A galaxy rapidly forming stars 700 million years after the Big Bang at redshift 7.51.

Of several dozen galaxies observed spectroscopically that are candidates for having a redshift (z) in excess of seven, only five have had their redshifts confirmed via Lyman α emission, at z = 7.008, 7.045, 7.109, 7.213 and 7.215 (refs 1-4). The small fraction of confirmed galaxies may indicate that the neutral fraction in the intergalactic medium rises quickly at z > 6.5, given that Lyman α is resonantly scattered by neutral gas. The small samples and limited depth of previous observations, however, makes these conclusions tentative. Here we report a deep near-infrared spectroscopic survey of 43 photometrically-selected galaxies with z > 6.5. We detect a near-infrared emission line from only a single galaxy, confirming that some process is making Lyman α difficult to detect. The detected emission line at a wavelength of 1.0343 micrometres is likely to be Lyman α emission, placing this galaxy at a redshift z = 7.51, an epoch 700 million years after the Big Bang. This galaxy's colours are consistent with significant metal content, implying that galaxies become enriched rapidly. We calculate a surprisingly high star-formation rate of about 330 solar masses per year, which is more than a factor of 100 greater than that seen in the Milky Way. Such a galaxy is unexpected in a survey of our size, suggesting that the early Universe may harbour a larger number of intense sites of star formation than expected.

Disease-based modeling to predict fluid response in intensive care units.

OBJECTIVE: To compare general and disease-based modeling for fluid resuscitation and vasopressor use in intensive care units. METHODS: Retrospective cohort study involving 2944 adult medical and surgical intensive care unit (ICU) patients receiving fluid resuscitation. Within this cohort there were two disease-based groups, 802 patients with a diagnosis of pneumonia, and 143 patients with a diagnosis of pancreatitis. Fluid resuscitation either progressing to subsequent vasopressor administration or not was used as the primary outcome variable to compare general and disease-based modeling. RESULTS: Patients with pancreatitis, pneumonia and the general group all shared three common predictive features as core variables, arterial base excess, lactic acid and platelets. Patients with pneumonia also had non-invasive systolic blood pressure and white blood cells added to the core model, and pancreatitis patients additionally had temperature. Disease-based models had significantly higher values of AUC (p < 0.05) than the general group (0.82 ± 0.02 for pneumonia and 0.83 ± 0.03 for pancreatitis vs. 0.79 ± 0.02 for general patients). CONCLUSIONS: Disease-based predictive modeling reveals a different set of predictive variables compared to general modeling and improved performance. Our findings add support to the growing body of evidence advantaging disease specific predictive modeling.

Breastfeeding in women with diabetes: lower rates despite greater rewards. A population-based study.

AIMS: To explore intention to breastfeed and breastfeeding rates in hospital and on discharge across women with pre-gestational or gestational diabetes mellitus, or no diabetes. METHODS: A retrospective cohort analysis was conducted using data from four Ontario hospitals. Women who delivered a viable infant between 1 April 2008 and 31 March 2010 were included in the study. Unadjusted and adjusted odds ratios were calculated for each outcome measure and were used to compare the breastfeeding rates among women with and without diabetes. RESULTS: After controlling for potential confounders, women with insulin-treated diabetes were less likely to intend to breastfeed, when compared with women without diabetes (adjusted odds ratio 0.49, 95% CI 0.27-0.89). In hospital, women with insulin-treated diabetes were least likely to breastfeed (odds ratio 0.42, 95% CI 0.26-0.67), followed by women with non-insulin-treated diabetes (odds ratio 0.50, 95% CI 0.26-0.96) and women with gestational diabetes (odds ratio 0.77, 95% CI 0.68-0.87) when compared with women without diabetes. On discharge, women with insulin-treated diabetes were least likely to breastfeed (odds ratio 0.38, 95% CI 0.24-0.60), followed by women with gestational diabetes (odds ratio 0.75, 95% CI 0.66-0.85); rates of breastfeeding among women with non-insulin-treated diabetes were comparable on discharge with those of women without diabetes. Women seeking care from an antenatal provider other than a physician were 2-3 times more likely to breastfeed in hospital and on discharge. CONCLUSIONS: Women with insulin-treated diabetes had the poorest outcomes with respect to breastfeeding rates. Gestational and non-insulin-treated diabetes were associated with lower rates of breastfeeding in hospital, while gestational diabetes was additionally associated with lower breastfeeding rates on discharge.

Reducing unnecessary lab testing in the ICU with artificial intelligence.

OBJECTIVES: To reduce unnecessary lab testing by predicting when a proposed future lab test is likely to contribute information gain and thereby influence clinical management in patients with gastrointestinal bleeding. Recent studies have demonstrated that frequent laboratory testing does not necessarily relate to better outcomes. DESIGN: Data preprocessing, feature selection, and classification were performed and an artificial intelligence tool, fuzzy modeling, was used to identify lab tests that do not contribute an information gain. There were 11 input variables in total. Ten of these were derived from bedside monitor trends heart rate, oxygen saturation, respiratory rate, temperature, blood pressure, and urine collections, as well as infusion products and transfusions. The final input variable was a previous value from one of the eight lab tests being predicted: calcium, PTT, hematocrit, fibrinogen, lactate, platelets, INR and hemoglobin. The outcome for each test was a binary framework defining whether a test result contributed information gain or not. PATIENTS: Predictive modeling was applied to recognize unnecessary lab tests in a real world ICU database extract comprising 746 patients with gastrointestinal bleeding. MAIN RESULTS: Classification accuracy of necessary and unnecessary lab tests of greater than 80% was achieved for all eight lab tests. Sensitivity and specificity were satisfactory for all the outcomes. An average reduction of 50% of the lab tests was obtained. This is an improvement from previously reported similar studies with average performance 37% by [1-3]. CONCLUSIONS: Reducing frequent lab testing and the potential clinical and financial implications are an important issue in intensive care. In this work we present an artificial intelligence method to predict the benefit of proposed future laboratory tests. Using ICU data from 746 patients with gastrointestinal bleeding, and eleven measurements, we demonstrate high accuracy in predicting the likely information to be gained from proposed future lab testing for eight common GI related lab tests. Future work will explore applications of this approach to a range of underlying medical conditions and laboratory tests.

Prognostic models in hepatocellular carcinoma (HCC) and statistical methodologies behind them.

Hepatocellular carcinoma (HCC) is estimated to be responsible for 250,000 deaths worldwide yearly. Aggressive surgical resection or liver transplantation still remain the only viable curative options for patients suffering the disease despite the multitude of emerging therapies for HCC. However, even with the most aggressive surgical intervention, survival varies widely within each particular stage of HCC. In order to improve utilization of available therapeutic modalities, a number of outcome prognostic models have been developed. This manuscript reviews the prognostic models most commonly utilized in clinical practice and the statistical methodologies on which these models are based. A multitude of statistical and mathematical techniques can be used for prognostic model development. The most common methodologies used for HCC prognostic model development can be generally divided into four groups: survival, artificial neural networks, analysis of variance, and cluster analysis. Survival methodologies (such as Cox proportional hazard model) are commonly employed for estimation of relative significance of risk factors for patient survival or cancer recurrence. Artificial neural networks (such as back-propagation network) can be supreme approximation tools for any continuous or binary function, and as such can be employed for prognostication of HCC recurrence (death). Analysis of variance and cluster analysis are the most common statistical tools of recently evolved microarrays technology, which, in turn, is one of the most promising tools available to the cancer researcher.

A 93 year old man with the PRSS1 R122H mutation, low SPINK1 expression, and no pancreatitis: insights into phenotypic non-penetrance.

BACKGROUND: The cationic trypsinogen (PRSS1) R122H mutation causes autosomal dominant hereditary pancreatitis (HP) with multiple attacks of acute pancreatitis, but the penetrance, frequency, and severity of attacks are highly variable. HP twins study suggests that modifier genes influence severity but not penetrance. AIM: To investigate potential trypsin associated factors in subjects with the PRSS1 R122H mutation and phenotypic non-penetrance. METHODS: Two subjects from HP families (including a 93 year old subject with PRSS1 R122H without pancreatitis), one with chronic pancreatitis and one with a normal pancreas, were studied. Relative expression of: (a) the PRSS1 R122 and H122 alleles; and (b) the PRSS1 and SPINK1 genes in pancreatitis were determined using complementary methods. RESULTS: PRSS1 wild-type (R122) and mutant (H122) allele expression was equivalent in multiple (> 3) samples from the phenotypically affected and non-penetrant subjects with R122H genotypes using allele specific quantitative reverse transcription-polymerase chain reaction (RT-PCR) and intron spanning nested RT-PCR followed by cDNA sequencing. Compared with PRSS1 mRNA levels, SPINK1 mRNA levels were low in normal appearing tissue but markedly increased in samples with chronic inflammation, independent of PRSS1 genotype. CONCLUSION: Attacks of acute pancreatitis in HP subjects appear to be independent of the relative expression of the mutant PRSS1 H122 allele or SPINK1 gene expression. The marked increase in SPINK1 gene expression with inflammation is consistent with its regulation as an acute phase protein.

Performance decrements resulting from illness in the workplace: the effect of headaches.

OBJECTIVES: Studies on the impact of illness on work productivity are important to rationally allocate healthcare resources and to design programs to mitigate these effects. This investigation was conducted to develop and apply daily measures of illness episodes, and to collect subjective and objective data on work performance impacts. Medical bill reviewers completed daily responses to a questionnaire about headache manifestations, severity, and speed of work using interactive voice response (IVR). Of 134 eligible enrolled subjects, 117 (86%) provided at least 30 daily reports over 3 months. Their responses were matched to difficulty-adjusted objective measures: daily output, time on the system, and productivity. Respondents were clinically classified as migraineurs (n = 56), other headache disorders (n = 47), or having no headache disorder (n = 14). Each headache episode was classified as a migraine or nonmigraine headache based on reported manifestations. RESULTS: The three groups were similar in a variety of demographic factors, and mean subject-specific measures of speed, output, and productivity. In a multivariate model using general estimating equations, only episode severity (not type of headache or person-specific diagnosis) was found to be associated with a significant decrement in speed or productivity. The self-reported decrement in speed (approximately 20%) was much greater than the actual measured effect on productivity (approximately 8%). Intensive daily diary collection by IVR on symptoms and work performance is feasible. However, analysis of detailed daily objective productivity data can be complex, with significant unmeasured sources of variance. Severity may be a more important determinant of headache effect on work performance than specific diagnosis. Future studies on illness episodes and work performance should measure informal accommodations that may enable employees to compensate for episodic illnesses.

Use of microsatellite marker loss of heterozygosity in accurate diagnosis of pancreaticobiliary malignancy from brush cytology samples.

BACKGROUND: Brush cytology of biliary strictures to diagnose pancreaticobiliary malignancy suffers from poor sensitivity. AIM: To improve the diagnostic yield of pancreaticobiliary brush cytology through analysis of tumour suppressor gene linked microsatellite marker loss of heterozygosity (LOH) and k-ras codon 12 mutation detection. METHODS: Twenty six patients with biliary strictures underwent endoscopic retrograde cholangiography with brush cytology. A panel of 12 polymorphic microsatellite markers linked to six tumour suppressor genes was developed. Genomic DNA from cell clusters acquired from brush cytology specimens and microdissected surgical malignant and normal tissue underwent polymerase chain amplification reaction (PCR). PCR products were compared for LOH and k-ras codon 12 mutations. RESULTS: Seventeen patients were confirmed to have pancreaticobiliary adenocarcinoma. Nine patients had benign strictures (eight proven surgically, one by follow up). Cytomorphological interpretation was positive for malignancy (n = 8), indeterminate (n = 10), and negative for malignancy (n = 8). Selected malignant appearing cytological cell clusters and microdissected histological samples from cancer showed abundant LOH characteristic of malignancy while brushings from nine cases without cancer carried no LOH (p<0.001). LOH and k-ras mutations profile of the cytological specimens was almost always concordant with the tissue samples. Presence of k-ras mutation predicted malignancy of pancreatic origin (p<0.001). CONCLUSION: LOH and k-ras codon 12 mutation analysis of PCR amplified DNA from biliary brush cytology discriminates reactive from malignant cells, with 100% sensitivity, specificity, and accuracy. Minor variations in LOH in brushings and in different sites within the same tumour likely reflect intratumoral mutational heterogeneity during clonal expansion of pre- and neoplastic lineages.

Genotypic analysis of pulmonary Langerhans cell histiocytosis.

Reported studies show that the systemic form of Langerhans cell histiocytosis (LCH) is a clonal expansion of Langerhans cells (LC) associated with aberrant expression of several oncogenes or tumor-suppressor genes. LCH of the lung is a heterogenous group of lesions thought to be a reactive rather than neoplastic process. The histogenesis of the LCH of the lung is uncertain, and to date there are no studies investigating its underlying molecular abnormalities. We performed comparative genotypic analysis by using allelic loss (LOH) of polymorphic microsatellite markers associated with tumor suppressor genes. Fourteen cases of formalin-fixed, paraffin-embedded LCH of the lung were studied. Microdissection of a total of 26 nodules from 14 patients and paired reference lung tissue was performed under stereomicroscopic visualization. To evaluate allelic loss, we used a panel of 11 polymorphic microsatellite markers that were situated at or near tumor suppressor genes on chromosomes 1p, 1q, 3p, 5p, 9p, 17p, and 22q. The PCR products were analyzed by using capillary electrophoresis to identify germline heterozygous alleles and LOH. Allelic loss at 1 or more tumor suppressor gene loci was identified in 19 of 24 nodules. The total fractional allelic loss (FAL) ranged from 6% (1q) to 41% (22q), with a mean of 22%. The FAL in individual cases ranged from 0 (7 nodules) to 57% (1 nodule). Fifteen discordant allelic losses at 1 to 3 chromosomal loci were identified in 8 patients with multiple synchronous nodules. Our results show that LOH of tumor suppressor genes is present in the LCH of the lung, and they indicate that the putative tumor suppressor genes situated on chromosomes 9p and 22q may play a role in the development of a subset of the LCH of the lung.

Biased epitope selection by recombinant vaccinia-virus (rVV)-infected mature or immature dendritic cells.

Recombinant expression vectors represent a powerful way to deliver whole antigens (Ags) for immunization. Sustained Ag expression in vector-infected dendritic cells (DC) combines Ag-specific stimulation with powerful costimulation and, simultaneously, through 'self-selection' of ad hoc epitopes broadens the scope of immunization beyond restrictions posed by individual patients' human leukocyte antigen (HLA) phenotype. In this study, therefore, we evaluated the efficiency of a recombinant vaccinia virus encoding the gp100/PMel17 melanoma Ag (rVV-gp100) to infect immature (iDC) or mature dendritic cells (mDC) derived from circulating mononuclear cells and the effect of infection on their status of maturation. In addition, we tested the ability of rVV-gp100-infected iDC and mDC to present the HLA-A*0201-associated gp100:209-217 epitope (g209). Irrespective of status of maturation, rVV-gp100 infection induced gp100 expression while only partially reversing the expression of some maturation markers. However, endogenous presentation of the wild-type g209 epitope was inefficient. The low efficiency was epitope-specific since infection of DC with rVV encoding a gp100 construct containing the modified gp100:209-217 (210M) (g209-2M) epitope characterized by high binding affinity for HLA-A*0201 restored efficient Ag presentation. Presentation of an HLA-class II-associated epitope and cytokine release by DC was not altered by rVV infection. Thus, Ag expression driven by rVV may be an efficient strategy for whole Ag delivery. However, since the effectiveness of Ag processing and presentation is subject to stringent HLA/epitope pairing, and for other yet undefined rules, the assumption that whole Ag delivery may circumvent HLA restriction is incorrect and recombinant expression vectors encoding well-characterized polyepitopic constructs may prove more effective.

Genotypic analysis of primary and metastatic cutaneous melanoma.

Microdissection genotyping was performed on 16 cases of melanoma, including two cutaneous and one lymph node metastases. Three benign nevi were used as controls. Where possible, tumor was microdissected at several sites. Genotyping involved assessment of loss of heterozygosity [LOH]), which was accomplished using a panel of nine polymorphic tetranucleotide microsatellites. Polymerase chain reaction was performed on the normal tissue sample to establish microsatellite heterozygous status. Informative markers were then tested on microdissected lesional tissue and scored for the presence and extent of allelic imbalance (AI). Microsatellite informativeness varied from 33% to 66%. Benign nevi were without AI. All invasive melanomas manifested acquired allelic loss, which involved 75% or 100% of the markers shown to be informative for each subject. Eleven of 13 (84%) primary melanomas demonstrated intratumoral heterogeneity of AI consistent with development of tumor subclones with differing genotypic profiles within thin as well as thick melanomas. Although a consistent pattern did not emerge among the markers, LOH of 9p21 (D9S254) occurred in 60% (9/15) of the cases followed by 40% of cases displaying LOH of 1p34, p53, 10q (MXI1), and 10q23 (D10S520) and 25% with 5q21 (D5S 592) abnormalities. A third of the cases including the metastatic foci demonstrated two different patterns of AI affecting alternative alleles of the same genomic marker within different parts of the melanoma. Two melanomas in situ did not display LOH of any markers in the informative cases although the in situ component in the invasive tumors had allelic losses that were in part similar to the invasive areas. The results of this study support the expanded use of microdissection genotyping and explore other markers to define the unique mutational profile for malignant melanoma that may complement other histologic characteristics of melanoma.

Healthcare expenditure in patients treated with venlafaxine or selective serotonin reuptake inhibitors for depression and anxiety.

We compared healthcare expenditure over a six-month period following initiation of therapy with either venlafaxine (immediate and extended-release) or a selective serotonin reuptake inhibitor (SSRI) in depressed patients with or without anxiety. Patients beginning treatment for a new depressive episode were identified retrospectively using the administrative data of the MEDSTAT MarketScan database for the period 1994-1999. Before beginning therapy, patients prescribed venlafaxine had more non-mental illnesses (0.85 vs 0.76; p<0.01) and hospitalisations for mental illness (0.53 vs 0.29; p<0.05) than patients prescribed SSRIs. In the six months after initiating treatment, venlafaxine was associated with lower hospitalisation expenditure for non-mental illness ($177 vs $526; p<0.01) than SSRIs, although total healthcare expenditure was not significantly different. Venlafaxine was associated with a 50% decrease in the odds of hospitalisation for non-mental illness compared with SSRIs, with significantly lower inpatient expenditure.

Prognostic value of quantitative reverse transcription-polymerase chain reaction in lymph node-negative esophageal cancer patients.

PURPOSE: In esophageal cancer, lymph node metastases are the strongest predictor of recurrence and poor outcome. However, many node-negative patients still recur despite a potentially curative resection. This is probably the result of microscopically occult metastases missed by histological examination. In this study, we used both standard, gel-based reverse transcription-PCR (RT-PCR) and Taqman quantitative RT-PCR (QRT-PCR) for carcinoembryonic antigen (CEA) mRNA to detect occult micrometastases in 387 lymph nodes from 30 histologically node-negative esophageal cancer patients. EXPERIMENTAL DESIGN: CEA expression was compared with clinical outcomes to determine correlation with disease recurrence. For quantitative data, an optimum CEA expression level cutoff value was defined as the value that most accurately classified patients on the basis of disease recurrence. Kaplan-Meier survival curves were generated, and multivariate analyses were performed to evaluate the prognostic value of QRT-PCR. RESULTS: CEA expression levels were above the optimum cutoff level in 12 tissue blocks, resulting in the identification of 11 CEA-positive patients. Of these patients, 9 suffered disease recurrence and 2 remain disease free. Of the 19 CEA-negative patients, there was 1 disease recurrence. The sensitivity and specificity for predicting disease recurrence were 90 and 90%, respectively. Kaplan-Meier analysis showed that CEA positivity resulted in significantly lower disease-free and overall survival (P <0.0001 and 0.0006 respectively). In multivariate analyses, CEA positivity measured by QRT-PCR was the strongest independent predictor of disease recurrence among other clinical and pathological factors examined. CONCLUSIONS: QRT-PCR offers significant benefits over standard RT-PCR and identifies node-negative patients at high risk for recurrence.

Myopodin, a synaptopodin homologue, is frequently deleted in invasive prostate cancers.

Prostate cancer is one of the leading causes of cancer-related deaths for men in the United States. Like other malignancies, prostate cancer is underscored by a variety of aberrant genetic alterations during its development. Although loss of heterozygosity or allelic loss is frequently identified among prostate cancers, few genes have been identified thus far as critical to the development of invasive prostate cancers. In this report, we used the recently developed technology, the "differential subtraction chain," to perform a genome-wide search for sequences that are deleted in an aggressive prostate cancer. Among the deleted sequences, we found that one sequence was deleted in >50% of prostate cancers we tested. We mapped this sequence to chromosome 4q25 by screening the Genebridge 4 hamster radiation panel with primers specific to this probe, and subsequently identify a 54-kb minimal common deletion region that contains the sequence encoding myopodin. Sequence analysis indicates that myopodin shares significant homology with synaptopodin, a protein closely associated with podocyte and neuron differentiation. Further study shows that frequent complete or partial deletions of the myopodin gene occurred among invasive prostate cancer cases (25 of 31 cases, or 80%). Statistical analysis indicates that deletion of myopodin is highly correlated with the invasiveness of prostate cancers, and thus may hold promise as an important prognostic marker for prostate cancers.

Identification of cyclin B1 as a shared human epithelial tumor-associated antigen recognized by T cells.

We eluted peptides from class I molecules of HLA-A2.1(+) breast adenocarcinoma and loaded reverse phase high-performance liquid chromatography (HPLC) fractions onto dendritic cells to prime naive CD8(+) T cells. Fractions that supported growth of tumor-specific cytotoxic T lymphocytes were analyzed by nano-HPLC micro-ESI tandem mass spectrometry. Six HLA-A2.1-binding peptides, four 9-mers (P1-P4) differing in the COOH-terminal residue, and two 10-mers (P5 and P6) with an additional COOH-terminal alanine, were identified in one fraction. Peptide sequences were homologous to cyclin B1. We primed CD8(+) T cells from another HLA-A2.1(+) healthy donor with synthetic peptides and generated P4-specific responses. We also detected memory T cells specific for one or more of these peptides in patients with breast cancer and squamous cell carcinomas of the head and neck (SCCHN). T cells from one patient, restimulated once in vitro, could kill the tumor cell line from which the peptides were derived. Immunohistochemical analysis of tumor lines and tissue sections showed cyclin B1 overexpression and aberrant localization in the cytoplasm instead of the nucleus. Sequencing genomic DNA and cDNA corresponding to P1-P6 region showed that differences in COOH-terminal residues were not due to either DNA mutations or errors in transcription, suggesting a high error rate in translation of cyclin B1 protein in tumors.

Arterial compliance abnormalities in isolated systolic hypertension.

Arterial compliance measurements using intraarterial pulse contour analysis and a modified Windkessel model were carried out in 19 patients with isolated systolic hypertension (> or = 160/< or = 90 mm Hg) and compared to measurements in 29 patients with essential hypertension (diastolic blood pressure [BP] > or = 95 mm Hg) and 47 normotensive control subjects. Arterial capacitive compliance was significantly lower in isolated systolic hypertension than in essential hypertension (P < .0002) and significantly lower in essential hypertension than in normotensive control subjects (P < .0001). Although the isolated systolic hypertension group was older than the essential hypertension group, the reduction of capacitive compliance in isolated systolic hypertension persisted even when comparison was made with a more nearly age-matched group of essential hypertension. In contrast, oscillatory compliance was reduced similarly in isolated systolic hypertension and essential hypertension compared to normotensive control subjects (P < .0001). Although pulse pressure was greater in isolated systolic hypertension than in essential hypertension, only a weak correlation (r = -0.34) existed between pulse pressure and capacitive compliance. These data indicate that both essential hypertension and isolated systolic hypertension patients exhibit comparably abnormal structure or tone of the small vessels that are the site of oscillations or reflections in the arterial vasculature. In isolated systolic hypertension there is a profound reduction in large artery or capacitive compliance that accounts for the increase in systolic BP and decrease in diastolic BP. This abnormality cannot be accurately assessed by pulse pressure alone.