To evaluate the interobserver agreement for the Neoplastic Spine Instability Score (SINS) among spine surgeons with or without experience in vertebral metastasis treatment and physicians in other specialties.
Case descriptions were produced based on the medical records of 40 patients with vertebral metastases. The descriptions were then published online. Physicians were invited to evaluate the descriptions by answering questions according to the Neoplastic Spine Instability Score (SINS). The agreement among physicians was calculated using the kappa coefficient.
Seventeen physicians agreed to participate: three highly experienced spine surgeons, seven less-experienced spine surgeons, three surgeons of other specialties, and four general practitioners (n = 17). The agreement for the final SINS score among all participants was fair, and it varied according to the SINS component. The agreement was substantial for the spine location only. The agreement was higher among experienced surgeons. The agreement was nearly perfect for spinal location among the spine surgeons who were highly experienced in vertebral metastases.
This study demonstrates that the experience of the evaluator has an impact on SINS scale classification. The interobserver agreement was only fair among physicians who were not spine surgeons and among spine surgeons who were not experienced in the treatment of vertebral metastases, which may limit the use of the SINS scale for the screening of unstable lesions by less-experienced evaluators.
Spine; Health Services Research; Models, Statistical; Observer Variation
A leaching experiment, where liquid manure spiked with Salmonella enterica serovar Typhimurium (Tet+) DSM554 was applied to soil surfaces, was conducted on intact soil monoliths (60 cm in diameter and 100 cm long). A total of 6.5 × 1010 CFU was applied to each column. We found that Salmonella serovar Typhimurium could be transported to a 1-m depth in loamy soil at concentrations reaching 1.3 × 105 CFU/ml of leachate. The test strain was found in concentrations ranging from 300 to 1.35 cells/ml in loamy soil throughout the 27 days of the experiment, while concentrations below 20 cells/ml were sporadically detected in the leachates from sandy monoliths. Real-time PCR targeting invA DNA showed a clear correspondence between the total and culturable numbers of cells in the leachate, indicating that most cells leached were viable. On day 28, distribution of Salmonella serovar Typhimurium at five depths in the four monoliths was determined. The highest recovery rate, ranging from 1.5% to 3.8% of the total applied inoculum, was found in the top 0.2 m.
A bacterial community from Danish agricultural soil was enriched with linuron [N-(3,4-dichlorophenyl)-N′-methoxy-N′-methylurea] as the sole carbon and nitrogen source. The community mineralized [ring-U-14C]linuron completely to 14CO2 and 14C-biomass. Denaturing gradient gel electrophoresis analysis and cultivation revealed that a Variovorax sp. was responsible for the mineralization activity.
Stem cell factor (SCF), a key regulator of hematopoiesis, potently synergizes with a number of hematopoietic growth factors. However, little is known about growth factors capable of inhibiting the actions of SCF. TNF-alpha has been shown to act as a bidirectional regulator of myeloid cell proliferation and differentiation. This study was designed to examine interactions between TNF-alpha and SCF. Here, we demonstrate that TNF-alpha potently and directly inhibits SCF-stimulated proliferation of CD34+ hematopoietic progenitor cells. Furthermore, TNF-alpha blocked all colony formation stimulated by SCF in combination with granulocyte colony-stimulating factor (CSF) or CSF-1. The synergistic effect of SCF observed in combination with GM-CSF or IL-3 was also inhibited by TNF-alpha, resulting in colony numbers similar to those obtained in the absence of SCF. These effects of TNF-alpha were mediated through the p55 TNF receptor, whereas little or no inhibition was signaled through the p75 TNF receptor. Finally, TNF-alpha downregulated c-kit cell-surface expression on CD34+ bone marrow cells, and this was predominantly a p55 TNF receptor-mediated event as well.
Ethanol reassimilation in Pichia stipitis CBS 6054 was studied by using continuous cultures, and the oxidation of [1-13C]ethanol was monitored by in vivo and in vitro 13C nuclear magnetic resonance spectroscopy. Acetate was formed when ethanol was reassimilated. The ATP/ADP ratio and the carbon dioxide production decreased, whereas the malate dehydrogenase activity increased, in ethanol-reassimilating cells. The results are discussed in terms of the low ethanol tolerance in P. stipitis compared with that in Saccharomyces cerevisiae (S. W. Brown, S. G. Oliver, D. E. F. Harrison, and R. C. Righelato, Eur. J. Appl. Microbiol. Biotechnol. 11:151-155, 1981).
Menopausal estrogen (E2) replacement therapy increases the risk of estrogen receptor (ER)-positive epithelial ovarian cancers (EOC). Whether E2 is tumorigenic or promotes expansion of undiagnosed pre-existing disease is unknown. To determine E2 effects on tumor promotion, we developed an intraperitoneal mouse xenograft model using ZsGreen fluorescent ER− 2008 and ER+ PEO4 human EOC cells. Tumor growth was quantified by in vivo fluorescent imaging. In ER+ tumors, E2 significantly increased size, induced progesterone receptors, and promoted lymph node metastasis, confirming that ER are functional and foster aggressiveness. Laser captured human EOC cells from ER− and ER+ xenografted tumors were profiled for expression of E2-regulated genes. Three classes of E-regulated EOC genes were defined, but less than 10% were shared with E-regulated breast cancer genes. Since breast cancer selective ER modulators (SERMs) are therapeutically ineffective in EOC, we suggest that our EOC-specific E-regulated genes can assist pharmacologic discovery of ovarian targeted SERM.
Ovarian Cancer; Xenograft; Estrogen; Metastasis; E-regulated genes
The comet analysis of DNA strand break levels in tissues and cells has become a common method of screening for genotoxicity. The large majority of published studies have used fresh tissues and cells processed immediately after collection. However, we have used frozen tissues and cells for more than 10 years, and we believe that freezing samples improve efficiency of the method. We compared DNA strand break levels measured in fresh and frozen bronchoalveolar cells, and lung and liver tissues from mice exposed to the known mutagen methyl methanesulphonate (0, 25, 75, 112.5mg/kg). We used a high-throughput comet protocol with fully automated scoring of DNA strand break levels. The overall results from fresh and frozen samples were in agreement [R
2 = 0.93 for %DNA in tail (%TDNA) and R
2 = 0.78 for tail length (TL)]. A slightly increased %TDNA was observed in lung and liver tissue from vehicle controls; and TL was slightly reduced in bronchoalveolar lavage cells from the high-dose group. In our comet protocol, a small block of tissue designated for comet analysis is frozen immediately at tissue collection and kept deep frozen until rapidly homogenised and embedded in agarose. To demonstrate the feasibility of long-term freezing of samples, we analysed the day-to-day variation of our internal historical negative and positive comet assay controls collected over a 10-year period (1128 observations, 11 batches of frozen untreated and H2O2-treated A549 lung epithelial cells). The H2O2 treatment explained most of the variation 57–77% and the day-to-day variation was only 2–12%. The presented protocol allows analysis of samples collected over longer time span, at different locations, with reduced variation by reducing number of electrophoreses and is suitable for both toxicological and epidemiological studies. The use of frozen tissues; however, requires great care during preparation before analysis, with handling as a major risk factor.
We demonstrate that the binding sites for highly conserved transcription factors vary extensively between human and mouse. We mapped the binding of four tissue-specific transcription factors (FOXA2, HNF1A, HNF4A, HNF6) to 4,000 orthologous gene pairs in hepatocytes purified from human and mouse livers. Despite the conserved function of these factors, from 41% to 89% of their binding events appear to be species-specific. When the same protein binds the promoters of orthologous genes, approximately two-thirds of the binding sites do not align.
Cellular decision-making is mediated by a complex interplay of external stimuli with the intracellular environment, in particular transcription factor regulatory networks. Here we have determined the expression of a network of 18 key haematopoietic transcription factors (TFs) in 597 single primary blood stem and progenitor cells isolated from mouse bone marrow. We demonstrate that different stem/progenitor populations are characterised by distinctive TF expression states, and through comprehensive bioinformatic analysis reveal positively and negatively correlated TF pairings, including previously unrecognised relationships between Gata2, Gfi1 and Gfi1b. Validation using transcriptional and transgenic assays confirmed direct regulatory interactions consistent with a regulatory triad in immature blood stem cells, where Gata2 may function to modulate cross-inhibition between Gfi1 and Gfi1b. Single cell expression profiling therefore identifies network states and allows reconstruction of network hierarchies involved in controlling stem cell fate choices, and provides a blueprint for studying both normal development and human disease.
The Western Ghats of India harbors a rich diversity of amphibians with more than 77% species endemic to this region. At least 42% of the endemic species are threatened due to several anthropogenic stressors. However, information on amphibian diseases and their impacts on amphibian populations in this region are scarce. We report the occurrence of Batrachochytridium dendrobatidis (Bd), an epidermal aquatic fungal pathogen that causes chytridiomycosis in amphibians, from the Western Ghats. In the current study we detected the occurrence of a native Asian Bd strain from three endemic and threatened species of anurans, Bombay Night Frog Nyctibatrachus humayuni, Leith's Leaping Frog Indirana leithii and Bombay Bubble Nest Frog Raorchestes bombayensis, for the first time from the northern Western Ghats of India based on diagnostic nested PCR, quantitative PCR, DNA sequencing and histopathology. While, the Bd infected I. leithii and R. bombayensis did not show any external symptoms, N. humayuni showed lesions on the skin, browning of skin and sloughing. Sequencing of Bd 5.8S ribosomal RNA gene, and the ITS1 and ITS2 regions, revealed that the current Bd strain is related to a haplotype endemic to Asia. Our findings confirm the presence of Bd in northern Western Ghats and the affected amphibians may or may not show detectable clinical symptoms. We suggest that the significance of diseases as potential threat to amphibian populations of the Western Ghats needs to be highlighted from the conservation point of view.
Evidence is mixed regarding long-term cognitive deficits in patients treated with chemotherapy. Previous meta-analyses have not focused specifically on the postchemotherapy period and have not incorporated several recent studies. The goal of the current study was to conduct a meta-analysis of cognitive functioning in breast cancer survivors who were treated with chemotherapy ≥ 6 months previously.
A search of PubMed, PsycInfo, Cumulative Index to Nursing and Allied Health Literature, and Cochrane Library yielded 2,751 abstracts, which were independently evaluated by pairs of raters. Meta-analysis was conducted on 17 studies of 807 patients previously treated with standard-dose chemotherapy for breast cancer. Neuropsychological tests were categorized according to eight cognitive domains: attention, executive functioning, information processing, motor speed, verbal ability, verbal memory, visual memory, and visuospatial ability.
Deficits in cognitive functioning were observed in patients treated with chemotherapy relative to controls or prechemotherapy baseline in the domains of verbal ability (g = −0.19; P < .01) and visuospatial ability (g = −0.27; P < .01). Patients treated with chemotherapy performed worse than noncancer controls in verbal ability and worse than patients treated without chemotherapy in visuospatial ability (both P < .01). Age, education, time since treatment, and endocrine therapy did not moderate observed cognitive deficits in verbal ability or visuospatial ability (all P ≥ .51).
Results indicate that, on average, observed cognitive deficits in patients with breast cancer previously treated with chemotherapy are small in magnitude and limited to the domains of verbal ability and visuospatial ability. This information can be used to inform interventions to educate patients with breast cancer regarding the long-term impact of chemotherapy on cognitive functioning.
In acute myeloid leukemia (AML), initial treatment response by morphologic analysis of bone marrow predicts long-term outcome. Response can now be assessed by minimal residual disease (MRD) monitoring with flow cytometry or polymerase chain reaction (PCR). We determined the relation among the results of these approaches and their prognostic value.
Patients and Methods
In the multicenter AML02 study, follow-up bone marrow samples from 203 children and adolescents with newly diagnosed AML were examined by flow cytometry (n = 1,514), morphology (n = 1,382), and PCR amplification of fusion transcripts (n = 508). Results were correlated with treatment outcome.
Among 1,215 samples with less than 5% leukemic myeloblasts by morphology, 100 (8.2%) were MRD positive (≥ 0.1%) by flow cytometry, whereas 96 (57.5%) of the 167 samples with ≥ 5% blasts were MRD negative. Virtually all (308 of 311; 99.0%) MRD-negative samples by PCR were also MRD negative by flow cytometry. However, only 19 (9.6%) of the 197 PCR-positive samples were flow cytometry positive, with analyses of AML1-ETO and CBFβ-MYH11 accounting for most discrepancies, whereas eight of 13 MLL-positive samples had detectable MRD by flow cytometry. MRD by flow cytometry after induction 1 or 2 predicted lower event-free survival and higher relapse rate (P < .001) and was an independent prognostic factor in a multivariable analysis; prediction was not improved by morphologic information or molecular findings.
In childhood AML, morphologic assessment of treatment response has limited value if MRD is measured by flow cytometry. MLL fusion transcripts can provide prognostic information in some patients, whereas monitoring of AML1-ETO and CBFβ-MYH11 transcripts is largely uninformative.
AIM: To determine if esophageal capsule endoscopy (ECE) is an adequate diagnostic alternative to esophagogastroduodenoscopy (EGD) in pre-bariatric surgery patients.
METHODS: We conducted a prospective pilot study to assess the diagnostic accuracy of ECE (PillCam ESO2, Given Imaging) vs conventional EGD in pre-bariatric surgery patients. Patients who were scheduled for bariatric surgery and referred for pre-operative EGD were prospectively enrolled. All patients underwent ECE followed by standard EGD. Two experienced gastroenterologists blinded to the patient’s history and the findings of the EGD reviewed the ECE and documented their findings. The gold standard was the findings on EGD.
RESULTS: Ten patients with an average body mass index of 50 kg/m2 were enrolled and completed the study. ECE identified 11 of 14 (79%) positive esophageal/gastroesophageal junction (GEJ) findings and 14 of 17 (82%) combined esophageal and gastric findings identified on EGD. Fisher’s exact test was used to compare the findings and no significant difference was found between ECE and EGD (P = 0.64 for esophageal/GEJ and P = 0.66 for combined esophageal and gastric findings respectively). Of the positive esophageal/GEJ findings, ECE failed to identify the following: hiatal hernia in two patients, mild esophagitis in two patients, and mild Schatzki ring in two patients. ECE was able to identify the entire esophagus in 100%, gastric cardia in 0%, gastric body in 100%, gastric antrum in 70%, pylorus in 60%, and duodenum in 0%.
CONCLUSION: There were no significant differences in the likelihood of identifying a positive finding using ECE compared with EGD in preoperative evaluation of bariatric patients.
Capsule endoscopy; Bariatric; Moderate sedation; Esophagogastroduodenoscopy; Esophageal capsule endoscopy
Fatigue is a common and distressing side effect of androgen deprivation therapy (ADT) for prostate cancer. The goal of the current study was to examine the relationship between changes in fatigue following initiation of ADT and single nucleotide polymorphisms (SNPs) in three pro-inflammatory cytokine genes: interleukin-1 beta (IL1B), interleukin-6 (IL6), and tumor necrosis factor alpha (TNFA).
As part of a larger study, men with prostate cancer (n=53) were recruited prior to initiation of ADT. Fatigue was assessed at recruitment and six months after initiation of ADT. DNA was extracted from blood drawn at baseline.
Patients with the IL6-174 (rs1800795) G/C or C/C genotype displayed greater increases in fatigue intrusiveness, frequency, and duration than the G/G genotype (p values≤0.05), although inclusion of age, race, and baseline depressive symptomatology in the model attenuated these relationships (p values≤0.09). Patients with the TNFA-308 (rs1800629) G/A genotype showed greater increases in fatigue severity than the G/G genotype (p=0.02). IL1B-511 (rs16944) genotype did not significantly predict changes in fatigue (p values>0.46). Patients with higher numbers of variants displayed greater increases in fatigue duration and interference (p values≤0.02) than patients with lower numbers of variants.
Prostate cancer patients treated with ADT who carry variant alleles of the IL6 and TNFA genes are susceptible to heightened fatigue. These preliminary data lend support for the role of genetic variation in the development of cancer-related fatigue secondary to ADT. Findings are relevant to attempts to develop personalized approaches to cancer treatment.
prostatic neoplasms; fatigue; polymorphism; single nucleotide
Cell lines derived from human ovarian and endometrial cancers, and their immortalized non-malignant counterparts, are critical tools to investigate and characterize molecular mechanisms underlying gynecologic tumorigenesis, and facilitate development of novel therapeutics. To determine the extent of misidentification, contamination and redundancy, with evident consequences for the validity of research based upon these models, we undertook a systematic analysis and cataloging of endometrial and ovarian cell lines.
Profiling of cell lines by analysis of DNA microsatellite short tandem repeats (STR), p53 nucleotide polymorphisms and microsatellite instability.
Fifty-one ovarian cancer lines were profiled with ten found to be redundant and five (A2008, OV2008, C13, SK-OV-4 and SK-OV-6) identified as cervical cancer cells. Ten endometrial cell lines were analyzed, with RL-92, HEC-1A, HEC-1B, HEC-50, KLE, and AN3CA all exhibiting unique, uncontaminated STR profiles. Multiple variants of Ishikawa and ECC-1 endometrial cancer cell lines were genotyped and analyzed by sequencing of mutations in the p53 gene. The profile of ECC-1 cells did not match the EnCa-101 tumor, from which it was reportedly derived, and all ECC-1 isolates genotyped as Ishikawa cells, MCF-7 breast cancer cells, or a combination thereof. Two normal, immortalized endometrial epithelial cell lines, HES cells and the hTERT-EEC line, were identified as HeLa cervical carcinoma and MCF-7 breast cancer cells, respectively.
Results demonstrate significant misidentification, duplication, and loss of integrity of endometrial and ovarian cancer cell lines. Authentication by STR DNA profiling is a simple and economical method to verify and validate studies undertaken with these models.
STR profiling; Endometrial; Ovarian; cell lines; authenticity
The amino acid cysteine has long been known to be toxic at elevated levels for bacteria, fungi, and humans. However, mechanisms of cysteine tolerance in microbes remain largely obscure. Here we show that the human pathogenic yeast Candida albicans excretes sulfite when confronted with increasing cysteine concentrations. Mutant construction and phenotypic analysis revealed that sulfite formation from cysteine in C. albicans relies on cysteine dioxygenase Cdg1, an enzyme with similar functions in humans. Environmental cysteine induced not only the expression of the CDG1 gene in C. albicans, but also the expression of SSU1, encoding a putative sulfite efflux pump. Accordingly, the deletion of SSU1 resulted in enhanced sensitivity of the fungal cells to both cysteine and sulfite. To study the regulation of sulfite/cysteine tolerance in more detail, we screened a C. albicans library of transcription factor mutants in the presence of sulfite. This approach and subsequent independent mutant analysis identified the zinc cluster transcription factor Zcf2 to govern sulfite/cysteine tolerance, as well as cysteine-inducible SSU1 and CDG1 gene expression. cdg1Δ and ssu1Δ mutants displayed reduced hypha formation in the presence of cysteine, indicating a possible role of the newly proposed mechanisms of cysteine tolerance and sulfite secretion in the pathogenicity of C. albicans. Moreover, cdg1Δ mutants induced delayed mortality in a mouse model of disseminated infection. Since sulfite is toxic and a potent reducing agent, its production by C. albicans suggests diverse roles during host adaptation and pathogenicity.
Cancer diagnosis and treatment, particularly chemotherapy, has well-established adverse effects on individuals. Exercise has been found to confer benefits to patients, although the current evidence base is limited primarily to patients assessed during or after treatment. Although exercise has been a target of intervention efforts, its relationship to quality of life in patients about to begin chemotherapy has not fully been examined.
To examine the relationship of pre-treatment exercise rates to patient quality of life.
One hundred and ninety-two adults diagnosed with stage I-IV cancer and Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2, provided data on exercise, distress (anxiety and depression), and health-related quality of life prior to their initial chemotherapy infusion.
As predicted, higher rates of exercise activity were associated with lower levels of anxiety and depression, and better overall mental and physical quality of life. These relationships were independent of demographic variables (i.e., body mass index and age) also associated with quality of life in the present analyses.
These findings further highlight the importance of assessing exercise before the start of chemotherapy as part of broader efforts to link patients to appropriate interventions aimed at enhancing quality of life. Findings also raise the possibility that assessing exercise rates could be useful in matching patients to the type of intervention most likely to benefit them. Future research should use prospective longitudinal designs to further explore this association.
Cancer; oncology; exercise; activity level; depression; anxiety
More than ever before, the world's increasing need for new infrastructure demands the construction of efficient, sustainable and durable buildings, requiring minimal climate-changing gas-generation in their production. Maintenance-free “greener” building materials made from blended cements have advantages over ordinary Portland cements, as they are cheaper, generate less carbon dioxide and are more durable. The key for the improved performance of blends (which substitute fine amorphous silicates for cement) is related to their resistance to water penetration. The mechanism of this water resistance is of great environmental and economical impact but is not yet understood due to the complexity of the cement's hydration reactions. Using neutron spectroscopy, we studied a blend where cement was replaced by ash from sugar cane residuals originating from agricultural waste. Our findings demonstrate that the development of a distinctive hydrogen bond network at the nano-scale is the key to the performance of these greener materials.
The in utero origins of breast cancer are an increasing focus of research. However, the long time period between exposure and disease diagnosis, and the lack of standardized perinatal data collection makes this research challenging. We assessed perinatal factors, as proxies for in utero exposures, and breast cancer risk using pooled, population-based birth and cancer registry data. Birth registries provided information on perinatal exposures. Cases were females born in Norway, Sweden or Denmark who were subsequently diagnosed with primary, invasive breast cancer (n = 1419). Ten controls for each case were selected from the birth registries matched on country and birth year (n = 14,190). Relative risks (RRs) and 95% confidence intervals (CIs) were estimated using unconditional regression models. Breast cancer risk rose 7% (95% CI 2–13%) with every 500 g (roughly 1 S.D.) increase in birth weight and 7% for every 1 s.d. increase in birth length (95% CI 1–14%). The association with birth length was attenuated after adjustment for birth weight, while the increase in risk with birth weight remained with adjustment for birth length. Ponderal index and small- and large-for-gestational-age status were not better predictors of risk than either weight or length alone. Risk was not associated with maternal education or age, gestational duration, delivery type or birth order, or with several pregnancy complications, including preeclampsia. These data confirm the positive association between birth weight and breast cancer risk. Other pregnancy characteristics, including complications such as preeclampsia, do not appear to be involved in later breast carcinogenesis in young women.
birth weight; breast cancer; early life; in utero; preeclampsia; prenatal
The IOM recommended that all patients receive survivorship care plans (SCPs) post-treatment to improve quality of follow-up care. However, little is known regarding how survivors utilize SCPs and the congruency between providers' and survivors' perspectives. Feedback from colorectal cancer survivors (in receipt of a personalized/individualized SCP) and oncology providers was obtained via interviews. Survivors noted SCPs benefits of reduced duplicative procedures and cancer worry with the synthesized treatment information. Providers noted billing/reimbursement and time investiture (for form completion) as potential barriers. Further investigation of survivorship care plans is warranted regarding utility prior to widespread adoption in follow-up care.
To investigate the association between childhood and adolescent obesity, the risk of gallstones and the potential effect modification by oral contraceptive use in girls.
For this population-based cross-sectional study, measured weight and height, oral contraceptive use, and diagnosis of cholelithiasis or choledocholithiasis were extracted from electronic medical records of 510,816 patients aged 10–19 years enrolled in an integrated health plan 2007–2009.
We identified 766 patients with gallstones. The adjusted ORs (95% CI) of gallstones for under/normal weight (=reference), overweight, moderate obesity, and extreme obesity in boys were 1.00, 1.46 (0.94–2.27), 1.83 (1.17–2.85), and 3.10 (1.99–4.83) and in girls 1.00, 2.73 (95% CI 2.18–3.42), 5.75 (4.62–7.17), and 7.71 (6.13–9.71), respectively (P for interaction sex × weightclass <0.001). Among girls, oral contraceptive use was associated with higher odds for gallstones (OR 2.00, 95% CI 1.66–2.40). Girls who used oral contraceptives were at higher odds for gallstones than their counterparts in the same weight class who did not use oral contraceptives (P for interaction weight class × oral contraceptive use = 0.023).
Due to the shift towards extreme childhood obesity, especially in minority children, pediatricians can expect to face increasing numbers of children and adolescents affected by gallstone disease.
obesity; body weight; childhood; gallstones; cholelithiasis; oral contraceptive use
The respective life histories of humans and mice are well defined and describe a unique story of evolutionary conservation extending from sequence identity within the genome to the underpinnings of biochemical, cellular, and physiological pathways. As a consequence, the hematopoietic lineages of both species are invariantly maintained, each with identifiable eosinophils. This canonical presence nonetheless does not preclude disparities between human and mouse eosinophils and/or their effector functions. Indeed, many books and reviews dogmatically highlight differences, providing a rationale to discount the use of mouse models of human eosinophilic diseases. We suggest that this perspective is parochial and ignores the wealth of available studies and the consensus of the literature that overwhelming similarities (and not differences) exist between human and mouse eosinophils. The goal of this review is to summarize this literature and in some cases provide the experimental details, comparing and contrasting eosinophils and eosinophil effector functions in humans vs. mice. In particular, our review will provide a summation and an easy to use reference guide to important studies demonstrating that while differences exist, more often than not their consequences are unknown and do not necessarily reflect inherent disparities in eosinophil function, but instead, species-specific variations. The conclusion from this overview is that despite nominal differences, the vast similarities between human and mouse eosinophils provide important insights as to their roles in health and disease and, in turn, demonstrate the unique utility of mouse-based studies with an expectation of valid extrapolation to the understanding and treatment of patients.
eosinophils; mouse; human; rodent; primate; hematology
To determine whether nocturia is associated with the development of diabetes mellitus, hypertension, coronary heart disease (CHD) and occurrence of death.
MATERIALS AND METHODS
We studied data obtained from a retrospective cohort of randomly selected men, aged 40–79 years in 1990, from Olmsted County, MN, USA.
Nocturia was defined as waking to urinate ≥2 times per night.
Men were followed every 2 years through repeated questionnaires and community medical records to assess development of diabetes mellitus and hypertension, and occurrence of death. CHD was ascertained through ongoing surveillance of heart disease in Olmsted County.
Cox proportional hazard models were used to estimate associations between baseline nocturia and each of the outcomes.
A total of 2447 men were followed for a median of 17.1 years (25th and 75th percentiles: 15.0, 17.4 years).
Nocturia was not significantly associated with the later development of diabetes mellitus or hypertension in this study.
Younger men (<60 years of age) with moderate nocturia were more likely to develop CHD later in life than younger men without nocturia (hazard ratio [HR]: 1.68; 95% confidence interval [CI]: 1.13, 2.49). This association was no longer significant when adjusted for age, body mass index (BMI) and urological medications (HR: 1.36; 95% CI: 0.87, 2.22).
Older men (≥60 years of age) with moderate nocturia were more likely to die than older men without moderate nocturia, even after adjusting for age, BMI, urological medications and CHD (HR: 1.48; 95% CI: 1.15, 1.91).
Nocturia may be a marker for increased risk of CHD in younger men, and death in older men.
nocturia; diabetes mellitus; cardiovascular disease; hypertension; cohort
Autoimmune safety evaluation is an important component of post-licensure vaccine safety evaluation. Recently, we published the findings from a large observational safety study of the quadrivalent human papillomavirus vaccine in females. From this study, based on two large managed care organizations, we have obtained some empirical data that may prove useful for the design of future vaccine safety studies within a managed care environment. For autoimmune conditions, a major challenge in vaccine safety study is to determine true incident cases in relation to the timing of vaccination. We found expert case review of medical records an indispensable component for autoimmune safety studies based on electronic health records. Case identification should also be expanded to include the use of laboratory test results or other relevant measures in addition to the disease specific ICD-9 diagnosis codes, when applicable. Furthermore, we recommend the parallel use of both safety signal evaluation that involves pattern evaluation for conditions that are more common, and statistical comparisons for conditions that are rather rare. Finally, we recommend an accompanying vaccine uptake study to understand the potential selection bias and confounding in a given study population that should be addressed with data collection and analytical techniques.
autoimmune conditions; vaccine safety; post-licensure safety study; methodology; HPV vaccine
Antibiotic use in humans has been associated with outgrowth of fungi. Here we used a murine model to investigate the gut microbiome over 76 days of treatment with vancomycin, ampicillin, neomycin, and metronidazole and subsequent recovery. Mouse stool was studied as a surrogate for the microbiota of the lower gastrointestinal tract. The abundance of fungi and bacteria was measured using quantitative PCR, and the proportional composition of the communities quantified using 454/Roche pyrosequencing of rRNA gene tags. Prior to treatment, bacteria outnumbered fungi by >3 orders of magnitude. Upon antibiotic treatment, bacteria dropped in abundance >3 orders of magnitude, so that the predominant 16S sequences detected became transients derived from food. Upon cessation of treatment, bacterial communities mostly returned to their previous numbers and types after 8 weeks, though communities remained detectably different from untreated controls. Fungal communities varied substantially over time, even in the untreated controls. Separate cages within the same treatment group showed radical differences, but mice within a cage generally behaved similarly. Fungi increased ∼40-fold in abundance upon antibiotic treatment but declined back to their original abundance after cessation of treatment. At the last time point, Candida remained more abundant than prior to treatment. These data show that 1) gut fungal populations change radically during normal mouse husbandry, 2) fungi grow out in the gut upon suppression of bacterial communities with antibiotics, and 3) perturbations due to antibiotics persist long term in both the fungal and bacterial microbiota.