quantitated by mass spectrometry in CFDNA in a cross-sectional survey of 473 asymptomatic subjects (237 HBV carriers and 236 noncarriers) recruited in three villages in the Gambia over a 10-month period. 1762^T/1764^A HBV mutations were detected by quantitative polymerase chain reaction. In addition, the HBV S gene was sequenced in 99 subjects positive for HBV surface antigen (HBsAg).Results: We observed a seasonal variation of serum R249S levels. Positivity for R249S and average concentration were significantly higher in HBsAg-positive subjects surveyed during April–July (61%; 5,690 ± 11,300 R249S copies/mL serum) than in those surveyed October–March [32% and 480 ± 1,030 copies/mL serum (odds ratio = 3.59; 95% confidence interval: 2.05, 6.30; p < 0.001)]. Positivity for HBV e antigen (HBeAg) (a marker of HBV replication) and viral DNA load also varied seasonally, with 15–30% of subjects surveyed between April and June HBeAg positive, compared with < 10% surveyed during other months. We detected 1762^T/1764^A mutations in 8% of carriers, half of whom were positive for R249S. We found HBV genotype E in 95 of 99 HBsAg-positive subjects.Conclusion: R249S is detectable in CFDNA of asymptomatic subjects. Evidence of temporal and quantitative variations suggests an interaction among AFB₁ exposure, HBV positivity, and replication on TP53 mutation formation or persistence.     

Impact of concurrent chemotherapy on definitive radiotherapy for women with FIGO IIIb cervical cancer

The purpose of this retrospective study is to investigate the impact of concurrent chemotherapy on definitive radiotherapy for the International Federation of Gynecology and Obstetrics (FIGO) IIIb cervical cancer. Between 2000 and 2009, 131 women with FIGO IIIb cervical cancer were treated by definitive radiotherapy (i.e. whole pelvic external beam radiotherapy for 40–60 Gy in 20–30 fractions with or without center shielding and concomitant high-dose rate intracavitary brachytherapy with 192-iridium remote after loading system for 6 Gy to point A of the Manchester method). The concurrent chemotherapy regimen was cisplatin (40 mg/m²/week). After a median follow-up period of 44.0 months (range 4.2–114.9 months) and 62.1 months for live patients, the five-year overall survival (OS), loco-regional control (LRC) and distant metastasis-free survival (DMFS) rates were 52.4, 80.1 and 59.9%, respectively. Univariate and multivariate analyses revealed that lack of concurrent chemotherapy was the most significant factor leading to poor prognosis for OS (HR = 2.53; 95% CI 1.44–4.47; P = 0.001) and DMFS (HR = 2.53; 95% CI 1.39–4.61; P = 0.002), but not for LRC (HR = 1.57; 95% CI 0.64–3.88; P = 0.322). The cumulative incidence rates of late rectal complications after definitive radiotherapy were not significantly different with or without concurrent chemotherapy (any grade at five years 23.9 vs 21.7%; P = 0.669). In conclusion, concurrent chemotherapy is valuable in definitive radiotherapy for Japanese women with FIGO IIIb cervical cancer.     

Exposure to ambient air fine particulate matter prevents VEGF-induced mobilization of endothelial progenitor cells from the bone marrow

Background: Exposure to ambient fine particulate matter air pollution (PM_2.5; < 2.5 µm in aerodynamic diameter) induces endothelial dysfunction and increases the risk for cardiovascular disease. Endothelial progenitor cells (EPCs) contribute to postnatal endothelial repair and regeneration. In humans and mice, EPC levels are decreased upon exposure to elevated levels of PM_2.5.Objective: We examined the mechanism by which PM_2.5 exposure suppresses circulating levels of EPCs.Methods: Mice were exposed to HEPA-filtered air or concentrated ambient fine particulate matter (CAP, 30–100 µg/m³) from downtown Louisville (Kentucky) air, and progenitor cells from peripheral blood or bone marrow were analyzed by flow cytometry or by culture ex vivo.Results: Exposure of the mice to CAP (6 hr/day) for 4–30 days progressively decreased circulating levels of EPCs positive for both Flk-1 and Sca-1 (Flk-1⁺/Sca-1⁺) without affecting stem cells positive for Sca-1 alone (Sca-1⁺). After 9 days of exposure, a 7-day exposure-free period led to complete recovery of the circulating levels of Flk-1⁺/Sca-1⁺ cells. CAP exposure decreased circulating levels of EPCs independent of apoptosis while simultaneously increasing Flk-1⁺/Sca-1⁺ cells in the bone marrow. We observed no change in tissue deposition of these cells. CAP exposure suppressed vascular endothelial growth factor (VEGF)-induced Akt and endothelial nitric oxide synthase (eNOS) phosphorylation in the aorta, and it prevented VEGF/AMD3100-induced mobilization of Flk-1⁺/Sca-1⁺ cells into the peripheral blood. Treatment with stem cell factor/AMD3100 led to a greater increase in circulating Flk-1⁺/Sca-1⁺ cells in CAP-exposed mice than in mice breathing filtered air.Conclusion: Exposure to PM_2.5 increases EPC levels in the bone marrow by preventing their mobilization to the peripheral blood via inhibition of signaling events triggered by VEGF-receptor stimulation that are upstream of c-kit activation. Suppression of EPC mobilization by PM_2.5 could induce deficits in vascular repair or regeneration.     

Effects of Combined Vitamin K2 and Vitamin D3 Supplementation on Na[18F]F PET/MRI in Patients with Carotid Artery Disease: The INTRICATE Rationale and Trial Design

INTRICATE is a prospective double-blind placebo-controlled feasibility study, assessing the influence of combined vitamin K2 and vitamin D3 supplementation on micro-calcification in carotid artery disease as imaged by hybrid Sodium [¹⁸F]Fluoride (Na[¹⁸F]F) positron emission tomography (PET)/ magnetic resonance imaging (MRI). Arterial calcification is an actively regulated process and results from the imbalance between calcification promoting and inhibiting factors. Considering the recent advancements in medical imaging, ultrasound (US), PET/MRI, and computed tomography (CT) can be used for the selection and stratification of patients with atherosclerosis. Fifty-two subjects with asymptomatic carotid artery disease on at least one side of the neck will be included in the study. At baseline, an Na[¹⁸F]F PET/MRI and CT examination will be performed. Afterwards, subjects will be randomized (1:1) to a vitamin K (400 µg MK-7/day) and vitamin D3 (80 µg/day) or to placebo. At the 3-month follow-up, subjects will undergo a second Na[¹⁸F]F PET/MRI and CT scan. The primary endpoint is the change in Na[¹⁸F]F PET/MRI (baseline vs. after 3 months) in the treatment group as compared to the placebo arm. Secondary endpoints are changes in plaque composition and in blood-biomarkers. The INTRICATE trial bears the potential to open novel avenues for future large scale randomized controlled trials to intervene in the plaque development and micro-calcification progression.     

Preliminary assessment of ecological exposure of adult residents in Fukushima Prefecture to radioactive cesium through ingestion and inhalation

Objective

This study aims to estimate the ecological exposure of adult residents of Fukushima Prefecture to ¹³⁴cesium (Cs) and ¹³⁷Cs through ingestion and inhalation between July 2 and July 8, 2011.

Methods

Fifty-five sets of meals with tap water, each representing one person’s daily intake, were purchased in local towns in Fukushima Prefecture. Locally produced cow’s milk (21 samples) and vegetables (43 samples) were also purchased. In parallel, air sampling was conducted at 12 different sites using a high-volume sampler. Nineteen sets of control meals were collected in Kyoto in July 2011. ¹³⁴Cs and ¹³⁷Cs levels in the samples were measured using a germanium detector.

Results

Radioactivity was detected in 36 of the 55 sample meals from Fukushima, compared with one of 19 controls from Kyoto. The median estimated dose level (μSv/year) was 3.0, ranging from not detectable to 83.1. None of the cow’s milk (21) or vegetable (49) samples showed levels of contamination above the current recommended limits (Bq/kg) of 200 for milk and 500 for vegetables. The total effective dose levels by inhalation were estimated to be <3 μSv/year at nine locations, but samples at three other locations close to the edge of the 20-km radius from the crippled nuclear power plant showed higher levels of contamination (μSv/year): 14.7 at Iitate, 76.9 at Namie, and 27.7 at Katsurao.

Conclusions

Levels of exposure to ¹³⁴Cs and ¹³⁷Cs in Fukushima by ingestion and inhalation are discernible, but generally within recommended limits.

Electronic supplementary material

The online version of this article (doi:10.1007/s12199-011-0251-9) contains supplementary material, which is available to authorized users.     

Strength estimation of a moving 125Iodine source during implantation in brachytherapy: application to linked sources

This study sought to demonstrate the feasibility of estimating the source strength during implantation in brachytherapy. The requirement for measuring the strengths of the linked sources was investigated. The utilized sources were ¹²⁵I with air kerma strengths of 8.38–8.63 U (μGy m² h^–1). Measurements were performed with a plastic scintillator (80 mm × 50 mm × 20 mm in thickness). For a source-to-source distance of 10.5 mm and at source speeds of up to 200 mm s^–1, a counting time of 10 ms and a detector-to-needle distance of 5 mm were found to be the appropriate measurement conditions. The combined standard uncertainty (CSU) with the coverage factor of 1 (k = 1) was ∼15% when using a grid to decrease the interference by the neighboring sources. Without the grid, the CSU (k = 1) was ∼5%, and an 8% overestimation due to the neighboring sources was found to potentially cause additional uncertainty. In order to improve the accuracy in estimating source strength, it is recommended that the measurment conditions should be optimized by considering the tradeoff between the overestimation due to the neighboring sources and the intensity of the measured value, which influences the random error.     

Association between frequency of drinking alcohol and chronic kidney disease in men

Objectives

Chronic kidney disease (CKD) is a major public health problem. Epidemiological studies of the relationship between alcohol intake and CKD are scarce in Japan. This cross-sectional study aims to investigate the relationship between frequency of drinking alcohol and CKD in Japanese men.

Methods

The subjects were 9,196 men (mean ± standard deviation age, 57.9 ± 5.1 years) who underwent a health check-up. CKD was defined as estimated glomerular filtration rate <60 mL/min/1.73 m². Frequency of alcohol drinking was obtained from questionnaire and divided into five categories: nondrinkers, once or twice a week, three or four times a week, five or six times a week, and everyday drinkers.

Results

Multivariable-adjusted [age, body mass index, hypertension, diabetes, hyper-low-density lipoprotein (LDL) cholesterolemia, smoking, and physical activity] odds ratios and 95% confidence intervals (CIs) were calculated using logistic regression analysis. Compared with the results for the nondrinkers, the multivariable-adjusted odds ratios of CKD were as follows: 0.76 (95% CI 0.60–0.95) for 1–2 drinks per week, 0.74 (95% CI 0.59–0.93) for 3–4 drinks per week, 0.79 (95% CI 0.64–0.97) for 5–6 drinks per week, and 0.60 (95% CI 0.51–0.71) for everyday drinkers. There was a significant inverse trend across increasing frequency of drinking alcohol (p = 0.001 for trend).

Conclusions

An inverse association was found between frequency of drinking alcohol and CKD in apparently healthy men.     

Polysaccharide isolated from Parmelia tinctorum ameliorates ionizing irradiation-induced damage in mice

In this study, WPT-A, a type of water-soluble homogeneous lichen polysaccharide, was isolated and purified from Parmelia tinctorum. We investigated whether WPT-A has radioprotective effects when administered before total-body irradiation (TBI). Mice were treated with WPT-A via intraperitoneal injection (i.p.) once per day for three consecutive days prior to 7, 7.5, 8.5, 10 or 10.5-Gy TBI. Our results indicated that the survival rate was enhanced at a range of levels of TBI. The calculated dose reduction factor (DRF) was 1.2. White blood cell (WBC) counts, spleen colony forming units (CFU-S) and bone marrow nucleated cell (BMNC) counts were used to investigate the radioprotective effects of WPT-A on the hematopoietic system. The treatment groups received WPT-A at 20, 50 and 80 mg/kg b.w. doses before 6.5-Gy TBI and showed significantly higher BMNC and WBC counts compared with the radiation-only group. The groups administered 50 and 80 mg/kg b.w. WPT-A showed a significant increase in CFU-S compared with the radiation-only group. We also carried out a single cell gel electrophoresis assay to explore the radioprotective effects of WPT-A on DNA damage. The results from single-cell gel electrophoresis of peripheral blood leukocytes showed that WPT-A attenuated radiation-induced DNA damage. These results indicate a potential use for WPT-A as a radioprotector.     

Comparison of dose-volume analysis between standard Manchester plan and magnetic resonance image-based plan of intracavitary brachytherapy for uterine cervical cancer

To investigate the feasibility of image-based intracavitary brachytherapy (IBICBT) for uterine cervical cancer, we evaluated the dose–volume histograms (DVHs) for the tumor and organs at risk (OARs) and compared results from the IBICBT plan and the standard Manchester system (Manchester plan) in eight patients as a simulation experiment. We performed magnetic resonance imaging (MRI) and computed tomography (CT) following MRI-adapted applicator insertion, then superimposed MR images on the planning CT images to describe the contours of high-risk clinical target volume (HR CTV) and OARs. The median volume of HR CTV was 29 cm³ (range, 21–61 cm³). Median D90 (HR CTV) and V100 (HR CTV) were 116.1% prescribed doses (PD) (90.0–150.8%) and 96.7% (84.2–100%), respectively, for the Manchester plan. In comparison, we confirmed that the median D90 (HR CTV) was 100% PD in the IBICBT plan for all patients. Mean D_2cc (bladder) was 101.8% PD for the Manchester plan and 83.2% PD for the IBICBT plan. Mean D_2cc (rectum) was 80.1% PD for the Manchester plan and 64.2% PD for the IBICBT plan. Mean D_2cc (sigmoid) was 75% PD for the Manchester plan and 57.5% PD for the IBICBT plan. One patient with a large tumor (HR CTV, 61 cm³) showed lower D90 (HR CTV) with the Manchester plan than with the IBICBT plan. The Manchester plan may represent overtreatment for small tumors but insufficient dose distribution for larger tumors. The IBICBT plan could reduce OAR dosage while maintaining adequate tumor coverage.Key words: Image-based intracavitary brachytherapy, MRI-adapted applicator, uterine cervical cancer, dose–volume histogram     

Increased paediatric hospitalizations for empyema in Australia after introduction of the 7-valent pneumococcal conjugate vaccine

Objective

To examine rates of paediatric hospitalization for empyema and pneumonia in Australia before and after the introduction of the seven-valent pneumococcal conjugate vaccine (PCV7).

Methods

Rates of paediatric hospitalization for empyema and pneumonia (bacterial, viral and all types) were calculated following the codes of the International Classification of Diseases, tenth revision (ICD-10) as a principal diagnosis. The expected number of hospitalizations after the PCV7 was introduced was estimated on the basis of the observed number of hospitalizations before the introduction of the PCV7. Incidence rate differences (IRDs) and incidence rate ratios (IRRs) were calculated. Hospitalization incidence in each study period was expressed as the number of hospitalizations per million (10⁶) person–years. The population of children aged 0–19 years in Australia from 1998 to 2004 and from 2005 to 2010, as reported by the Australian Bureau of Statistics, was used to calculate the number of person–years in each period.

Findings

In the 5 years following the introduction of the PCV7, hospitalizations for pneumonia were fewer than expected (15 304 fewer; 95% confidence interval, CI: 14 646–15 960; IRD: −552 per 10⁶ person–years; 95% CI: −576 to −529 per 10⁶ person–years; IRR: 0.78; 95% CI: 0.77–0.78). Hospitalizations for empyema, on the other hand, were more than expected (83 more; 95% CI: 37–128; IRD: 3 per 10⁶ person–years; 95% CI: 1–5 per 10⁶ person–years; IRR: 1.35; 95% CI: 1.14–1.59). Reductions in hospitalizations were observed for all ICD-10 pneumonia codes across all age groups. The increase in empyema hospitalizations was only significant among children aged 1 to 4 years.

Conclusion

The introduction of the PCV7 in Australia was associated with a substantial decrease in hospitalizations for childhood pneumonia and a small increase in hospitalizations for empyema.     

198Au grain implantation for early tongue cancer in patients of advanced age or poor performance status

Brachytherapy using ¹⁹⁸Au grains is minimally invasive and the only curative treatment for early tongue cancer in patients of advanced age or poor performance status available in our institution. From March 1993 to February 2008, ¹⁹⁸Au grains were used to treat a group of 96 Stage I–II tongue cancer patients who could not undergo surgery or brachytherapy using ¹⁹²Ir pins because of an advanced age (≥75 years) or poor performance status (≥2). The patients were followed for 3.9 ± 3.3 years, and the cause-specific survival and local control rates were determined. Survival analyses were performed using the Kaplan-Meier method, and univariate and multivariate analyses were performed using the Cox proportional hazard model. The results were compared with those for a group of 193 early tongue-cancer patients who underwent treatment using iridium pins. The 5-year cause-specific survival and local control rates of the ¹⁹⁸Au grains group were 71% and 68%, respectively, both of which were 16% lower than the corresponding rates for the ¹⁹²Ir pins group. Our study demonstrated that as the last curative treatment available, ¹⁹⁸Au grain implantation could be used to achieve moderate treatment results for early tongue cancer in patients of advanced age or poor performance status.     

Ambient air pollution and lipoprotein-associated phospholipase A₂ in survivors of myocardial infarction

Background: Increasing evidence suggests a proatherogenic role for lipoprotein-associated phospholipase A₂ (Lp-PLA2). A meta-analysis of published cohorts has shown that Lp-PLA2 is an independent predictor of coronary heart disease events and stroke.Objective: In this study, we investigated whether the association between air pollution and cardiovascular disease might be partly explained by increased Lp-PLA2 mass in response to exposure.Methods: A prospective longitudinal study of 200 patients who had had a myocardial infarction was performed in Augsburg, Germany. Up to six repeated clinical examinations were scheduled every 4–6 weeks between May 2003 and March 2004. Supplementary to the multicenter AIRGENE protocol, we assessed repeated plasma Lp-PLA2 concentrations. Air pollution data from a fixed monitoring site representing urban background concentrations were collected. We measured hourly means of particle mass [particulate matter (PM) < 10 µm (PM₁₀) and PM < 2.5 µm (PM_2.5) in aerodynamic diameter] and particle number concentrations (PNCs), as well as the gaseous air pollutants carbon monoxide (CO), sulfur dioxide (SO₂), ozone (O₃), nitric oxide (NO), and nitrogen dioxide (NO₂). Data were analyzed using mixed models with random patient effects.Results: Lp-PLA2 showed a positive association with PM₁₀, PM_2.5, and PNCs, as well as with CO, NO₂, NO, and SO₂ 4–5 days before blood withdrawal (lag 4–5). A positive association with O₃ was much more immediate (lag 0). However, inverse associations with some pollutants were evident at shorter time lags.Conclusion: These preliminary findings should be replicated in other study populations because they suggest that the accumulation of acute and subacute effects or the chronic exposure to ambient particulate and gaseous air pollution may result in the promotion of atherosclerosis, mediated, at least in part, by increased levels of Lp-PLA2.     

Pharmacokinetics of Sodium and Calcium Salts of (6S)-5-Methyltetrahydrofolic Acid Compared to Folic Acid and Indirect Comparison of the Two Salts

(6S)-5-Methyltetrahydrofolic acid ((6S)-5-Methyl-THF) salts and folic acid may differ in their abilities to raise plasma (6S)-5-Methyl-THF levels. We compared the area under the curve (AUC), C_max, and T_max of plasma (6S)-5-Methyl-THF after intakes of (6S)-5-Methyl-THF-Na salt (Arcofolin^®) and folic acid. Moreover, we compared the AUCs after intakes of (6S)-5-Methyl-THF-Na and the calcium salt, (6S)-5-Methyl-THF-Ca, that were tested against folic acid in two independent studies. The study was randomized, double blind, and cross over. Twenty-four adults (12 men and 12 women) received a single oral dose of 436 µg (6S)-5-Methyl-THF-Na and an equimolar dose of folic acid (400 µg) on two kinetic days with two weeks washout period in between. The plasma concentrations of (6S)-5-Methyl-THF were measured at 9 time points between 0 and 8 h. We found that the AUC_{0–8 h} of plasma (6S)-5-Methyl-THF (mean (SD) = 126.0 (33.6) vs. 56.0 (25.3) nmol/L*h) and C_max (36.8 (10.8) vs. 11.1 (4.1) nmol/L) were higher after administration of (6S)-5-Methyl-THF-Na than after the administration of folic acid (p < 0.001 for both). These differences were present in men and women. Only administration of folic acid resulted in a transient increase in plasma unmetabolized folic acid (2.5 (2.0) nmol/L after 0.5 h and 4.7 (2.9) nmol/L after 1 h). Intake of (6S)-5-Methyl-THF-Na was safe. The ratios of the AUC_{0–8 h} for (6S)-5-Methyl-THF-Na and (6S)-5-Methyl-THF-Ca to the corresponding folic acid reference group and the delta of these AUC_{0–8 h} did not differ between the studies. In conclusion, a single oral dose of (6S)-5-Methyl-THF-Na caused higher AUC_{0–8 h} and C_max of plasma (6S)-5-Methyl-THF compared to folic acid. The Na- and Ca- salts of (6S)-5-Methyl-THF are not likely to differ in their pharmacokinetics. Further studies may investigate whether supplementation of the compounds for a longer time will lead to differences in circulating or intracellular/tissue folate concentrations.