Bioaugmentation of pilot-scale slow sand filters can achieve compliant levels for the micropollutant metaldehyde in a real water matrix.

Metaldehyde is a polar, mobile, low molecular weight pesticide that is challenging to remove from drinking water with current adsorption-based micropollutant treatment technologies. Alternative strategies to remove this and compounds with similar properties are necessary to ensure an adequate supply of safe and regulation-compliant drinking water. Biological removal of metaldehyde below the 0.1 µg•L-1 regulatory concentration was attained in pilot-scale slow sand filters (SSFs) subject to bioaugmentation with metaldehyde-degrading bacteria. To achieve this, a library of degraders was first screened in bench-scale assays for removal at micropollutant concentrations in progressively more challenging conditions, including a mixed microbial community with multiple carbon sources. The best performing strains, A. calcoaceticus E1 and Sphingobium CMET-H, showed removal rates of 0.0012 µg•h-1•107 cells-1 and 0.019 µg•h-1•107 cells-1 at this scale. These candidates were then used as inocula for bioaugmentation of pilot-scale SSFs. Here, removal of metaldehyde by A. calcoaceticus E1, was insufficient to achieve compliant water regardless testing increasing cell concentrations. Quantification of metaldehyde-degrading genes indicated that aggregation and inadequate distribution of the inoculum in the filters were the likely causes of this outcome. Conversely, bioaugmentation with Sphingobium CMET-H enabled sufficient metaldehyde removal to achieve compliance, with undetectable levels in treated water for at least 14 d (volumetric removal: 0.57 µg•L-1•h-1). Bioaugmentation did not affect the background SSF microbial community, and filter function was maintained throughout the trial. Here it has been shown for the first time that bioaugmentation is an efficient strategy to remove the adsorption-resistant pesticide metaldehyde from a real water matrix in upscaled systems. Swift contaminant removal after inoculum addition and persistent activity are two remarkable attributes of this approach that would allow it to effectively manage peaks in metaldehyde concentrations (due to precipitation or increased application) in incoming raw water by matching them with high enough degrading populations. This study provides an example of how stepwise screening of a diverse collection of degraders can lead to successful bioaugmentation and can be used as a template for other problematic adsorption-resistant compounds in drinking water purification.

Decrease in scale invariance of activity fluctuations with aging and in patients with suprasellar tumors.

Motor activity in healthy young humans displays intrinsic fluctuations that are scale-invariant over a wide range of time scales (from minutes to hours). Human postmortem and animal lesion studies showed that the intact function of the suprachiasmatic nucleus (SCN) is required to maintain such scale-invariant patterns. We therefore hypothesized that scale invariance is degraded in patients treated for suprasellar tumors that compress the SCN. To test the hypothesis, we investigated 68 patients with nonfunctioning pituitary macroadenoma and 22 patients with craniopharyngioma, as well as 72 age-matched healthy controls (age range 21.0-70.6 years). Spontaneous wrist locomotor activity was measured for 7 days with actigraphy, and detrended fluctuation analysis was applied to assess correlations over a range of time scales from minutes to 24 h. For all the subjects, complex scale-invariant correlations were only present for time scales smaller than 1.5 h, and became more random at time scales 1.5-10 h. Patients with suprasellar tumors showed a larger decrease in correlations at 1.5-10 h as compared to healthy controls. Within healthy subject, gender and age >33 year were associated with attenuated scale invariance. Conversely, activity patterns at time scales between 10 and 24 h were significantly more regular than all other time scales, and this was mostly associated with age. In conclusion, scale invariance is degraded in healthy subjects at the ages of >33 year as characterized by attenuation of correlations at time scales 1.5-10 h. In addition, scale invariance was more degraded in patients with suprasellar tumors as compared to healthy subjects.

Treatment patterns and clinical outcomes in patients with renal cell carcinoma in the UK: insights from the RECCORD registry.

BACKGROUND: The aim of the RECCORD registry was to gather real-world UK data on the use of targeted therapies in renal cell carcinoma (RCC) and assess clinical outcomes. Here, demographic and outcome data are presented with the treatment patterns and demographic profile of patients on the registry. PATIENTS AND METHODS: Patients were retrospectively identified at seven UK hospitals with large cancer centres in England (5), Scotland (1) and Wales (1). Anonymised data were collected through an online registry covering demographics, treatments and outcomes. Five hundred and fourteen UK adult patients with metastatic RCC were included in the study for analysis. Patients were included if they were treated for metastatic RCC at one of the seven centres, and started systemic anti-cancer treatment from March 2009 to November 2012 inclusive. In addition to demographic factors, the principal outcome measures were overall survival (OS), time to disease progression and toxicity. RESULTS: The majority of first-line treatment was with sunitinib; first-line use of pazopanib increased as the study progressed. 15.8% of patients received second-line treatment, half of whom were prescribed everolimus. Median OS (from initiation of first-line treatment) was 23.9 months (95% confidence interval [CI] 18.6-29.1 months), similar to that reported for clinical trials of targeted RCC therapies [Ljungberg B, Campbell SC, Choi HY et al. The epidemiology of renal cell carcinoma. Eur Urol 2011; 60: 615-621; Abe H, Kamai T. Recent advances in the treatment of metastatic renal cell carcinoma. Int J Urol 2013; 20: 944-955; Motzer RJ, Hutson TE, Tomczak P et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009; 27: 3584-3590]. OS was significantly longer for those who received second-line treatment after disease progression (33.0 months; 95% CI 30.8-35.2 months) than those who did not (20.9 months; 95% CI 16.4-25.3 months; P = 0.008). CONCLUSIONS: RECCORD is a large 'real-world' database assessing metastatic RCC treatment patterns and outcomes. Treatment patterns changed over time as targeted therapies were approved and became widely available; survival data in RECCORD are consistent with those reported for systemic treatments in clinical trials. Kaplan-Meier analysis of results demonstrated that receiving second-line therapy was a major prognostic factor for longer OS.

Phase II trial of docetaxel, cisplatin and 5FU chemotherapy in locally advanced and metastatic penis cancer (CRUK/09/001).

BACKGROUND: Penis cancer is rare and clinical trial evidence on which to base treatment decisions is limited. Case reports suggest that the combination of docetaxel, cisplatin and 5-flurouracil (TPF) is highly active in this disease. METHODS: Twenty-nine patients with locally advanced or metastatic squamous carcinoma of the penis were recruited into a single-arm phase II trial from nine UK centres. Up to three cycles of chemotherapy were received (docetaxel 75 mg m(-2) day 1, cisplatin 60 mg m(-2) day 1, 5-flurouracil 750 mg m(-2) per day days 1-5, repeated every 3 weeks). Primary outcome was objective response (assessed by RECIST). Fourteen or more responses in 26 evaluable patients were required to confirm a response rate of 60% or higher (Fleming-A'Hern design), warranting further evaluation. Secondary endpoints included toxicity and survival. RESULTS: 10/26 evaluable patients (38.5%, 95% CI: 20.2-59.4) achieved an objective response. Two patients with locally advanced disease achieved radiological complete remission. 65.5% of patients experienced at least one grade 3/4 adverse event. CONCLUSION: Docetaxel, cisplatin and 5FU did not reach the pre-determined threshold for further research and caused significant toxicity. Our results do not support the routine use of TPF. The observed complete responses support further investigation of combination chemotherapy in the neoadjuvant setting.

A prospective study of chemotherapy-induced febrile neutropenia in the South West London Cancer Network. Interpretation of study results in light of NCAG/NCEPOD findings.

BACKGROUND: Chemotherapy-induced febrile neutropenia is a medical emergency complicating the treatment of many cancer patients. It is associated with considerable morbidity and mortality, as well as impacting on healthcare resources. METHODS: A prospective study of all cases of chemotherapy-induced febrile neutropenia in the South West London Cancer Network was conducted over a 4-month period. Factors including demographics, treatment history, management of febrile neutropenia and outcome were recorded. RESULTS AND CONCLUSION: Our results reflect those of the recent National Chemotherapy Advisory Group (NCEPOD, 2008)/National Confidential Enquiry into Patient Outcomes and Death reports (NCAG, 2009) and highlight the need for network-wide clinical care pathways to improve outcomes in this area.

A phase I/II trial of sorafenib and infliximab in advanced renal cell carcinoma.

BACKGROUND: There is clinical evidence to suggest that tumour necrosis factor-α (TNF-α) may be a therapeutic target in renal cell carcinoma (RCC). Multi-targeted kinase inhibitors, such as sorafenib and sunitinib, have become standard of care in advanced RCC. The anti-TNF-α monoclonal antibody infliximab and sorafenib have differing cellular mechanisms of action. We conducted a phase I/II trial to determine the safety and efficacy of infliximab in combination with sorafenib in patients with advanced RCC. METHODS: Eligible patients were systemic treatment-naive or had received previous cytokine therapy only. Sorafenib and infliximab were administered according to standard schedules. The study had two phases: in phase I, the safety and toxicity of the combination of full-dose sorafenib and two dose levels of infliximab were evaluated in three and three patients, respectively, and in phase II, further safety, toxicity and efficacy data were collected in an expanded patient population. RESULTS: Acceptable safety was reported for the first three patients (infliximab 5 mg kg⁻¹) in phase 1. Sorafenib 400 mg twice daily and infliximab 10 mg kg⁻¹ were administered to a total of 13 patients (three in phase 1 and 10 in phase 2). Adverse events included grade 3 hand-foot syndrome (31%), rash (25%), fatigue (19%) and infection (19%). Although manageable, toxicity resulted in 75% of the patients requiring at least one dose reduction and 81% requiring at least one dose delay of sorafenib. Four patients were progression-free at 6 months (PFS6 31%); median PFS and overall survival were 6 and 14 months, respectively. CONCLUSION: Sorafenib and infliximab can be administered in combination, but a significant increase in the numbers of adverse events requiring dose adjustments of sorafenib was observed. There was no evidence of increased efficacy compared with sorafenib alone in advanced RCC. The combination of sorafenib and infliximab does not warrant further evaluation in patients with advanced RCC.

Targeted therapy in colorectal carcinoma: more than a theory.

OBJECTIVE: The aim of this review was to examine clinical trial data reporting the use of targeted therapies in colorectal cancer. METHOD: Candidate trials were identified by a comprehensive literature search. RESULTS: The data on the use of targeted therapies; usually combined with chemotherapy in the treatment of colorectal cancer is accumulating rapidly. These new agents will increasingly become incorporated into standard treatment schedules. CONCLUSION: Targeted therapy has moved rapidly from the laboratory to the clinic and is opening up potentially new and exciting areas for the development of the systemic treatment of colorectal cancer.

The longer term outcome of children born to mothers with epilepsy.

OBJECTIVES: To determine the prevalence of cognitive delay and possible associated dysmorphic features in children exposed to antiepileptic drugs (AEDs) in utero. DESIGN: Retrospective study of children born to mothers with epilepsy. SETTING: Regional epilepsy clinics in Liverpool and Manchester, UK. PARTICIPANTS: Children aged between 6 months and 16 years born to mothers with epilepsy. MAIN OUTCOME MEASURES: Structured interviews, hospital records, clinical examination, and psychometric tests (Wechsler) were used to assess exposure and intelligence quotient (IQ). Blinded assessment of photographs was used to score children with characteristic dysmorphic features. RESULTS: A total of 249 children aged 6 and over were studied: 41 were exposed to sodium valproate, 52 to carbamazepine, 21 to phenytoin, 49 to polytherapy, and 80 were unexposed. Mean verbal IQ was significantly lower in the valproate group compared to unexposed and other monotherapy groups. Multiple regression analysis showed that both valproate exposure and frequent tonic-clonic seizures in pregnancy were significantly associated with a lower verbal IQ despite adjusting for other confounding factors. There was a significant negative correlation between dysmorphic features and verbal IQ in children exposed to valproate. CONCLUSIONS: This study identifies valproate as a drug carrying potential risks for developmental delay and cognitive impairment and is the first to suggest that frequent tonic-clonic seizures have a similar effect. Our results need to be interpreted with caution given their retrospective nature. Women with epilepsy need careful counselling about individual risk benefit of AED treatment before pregnancy.

Genetic diversity among sapoviruses.

Norovirus and Sapovirus are two genera of the family Caliciviridae that contain viruses that can cause acute gastroenteritis in humans. Noroviruses (NOR) are genetically highly diverse but limited studies of the genetic diversity of sapoviruses (SAP) have been reported. In this study we characterized twenty-five SAP detected in our laboratory from outbreaks or sporadic cases of acute gastroenteritis in children from different geographical locations and in adults involved in a cruise ship outbreak investigation and a nursing home outbreak. Based on significant differences of partial RNA polymerase sequences (278-286 nt), the 25 strains were grouped into 12 genetic clusters, including 9 potential new clusters. Extended sequence analysis of the capsid gene of selected strains representing five potential new clusters supported this grouping. Four strains (Hou7-1181/90, Mex340/90, Cruise ship/00 and Argentina39) had <84% amino acid (aa) identity to each other and to the published sequences in the GenBank. Mex14917/00 was almost identical to Stockholm/97/SE whose RNA polymerase sequence was unknown. Phylogenetic and distance analyses of the capsid region of the four new strains showed that Hou7-1181/90 and Argentina39 represent two new genogroups and Mex340/90 and Cruise ship/00 belong to two new clusters within the London/92 genogroup. Thus, based on the capsid sequences we propose to classify the currently known SAP into nine genetic clusters within five genogroups, including one genogroup that is represented by an animal calicivirus, the porcine enteric calicivirus (PEC).

The role of bisphosphonates in breast cancer management: review article.

Bone metastases are a common problem in the management of breast cancer and are associated with considerable morbidity. Bone pain, hypercalcaemia, fractures and cord compression all occur requiring interventions such as analgesia, radiotherapy and surgery. Bisphosphonates are drugs that are active in the bone microenvironment. Their effects on osteoclasts are well described: they potently inhibit osteoclast mediated bone resorption by delaying the maturation of immature osteoclasts and by directly inducing osteoclast apoptosis. It has been known for some time that bisphosphonates, in combination with intravenous rehydration, effectively treat hypercalcaemia associated with solid malignancies. It has now been demonstrated In clinical trials in breast cancer patients that regular bisphosphonate administration reduces the morbidity associated with osteolytic skeletal metastases. There is an emerging suggestion from clinical trial work that bisphosphonates may be able to reduce or delay the development of skeletal metastases although this remains controversial as the three published trials present conflicting results. The more potent third-generation bisphosphonates, such as zoledronate, are now being tested for each of these indications with promising results and may replace other bisphosphonates in the future. Laboratory studies have recently demonstrated that bisphosphonates have direct cytotoxic effects against breast cancer cells in vitro, inducing apoptosis and preventing adhesion to bone. This adds support to the hypothesis that bisphosphonates may have a genuine beneficial effect in the adjuvant setting.

Attitudes, practices, and preferences of pediatricians regarding initiation of hepatitis B immunization at birth.

OBJECTIVES: To explore practices and attitudes of pediatricians toward administration of the first dose of hepatitis B vaccine to infants, and to identify factors influencing the decision of pediatricians to initiate immunization at birth versus at 1 to 2 months of age. METHODS: A random sample of 600 pediatricians obtained from the American Academy of Pediatrics membership database was surveyed by mail. RESULTS: Three hundred eighty (68%) of the 563 pediatricians who were located responded to the survey. Of these 380 pediatricians, 279 provided routine immunizations to children. Of the 270 pediatricians who vaccinated children with hepatitis B vaccine and indicated their practice regarding the birth dose, 50% offered the first dose of hepatitis B vaccine at birth to all infants; the rest either offered the vaccine at birth only to infants of hepatitis B surface antigen-positive mothers and mothers whose serostatus is unknown, or did not offer the birth dose to any infants at all. Practicing in the inner city, working for a medical school or government hospital, and living in a state with universal immunization supply policies were associated with the respondent giving the birth dose. The strongest perceived barriers to giving the birth dose in the hospital were the difficulty tracking these vaccines (39%), the increased cost (27%), and the lack of reimbursement from insurance companies (26%). If a combination vaccine that includes hepatitis B; diphtheria, tetanus, pertussis (diphtheria and tetanus toxoids and acellular pertussis vaccine); and polio (inactivated poliovirus vaccine) antigens become available in the near future, then 38% of physicians who currently give the birth dose to all infants would prefer to wait until 2 months of age to initiate hepatitis B immunization. CONCLUSIONS: Efforts to achieve high implementation of hepatitis B birth dose administration may falter once a hepatitis B-containing pentavalent combination vaccine becomes available. Programmatic efforts should ensure prevention of perinatal hepatitis B virus transmission through universal prenatal hepatitis B surface antigen screening and immunoprophylaxis of high-risk newborn infants.

Intussusception, infection, and immunization: summary of a workshop on rotavirus.

This article summarizes the proceedings of a workshop sponsored by the National Institutes of Health and the National Vaccine Program Office, and held in Bethesda, Maryland, on January 21, 2000. The objective of the meeting was to focus research toward an understanding of the basis for the possible association between intussusception and the reassortant rhesus-human rotavirus vaccine tetravalent (RRV-TV). After numerous reports of intussusception after administration of RRV-TV, the manufacturers of this vaccine voluntarily withdrew it from the United States market. The American Academy of Pediatrics, the Advisory Committee on Immunization Practices, and the American Academy of Family Physicians also withdrew their original recommendations for administration of RRV-TV to children at 2, 4, and 6 months of age. These actions will have global implications for the prevention of morbidity and mortality attributable to rotavirus infection. Benefit-cost ratios for the use of RRV-TV will be substantially different in developing countries compared with developed countries. Therefore, extensive research is needed in both of these settings, to further our understanding of the epidemiology, pathogenesis, and pathology of both rotavirus disease and intussusception to enable optimal prevention. The workshop reviewed the current understanding of the possible association between RRV-TV and intussusception, as well as the possible association between a variety of viral infections and intussusception. The workshop also identified critical areas of research regarding this possible association. This research will be essential not only for the development of safe and effective rotavirus vaccines, but for the development of other oral vaccines as well.

Fucosylated human milk oligosaccharides vary between individuals and over the course of lactation.

Specific human milk oligosaccharides, especially fucosylated neutral oligosaccharides, protect infants against specific microbial pathogens. To study the concentrations of individual neutral oligosaccharides during lactation, a total of 84 milk samples were obtained from 12 women at 7 time periods during weeks 1-49 postpartum. The neutral oligosaccharides from each sample were isolated, perbenzoylated, resolved, and quantified by reversed-phase high-performance liquid chromatography. The resultant oligosaccharide peaks, identified by co-elution with authentic standards and mass spectrometry, ranged in size from tri- to octasaccharides. The total concentration of oligosaccharides declined over the course of lactation; the mean concentration at 1 year was less than half that in the first few weeks postpartum. One of the 12 donors produced milk fucosyloligosaccharides that were essentially devoid of alpha1,2 linkages (but contained alpha1,3- and alpha1,4-linked fucose) until late in lactation, consistent with the nonsecretor phenotype. In milk samples from the remaining 11 donors, fucosyloligosaccharides containing alpha1,2-linked fucose were prevalent, and their profiles were distinct from those of fucosyloligosaccharides devoid of alpha1,2-linked fucose. The ratio of alpha1,2-linked oligosaccharide concentrations to oligosaccharides devoid of alpha1,2-linked fucose changed during the first year of lactation from 5:1 to 1:1. Furthermore, the absolute and the relative concentrations of individual oligosaccharides varied substantially, both between individual donors and over the course of lactation for each individual. The patterns of milk oligosaccharides among individuals suggest the existence of many genotype subpopulations. This variation in individual oligosaccharide concentrations suggests that the protective activities of human milk could also vary among individuals and during lactation.

Molecular characterization of invasive and noninvasive Campylobacter jejuni and Campylobacter coli isolates.

Campylobacter jejuni is one of the most common causes of bacterial diarrhea worldwide and is the primary bacterial cause of food-borne illness. Adherence to and invasion of epithelial cells are the most important pathogenic mechanisms of Campylobacter diarrhea. Molecular characterization of invasive and noninvasive Campylobacter isolates from children with diarrhea and symptom-free children was performed by random amplified polymorphic DNA techniques (RAPD). A distinct RAPD profile with a DNA band of 1.6 kb was observed significantly more frequently among invasive (63%) than among noninvasive (16%) Campylobacter isolates (P = 0.000005). The 1.6-kb band was named the invasion-associated marker (IAM). Using specifically designed primers, a fragment of 518 bp of the iam locus was amplified in 85% of invasive and 20% of noninvasive strains (P = 0.0000000). Molecular typing with a PCR-restriction fragment length polymorphism assay which amplified the entire iam locus showed a HindIII restriction fragment polymorphism pattern associated mainly with invasive strains. Although cluster analysis of the RAPD fingerprinting showed genetic diversity among strains, two main clusters were identified. Cluster I comprised significantly more pathogenic and invasive isolates, while cluster II grouped the majority of nonpathogenic, noninvasive isolates. These data indicate that most of the invasive Campylobacter strains could be differentiated from noninvasive isolates by RAPD analysis and PCR using specific primers that amplify a fragment of the iam locus.

Molecular epidemiology of human astrovirus diarrhea among children from a periurban community of Mexico City.

Human astroviruses (HAstVs) were detected in 23 stool samples from 365 diarrhea episodes among 214 children (<18 months old) prospectively monitored for diarrhea in Mexico City. Stool samples were tested by EIA and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. EIA was less sensitive (74%) and equally specific, compared with RT-PCR analysis using type-common primers for HAstV detection. Of 31 HAstV isolates, EIA typed 18 (69%) of 26 EIA-positive samples, and RT-PCR analysis typed 26 (84%) of 31 RT-PCR-positive samples. Phylogenetic analysis of the 3' end of the capsid region (363 nucleotides) confirmed the type assignment by EIA and RT-PCR analysis and determined the type for 5 previously untyped samples. Six HAstV antigenic types cocirculated in the community: HAstV-2 (42%), HAstV-4 (23%), HAstV-3 (13%), HAstV-1 (10%), HAstV-5 (6%), and HAstV-7 (6%). RT-PCR and sequence analysis provided more detailed epidemiology of HAstV in the community than did antigenic detection methods.