Technical note: Investigating the suitability of existing facilities for a new Lu-177 prostate-specific membrane antigen therapy program.

BACKGROUND: 177 Lu prostate-specific membrane antigen (PSMA) therapy prolongs survival for some prostate cancer patients. To adopt this technique, institutions may need to evaluate the suitability of existing infrastructure. PURPOSE: Develop a methodology to determine whether existing facilities can accommodate a 177 Lu-PSMA therapy program. METHODS: Room suitability is defined by both the ability to accommodate 177 Lu-PSMA therapy workflow and to provide appropriate radiation shielding. Two methods of shielding calculation were performed: (1) National Council on Radiation Protection and Measurements report 151 (NCRP-151), with workload defined in terms of the activity of 177 Lu administered, and (2) using the RadPro shielding calculator. This methodology was applied to 131 I therapy, PET-CT uptake, PET-SPECT injection, and orthovoltage therapy rooms. RESULTS: 131 I therapy rooms were found to meet both shielding and workflow requirements. The shielding was found to be adequate for orthovoltage and PET-SPECT facilities, neglecting patient transit between external washrooms. The workflow was the limiting factor for these rooms due to the requirement of dedicated washrooms that shield the patient and contain possible contamination. The PET-CT facility did not meet either criteria. The NCRP-151 method generally predicted a higher dose rate on the other side of shielding than did the RadPro calculator. The dose rate on the other side of concrete shielding as predicted by the NCRP-151 method increased relative to the dose rate predicted by the RadPro calculator as shielding thickness increased. For lead shielding, the dose rate predicted by the NCRP-151 method decreased relative to the result predicted by the RadPro calculator with increasing material thickness. CONCLUSIONS: 131 I therapy, PET-CT uptake, PET-SPECT injection, and orthovoltage therapy rooms were considered. The 131 I treatment rooms were the best candidate for 177 Lu-PSMA therapy, due to their shielding and capability to accommodate the necessary workflow.

Specific class of intrapartum antibiotics relates to maturation of the infant gut microbiota: a prospective cohort study.

OBJECTIVE: To evaluate the potential impact of intrapartum antibiotics, and their specific classes, on the infant gut microbiota in the first year of life. DESIGN: Prospective study of infants in the New Hampshire Birth Cohort Study (NHBCS). SETTINGS: Rural New Hampshire, USA. POPULATION OR SAMPLE: Two hundred and sixty-six full-term infants from the NHBCS. METHODS: Intrapartum antibiotic use during labour and delivery was abstracted from medical records. Faecal samples collected at 6 weeks and 1 year of age were characterised by 16S rRNA sequencing, and metagenomics analysis in a subset of samples. EXPOSURES: Maternal exposure to antibiotics during labour and delivery. MAIN OUTCOME MEASURE: Taxonomic and functional profiles of faecal samples. RESULTS: Infant exposure to intrapartum antibiotics, particularly to two or more antibiotic classes, was independently associated with lower microbial diversity scores as well as a unique bacterial community at 6 weeks (GUnifrac, P = 0.02). At 1 year, infants in the penicillin-only group had significantly lower α diversity scores than infants not exposed to intrapartum antibiotics. Within the first year of life, intrapartum exposure to penicillins was related to a significantly lower increase in several taxa including Bacteroides, use of cephalosporins was associated with a significantly lower rise over time in Bifidobacterium and infants in the multi-class group experienced a significantly higher increase in Veillonella dispar. CONCLUSIONS: Our findings suggest that intrapartum antibiotics alter the developmental trajectory of the infant gut microbiome, and specific antibiotic types may impact community composition, diversity and keystone immune training taxa. TWEETABLE ABSTRACT: Class of intrapartum antibiotics administered during delivery relates to maturation of infant gut microbiota.

The Impact of Rimed Ice Hydrometeors on Global and Regional Climate.

Rimed hydrometeors (graupel or hail) are added to a stratiform cloud scheme for global models and tested in a variety of configurations. Off-line tests compare well to other cloud microphysics schemes with rimed ice used in mesoscale models. Tests in single column and climate mode show expected production of small amounts of rimed ice in the middle troposphere and at high latitudes. The overall climate impacts of rimed ice (hail or graupel) at 100-km horizontal grid spacing are small. There are some changes to partitioning between cloud ice and snow that affect upper troposphere water budgets and clouds. High-resolution simulations are conducted with a global but regionally refined grid at 14 km over the Contiguous United States. High-resolution simulations show local production of graupel with realistic size and number concentrations. The maximum graupel frequency at high resolution is over Western U.S. mountain ranges. Differences in total precipitation with the addition of rimed ice in 8-year simulations are statistically significant only for orographic precipitation over the Cascade and Rocky mountains, reducing model biases when rimed ice is included. Rimed ice slightly improves summer precipitation intensity relative to observations. Thus, while the global climate impact of rimed ice in stratiform clouds may be negligible, there are potentially important and systematic regional effects, particularly for orographic precipitation. Rimed ice in cumulus clouds is not yet treated but is an important next step.

Merlin modulates process outgrowth and synaptogenesis in the cerebellum.

Neurofibromatosis type 2 (NF2) patients are prone to develop glial-derived tumors in the peripheral and central nervous system (CNS). The Nf2 gene product -Merlin is not only expressed in glia, but also in neurons of the CNS, where its function still remains elusive. Here, we show that cerebellar Purkinje cells (PCs) of isoform-specific Merlin-deficient mice were innervated by smaller vGluT2-positive clusters at presynaptic terminals than those of wild-type mice. This was paralleled by a reduction in frequency and amplitude of miniature excitatory postsynaptic currents (mEPSC). On the contrary, in conditional transgenic mice in which Merlin expression was specifically ablated in PCs (L7Cre;Nf2fl/fl), we found enlarged vGluT2-positive clusters in their presynaptic buttons together with increased amplitudes of miniature postsynaptic currents. The presynaptic terminals of these PCs innervating neurons of the deep cerebellar nuclei were also enlarged. When exploring mice with Merlin-deficient granule cells (GCs) (Math1Cre;Nf2fl/fl), we found cerebellar extracts to contain higher amounts of vGluT1 present in parallel fiber terminals. In parallel, mEPSC frequency was increased in Math1Cre;Nf2fl/fl mice. On the contrary, VGluT2 clusters in cerebellar glomeruli composed of NF2-deficient presynaptic Mossy fiber terminals and NF2-deficient postsynaptic GC were reduced in size as shown for isoform-specific knockout mice. These changes in Math1Cre;Nf2fl/fl-deficient mice were paralleled by an increased activation of Rac1-Cofilin signaling which is known to impact on cytoskeletal reorganization and synapse formation. Consistent with the observed synaptic alterations in these transgenic mice, we observed altered ultrasonic vocalization, which is known to rely on proper cerebellar function. No gross morphological changes or motor coordination deficits were observed in any of these transgenic mice. We therefore conclude that Merlin does not regulate overall cerebellar development, but impacts on pre- and post-synaptic terminal organization.

Beyond neurovascular coupling, role of astrocytes in the regulation of vascular tone.

The brain possesses two intricate mechanisms that fulfill its continuous metabolic needs: cerebral autoregulation, which ensures constant cerebral blood flow over a wide range of arterial pressures and functional hyperemia, which ensures rapid delivery of oxygen and glucose to active neurons. Over the past decade, a number of important studies have identified astrocytes as key intermediaries in neurovascular coupling (NVC), the mechanism by which active neurons signal blood vessels to change their diameter. Activity-dependent increases in astrocytic Ca(2+) activity are thought to contribute to the release of vasoactive substances that facilitate arteriole vasodilation. A number of vasoactive signals have been identified and their role on vessel caliber assessed both in vitro and in vivo. In this review, we discuss mechanisms implicating astrocytes in NVC-mediated vascular responses, limitations encountered as a result of the challenges in maintaining all the constituents of the neurovascular unit intact and deliberate current controversial findings disputing a main role for astrocytes in NVC. Finally, we briefly discuss the potential role of pericytes and microglia in NVC-mediated processes.

Optical projection tomography permits efficient assessment of infarct volume in the murine heart postmyocardial infarction.

The extent of infarct injury is a key determinant of structural and functional remodeling following myocardial infarction (MI). Infarct volume in experimental models of MI can be determined accurately by in vivo magnetic resonance imaging (MRI), but this is costly and not widely available. Experimental studies therefore commonly assess injury by histological analysis of sections sampled from the infarcted heart, an approach that is labor intensive, can be subjective, and does not fully assess the extent of injury. The present study aimed to assess the suitability of optical projection tomography (OPT) for identification of injured myocardium and for accurate and efficient assessment of infarct volume. Intact, perfusion-fixed, optically cleared hearts, collected from mice 7 days after induction of MI by coronary artery occlusion, were scanned by a tomograph for autofluorescence emission after UV excitation, generating >400 transaxial sections for reconstruction. Differential autofluorescence permitted discrimination between viable and injured myocardium and highlighted the heterogeneity within the infarct zone. Two-dimensional infarct areas derived from OPT imaging and Masson's trichrome staining of slices from the same heart were highly correlated (r(2) = 0.99, P < 0.0001). Infarct volume derived from reconstructed OPT sections correlated with volume derived from in vivo late gadolinium enhancement MRI (r(2) = 0.7608, P < 0.005). Tissue processing for OPT did not compromise subsequent immunohistochemical detection of endothelial cell and inflammatory cell markers. OPT is thus a nondestructive, efficient, and accurate approach for routine in vitro assessment of murine myocardial infarct volume.

Status Report--Retracing the history of the early development of national chronic disease surveillance in Canada and the major role of the Laboratory Centre for Disease Control (LCDC) from 1972 to 2000.

TITRE: Rapport d'étape - Historique des débuts de la surveillance nationale des maladies chroniques au Canada et rôle majeur du Laboratoire de lutte contre la maladie (LLCM) de 1972 à 2000. INTRODUCTION: La surveillance de la santé consiste en l'utilisation systématique et continue de données sur la santé recueillies régulièrement en vue d'orienter les mesures de santé publique en temps opportun. Ce document décrit la création et l'essor des systèmes nationaux de surveillance au Canada et les répercussions de ces systèmes sur la prévention des maladies chroniques et des blessures. En 2008, les auteurs ont commencé à retracer l'historique des débuts de la surveillance nationale des maladies chroniques au Canada, en commençant à 1960, et ils ont poursuivi leur examen jusqu'en 2000. Une publication de 1967 a retracé l'historique de la création du Laboratoire d'hygiène de 1921 à 1967. Notre étude fait suite à cette publication et décrit l'historique de l'établissement de la surveillance nationale des maladies chroniques au Canada, à la fois avant et après la création du Laboratoire de lutte contre la maladie (LCDC).

Glycemic index, glycemic load and cancer risk.

BACKGROUND: Dietary glycemic index (GI) and glycemic load (GL) have been related to the risk of selected cancers, but the issue remains open. PATIENTS AND METHODS: Mailed questionnaires were completed between 1994 and 1997 in eight Canadian provinces for incident, histologically confirmed cases of the stomach (n=1182), colon (n=1727), rectum (n=1447), liver (n=309), pancreas (n=628), lung (n=3341), breast (n=2362), ovary (n=442), prostate (n=1799), testis (n=686), kidney (n=1345), bladder (n=1029), brain (n=1009), non-Hodgkin's lymphomas (NHL, n=1666), leukemias (n=1069), multiple myelomas (n=343), and 5039 population controls. Dietary information on eating habits 2 years before participants' enrollment in the study was obtained using a validated food frequency questionnaire (FFQ). Odds ratios (ORs) and 95% confidence intervals (CI) were derived by unconditional logistic regression including recognized confounding factors. RESULTS: Dietary GI was positively associated with the risk of prostate cancer (OR, 1.26 for the highest versus the lowest quartile). A higher dietary GL significantly increased the risk of colorectal (OR, 1.28), rectal (OR, 1.44) and pancreatic (OR, 1.41) cancers. No other significant associations were found. CONCLUSIONS: Our findings suggest that a diet high in GI and GL is associated with increased risk of selected cancers.

Serial analysis of the gut and respiratory microbiome in cystic fibrosis in infancy: interaction between intestinal and respiratory tracts and impact of nutritional exposures.

UNLABELLED: Pulmonary damage caused by chronic colonization of the cystic fibrosis (CF) lung by microbial communities is the proximal cause of respiratory failure. While there has been an effort to document the microbiome of the CF lung in pediatric and adult patients, little is known regarding the developing microflora in infants. We examined the respiratory and intestinal microbiota development in infants with CF from birth to 21 months. Distinct genera dominated in the gut compared to those in the respiratory tract, yet some bacteria overlapped, demonstrating a core microbiota dominated by Veillonella and Streptococcus. Bacterial diversity increased significantly over time, with evidence of more rapidly acquired diversity in the respiratory tract. There was a high degree of concordance between the bacteria that were increasing or decreasing over time in both compartments; in particular, a significant proportion (14/16 genera) increasing in the gut were also increasing in the respiratory tract. For 7 genera, gut colonization presages their appearance in the respiratory tract. Clustering analysis of respiratory samples indicated profiles of bacteria associated with breast-feeding, and for gut samples, introduction of solid foods even after adjustment for the time at which the sample was collected. Furthermore, changes in diet also result in altered respiratory microflora, suggesting a link between nutrition and development of microbial communities in the respiratory tract. Our findings suggest that nutritional factors and gut colonization patterns are determinants of the microbial development of respiratory tract microbiota in infants with CF and present opportunities for early intervention in CF with altered dietary or probiotic strategies. IMPORTANCE: While efforts have been focused on assessing the microbiome of pediatric and adult cystic fibrosis (CF) patients to understand how chronic colonization by these microbes contributes to pulmonary damage, little is known regarding the earliest development of respiratory and gut microflora in infants with CF. Our findings suggest that colonization of the respiratory tract by microbes is presaged by colonization of the gut and demonstrated a role of nutrition in development of the respiratory microflora. Thus, targeted dietary or probiotic strategies may be an effective means to change the course of the colonization of the CF lung and thereby improve patient outcomes.

Prevalence of streptococci and increased polymicrobial diversity associated with cystic fibrosis patient stability.

Diverse microbial communities chronically colonize the lungs of cystic fibrosis patients. Pyrosequencing of amplicons for hypervariable regions in the 16S rRNA gene generated taxonomic profiles of bacterial communities for sputum genomic DNA samples from 22 patients during a state of clinical stability (outpatients) and 13 patients during acute exacerbation (inpatients). We employed quantitative PCR (qPCR) to confirm the detection of Pseudomonas aeruginosa and Streptococcus by the pyrosequencing data and human oral microbe identification microarray (HOMIM) analysis to determine the species of the streptococci identified by pyrosequencing. We show that outpatient sputum samples have significantly higher bacterial diversity than inpatients, but maintenance treatment with tobramycin did not impact overall diversity. Contrary to the current dogma in the field that Pseudomonas aeruginosa is the dominant organism in the majority of cystic fibrosis patients, Pseudomonas constituted the predominant genera in only half the patient samples analyzed and reported here. The increased fractional representation of Streptococcus in the outpatient cohort relative to the inpatient cohort was the strongest predictor of clinically stable lung disease. The most prevalent streptococci included species typically associated with the oral cavity (Streptococcus salivarius and Streptococcus parasanguis) and the Streptococcus milleri group species. These species of Streptococcus may play an important role in increasing the diversity of the cystic fibrosis lung environment and promoting patient stability.

Acinetobacter, Aeromonas and Trichococcus populations dominate the microbial community within urban sewer infrastructure.

We evaluated the population structure and temporal dynamics of the dominant community members within sewage influent from two wastewater treatment plants (WWTPs) in Milwaukee, WI. We generated > 1.1 M bacterial pyrotag sequences from the V6 hypervariable region of 16S rRNA genes from 38 influent samples and two samples taken upstream in the sanitary sewer system. Only a small fraction of pyrotags from influent samples (∼ 15%) matched sequences from human faecal samples. The faecal components of the sewage samples included enriched pyrotag populations from Lactococcus and Enterobacteriaceae relative to their fractional representation in human faecal samples. In contrast to the large number of distinct pyrotags that represent faecal bacteria such as Lachnospiraceae and Bacteroides, only one or two unique V6 sequences represented Acinetobacter, Aeromonas and Trichococcus, which collectively account for nearly 35% of the total sewage community. Two dominant Acinetobacter V6 pyrotags (designated Acineto tag 1 and Acineto tag 2) fluctuated inversely with a seasonal pattern over a 3-year period, suggesting two distinct Acinetobacter populations respond differently to ecological forcings in the system. A single nucleotide change in the V6 pyrotags accounted for the difference in these populations and corresponded to two phylogenetically distinct clades based on full-length sequences. Analysis of wavelet functions, derived from a mathematical model of temporal fluctuations, demonstrated that other abundant sewer associated populations including Trichococcus and Aeromonas had temporal patterns similar to either Acineto tag 1 or Acineto tag 2. Populations with related temporal fluctuations were found to significantly correlate with the same WWTP variables (5-day BOD, flow, ammonia, total phosphorous and suspended solids). These findings illustrate that small differences in V6 sequences can represent phylogenetically and ecologically distinct taxa. This work provides insight into microbial community composition and dynamics within the defined environment of urban sewer infrastructure.

Dietary cholesterol intake and cancer.

BACKGROUND: This study assesses the association between dietary cholesterol intake and the risk of various cancers. PATIENTS AND METHODS: Mailed questionnaires were completed between 1994 and 1997 in eight Canadian provinces by 1182 incident histologically confirmed cases of the stomach, 1727 of the colon, 1447 of the rectum, 628 of the pancreas, 3341 of the lung, 2362 of the breast, 442 of the ovary, 1799 of the prostate, 686 of the testis, 1345 of the kidney, 1029 of the bladder, 1009 of the brain, 1666 non-Hodgkin's lymphomas (NHL), 1069 leukemia and 5039 population controls. Information on dietary habits and nutrition intake were obtained using a food frequency questionnaire, which provided data on eating habits 2 years before the study. Odds ratios (ORs) were derived by unconditional logistic regression to adjust for total energy intake and other potential confounding factors. RESULTS: Dietary cholesterol was positively associated with the risk of cancers of the stomach, colon, rectum, pancreas, lung, breast (mainly postmenopausal), kidney, bladder and NHL: the ORs for the highest versus the lowest quartile ranged from 1.4 to 1.7. In contrast, cholesterol intake was inversely associated with prostate cancer. CONCLUSIONS: Our findings add to the evidence that high cholesterol intake is linked to increased risk of various cancers. A diet low in cholesterol may play a role in the prevention of several cancers.

Dietary sodium intake among Canadian adults with and without hypertension.

INTRODUCTION: Almost 30% of hypertension among Canadians may be attributed to excess dietary sodium. METHODS: We examined the average sodium intake of Canadians aged 30 years and over, with and without hypertension, by age, sex and diabetes status using 24-hour recall data from the 2004 Canadian Community Health Survey, Cycle 2.2, Nutrition. We compared absolute (crude) average sodium intake levels of those with and without hypertension to the 2009 Canadian Hypertension Education Program (CHEP) guidelines and adjusted average sodium intake between those with and without hypertension. RESULTS: Both those with and without diagnosed hypertension display average sodium intakes well above the 1500 mg/day recommended by the 2009 CHEP guidelines (2950 mg/day and 3175 mg/day, respectively). After confounding adjustment, those with hypertension have significantly higher average sodium intake (p = .0124). Stratified subgroup analyses found the average sodium intake among those with hypertension was higher for men between 30 and 49 years old (p = .0265), women between 50 and 69 years old (p = .0083) and those without diabetes (p = .0071) when compared to their counterparts without hypertension. CONCLUSION: Better approaches are needed to reduce sodium intake in hypertension patients, as well as the general population.

Evaluation of multiplex ligation-dependent probe amplification as a method for the detection of copy number abnormalities in B-cell precursor acute lymphoblastic leukemia.

Recent genomic studies have shown that copy number abnormalities (CNA) of genes involved in lymphoid differentiation and cell cycle control are common in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). We have evaluated Multiplex Ligation-dependent Probe Amplification (MLPA) on 43 BCP-ALL patients for the detection of the most common deletions among these genes and compared the results to those obtained by fluorescence in situ hybridization (FISH) and genomic quantitative PCR (qPCR). There was good correlation between methods for CDKN2A/B, IKZF1, and PAX5 deletions in the majority of cases and MLPA confirmed the presence of deletions within the PAR1 region in two of three cases identified by FISH. Small intragenic aberrations detected by MLPA, which were below the resolution of FISH for CDKN2A/B (n = 7), IKZF1 (n = 3), and PAX5 (n = 3) were confirmed by qPCR. MLPA and qPCR were unable to detect populations present at a low level (<20%) by FISH. In addition, although MLPA identified the presence of a deletion, it was unable to discern the presence of mixed cell populations which had been identified by FISH: CDKN2A/B (n = 3), IKZF1 (n = 1), PAX5 (n = 2), and PAR1 deletion (n = 1). Nevertheless, this study has demonstrated that MLPA is a robust technique for the reliable detection of CNA involving multiple targets in a single test and thus is ideal for rapid high throughput testing of large cohorts with a view to establishing incidence and prognostic significance.

Trends in diabetes treatment in Canadians, 1994-2004.

OBJECTIVE: To examine trends in the treatment of diabetes using the biannual interviews of the longitudinal National Population Health Survey (NPHS), 1994-2004 as they relate to changes in Clinical Practice Guidelines (CPGs). METHODS: A sample of 17 276 Canadians 18 years and older was selected for repeated interviews at two-year intervals from 1994 to 2004 for the NPHS. The population used for this study includes all respondents aged 40 to 79 for any of the cycles. RESULTS: CPGs issued by the Canadian Diabetes Association in 1998 and 2004 recommend a stepwise introduction of lifestyle changes, to be followed by single then multiple oral antidiabetic agents (OA), and finally insulin until adequate control is achieved. While the use of OA increased, only a small proportion indicated diet or physical exercise as part of their treatment; those with no drug treatment reported less diet modification and physical exercise. Antihypertensives and statin use in Canadians with diabetes increased to double that of Canadians overall, but remained underutilized. CONCLUSION: This study provides an update on the treatment of diabetes in Canada between 1994 and 2004. While some changes in diabetes treatment were compatible with CPGs, there is room for improvement, especially in lifestyle modifications.

Use of paediatric versus adult oncology treatment centres by adolescents 15-19 years old: the Canadian Childhood Cancer Surveillance and Control Program.

The aim of this study was to evaluate the treatment patterns of adolescents with cancer in Canada to ensure this population is receiving the most appropriate care. The Treatment and Outcome Surveillance (TOS) system was compared with the Canadian Cancer Registry (CCR) to estimate the proportion of adolescents (15-19 years) treated in Canadian paediatric oncology centres from 1995 to 2000 inclusive. Using TOS, the demographic, disease, and clinical characteristics of adolescents treated in paediatric versus adult centres in the Prairies were compared and differences were tested statistically. Approximately 30% of Canadian adolescents with cancer were treated in a paediatric centre. Adolescents treated in an adult centre were older at diagnosis and more likely to have carcinoma or germ cell tumours. The time between symptom onset and first treatment was longer for these adolescents, primarily due to the time between first health-care contact and assessment by a treating oncologist or surgeon. They were less likely to be enrolled in a clinical trial. These results suggest that care for adolescents with cancer in Canada is less satisfactory than for younger children, and can be improved.

Three retrotransposon families in the genome of Giardia lamblia: two telomeric, one dead.

Transposable elements inhabiting eukaryotic genomes are generally regarded either as selfish DNA, which is selectively neutral to the host organism, or as parasitic DNA, deleterious to the host. Thus far, the only agreed-upon example of beneficial eukaryotic transposons is provided by Drosophila telomere-associated retrotransposons, which transpose directly to the chromosome ends and thereby protect them from degradation. This article reports the transposon content of the genome of the protozoan Giardia lamblia, one of the earliest-branching eukaryotes. A total of three non-long terminal repeat retrotransposon families have been identified, two of which are located at the ends of chromosomes, and the third one contains exclusively dead copies with multiple internal deletions, nucleotide substitutions, and frame shifts. No other reverse transcriptase- or transposase-related sequences were found. Thus, the entire genome of this protozoan, which is not known to reproduce sexually, contains only retrotransposons that are either confined to telomeric regions and possibly beneficial, or inactivated and completely nonfunctional.