A 500-kiloton airburst over Chelyabinsk and an enhanced hazard from small impactors.

Most large (over a kilometre in diameter) near-Earth asteroids are now known, but recognition that airbursts (or fireballs resulting from nuclear-weapon-sized detonations of meteoroids in the atmosphere) have the potential to do greater damage than previously thought has shifted an increasing portion of the residual impact risk (the risk of impact from an unknown object) to smaller objects. Above the threshold size of impactor at which the atmosphere absorbs sufficient energy to prevent a ground impact, most of the damage is thought to be caused by the airburst shock wave, but owing to lack of observations this is uncertain. Here we report an analysis of the damage from the airburst of an asteroid about 19 metres (17 to 20 metres) in diameter southeast of Chelyabinsk, Russia, on 15 February 2013, estimated to have an energy equivalent of approximately 500 (±100) kilotons of trinitrotoluene (TNT, where 1 kiloton of TNT = 4.185×10(12) joules). We show that a widely referenced technique of estimating airburst damage does not reproduce the observations, and that the mathematical relations based on the effects of nuclear weapons--almost always used with this technique--overestimate blast damage. This suggests that earlier damage estimates near the threshold impactor size are too high. We performed a global survey of airbursts of a kiloton or more (including Chelyabinsk), and find that the number of impactors with diameters of tens of metres may be an order of magnitude higher than estimates based on other techniques. This suggests a non-equilibrium (if the population were in a long-term collisional steady state the size-frequency distribution would either follow a single power law or there must be a size-dependent bias in other surveys) in the near-Earth asteroid population for objects 10 to 50 metres in diameter, and shifts more of the residual impact risk to these sizes.

Reliability of frailty assessment in the critically ill: a multicentre prospective observational study.

Demand for critical care among older patients is increasing in many countries. Assessment of frailty may inform discussions and decision making, but acute illness and reliance on proxies for history-taking pose particular challenges in patients who are critically ill. Our aim was to investigate the inter-rater reliability of the Clinical Frailty Scale for assessing frailty in patients admitted to critical care. We conducted a prospective, multi-centre study comparing assessments of frailty by staff from medical, nursing and physiotherapy backgrounds. Each assessment was made independently by two assessors after review of clinical notes and interview with an individual who maintained close contact with the patient. Frailty was defined as a Clinical Frailty Scale rating > 4. We made 202 assessments in 101 patients (median (IQR [range]) age 69 (65-75 [60-80]) years, median (IQR [range]) Acute Physiology and Chronic Health Evaluation II score 19 (15-23 [7-33])). Fifty-two (51%) of the included patients were able to participate in the interview; 35 patients (35%) were considered frail. Linear weighted kappa was 0.74 (95%CI 0.67-0.80) indicating a good level of agreement between assessors. However, frailty rating differed by at least one category in 47 (47%) cases. Factors independently associated with higher frailty ratings were: female sex; higher Acute Physiology and Chronic Health Evaluation II score; higher category of pre-hospital dependence; and the assessor having a medical background. We identified a good level of agreement in frailty assessment using the Clinical Frailty Scale, supporting its use in clinical care, but identified factors independently associated with higher ratings which could indicate personal bias.

Self-regulation and household routines at age three and obesity at age eleven: longitudinal analysis of the UK Millennium Cohort Study.

OBJECTIVE: To examine, in a population-based cohort of 3-year-old children, the association between self-regulation and exposure to the household routines of regular bedtime, regular mealtime and limits on watching television/video, and to determine whether self-regulation and these routines predict the risk of obesity at age 11. METHODS: Analyses included 10 955 children in the nationally representative UK Millennium Cohort Study. When children were age 3, parents reported whether children had a regular bedtime and mealtime, and the amount of television/video watched. Emotional and cognitive self-regulation at age 3 were assessed by parent-report with the Child Social Behaviour Questionnaire. Children's height and weight were measured at age 11 and obesity was defined using the International Obesity Task Force (IOTF) criteria. RESULTS: At age 3, 41% of children always had a regular bedtime, 47% always had a regular mealtime and 23% were limited to ⩽1 h television/video daily. At age 11, 6.2% of children were obese. All three household routines were significantly associated with better emotional self-regulation, but not better cognitive self-regulation. In a multi-variable logistic regression model, including emotional and cognitive self-regulation, all routines and controlling for sociodemographic covariates, a 1-unit difference in emotional self-regulation at age 3 was associated with an OR (95% CI) for obesity of 1.38 (1.11, 1.71) at age 11, and inconsistent bedtimes with an OR (95% CI) for obesity of 1.87 (1.39, 2.51) at age 11. There was no evidence that emotional self-regulation mediated the relationship between regular bedtimes and later obesity. Cognitive self-regulation was not associated with later obesity. CONCLUSIONS: Three-year-old children who had regular bedtimes, mealtimes and limits on their television/video time had better emotional self-regulation. Lack of a regular bedtime and poorer emotional self-regulation at age 3 were independent predictors of obesity at age 11.

"Snacks are not food". Low-income, urban mothers' perceptions of feeding snacks to their preschool-aged children.

Snacking has become more frequent among US preschool-aged children in recent decades and represents a significant proportion of daily energy intake. Social influences on snacking among children, however, are not well understood. This qualitative research described low-income, urban mothers' perceptions of feeding snacks to their preschool-aged children using data from 7 focus groups with 32 participants. Focus group transcripts were analyzed using a constant comparative method to identify themes. Mothers described snacks as involving less preparation, balance, and sustenance than meals (Theme 1). Mothers also made reference to some snacks as not being "real food" (Theme 2). At the same time, snacks had significant hedonic value as reflected in mothers' enjoyment of those foods (Theme 3), the effectiveness of snacks to manage children's behavior (Theme 4), and the variety of restrictions that mothers placed on children's access to snacks, such as locking cabinets, offering small servings, and reducing the number of snacks in sight (Theme 5). Two overarching themes highlighted distinctions mothers made in feeding children snacks vs. meals as well as the powerful hedonic appeal of snacks for both mother and child. These observations suggest that low-income, urban mothers of preschool-aged children may perceive snacks as serving a more important role in managing children's behavior than in providing nutrition. Child feeding interventions should address non-food related ways of managing children's behavior as well as encouraging caregivers to see snacks as structured opportunities for nutrition and connecting with their children.

Teachers' perceptions about children's movement and learning in early childhood education programmes.

BACKGROUND: Efforts to improve the academic skills of preschool-aged children have resulted in approaches that tend to limit children's movement. However, movement experiences have long been considered important to children's learning and have received increased attention because of the obesity epidemic. Early childhood educators are important sources of information about if and how to promote learning and school readiness through movement, but little effort has been made to understand teachers' views on this topic. METHODS: We conducted six focus groups with 37 teachers from a Head Start programme with centres in three cities in eastern Pennsylvania. We inquired about: (1) how movement influences children's learning; (2) what types of movement experiences are most beneficial for children; (3) what settings best support children's movement; and (4) challenges related to children's movement. To identify key themes from the focus groups, transcripts were analysed using an inductive method of coding. RESULTS: Teachers' views were expressed in four major themes. First, young children have an innate need to move, and teachers respond to this need by using movement experiences to prepare children to learn and to teach academic concepts and spatial awareness. However, teachers wanted more training in these areas. Second, movement prepares children for school and for life by building children's confidence and social skills. Third, teachers and children benefit from moving together because it motivates children and promotes teacher-child relationships. Finally, moving outdoors promotes learning by engaging children's senses and promoting community interaction. CONCLUSIONS: More training may be required to help early childhood educators use movement experiences to teach academic concepts and improve children's spatial awareness. Future interventions could examine the impacts on children's movement and learning of having teachers move with children during outdoor free play and including more natural features in the design of outdoor play areas.

The Viking viewer for connectomics: scalable multi-user annotation and summarization of large volume data sets.

Modern microscope automation permits the collection of vast amounts of continuous anatomical imagery in both two and three dimensions. These large data sets present significant challenges for data storage, access, viewing, annotation and analysis. The cost and overhead of collecting and storing the data can be extremely high. Large data sets quickly exceed an individual's capability for timely analysis and present challenges in efficiently applying transforms, if needed. Finally annotated anatomical data sets can represent a significant investment of resources and should be easily accessible to the scientific community. The Viking application was our solution created to view and annotate a 16.5 TB ultrastructural retinal connectome volume and we demonstrate its utility in reconstructing neural networks for a distinctive retinal amacrine cell class. Viking has several key features. (1) It works over the internet using HTTP and supports many concurrent users limited only by hardware. (2) It supports a multi-user, collaborative annotation strategy. (3) It cleanly demarcates viewing and analysis from data collection and hosting. (4) It is capable of applying transformations in real-time. (5) It has an easily extensible user interface, allowing addition of specialized modules without rewriting the viewer.

Variation in rapid sequence induction techniques: current practice in Wales.

A questionnaire survey examining rapid sequence induction techniques was sent to all anaesthetists in Wales. The questionnaire presented five common clinical scenarios: emergency appendicectomy; elective knee arthroscopy with a symptomatic hiatus hernia; elective knee arthroscopy with an asymptomatic hiatus hernia; elective Caesarean section; and emergency laparotomy for bowel obstruction. Completed surveys were received from 421 anaesthetists, a 68% response rate. Rapid sequence induction was chosen by 398/400 respondents (100%) for bowel obstruction, 392/399 (98%) for Caesarean section, 388/408 (95%) for appendicectomy, 328/395 (83%) for symptomatic hiatus hernia but only 98/399 (25%) for asymptomatic hiatus hernia (p < 0.001). Trainees were more likely to use a rapid sequence induction technique than consultants and staff grades for the appendicectomy (p = 0.025), symptomatic hiatus hernia (p = 0.004) and asymptomatic hiatus hernia (p = 0.001) scenarios and were also more likely to use a thiopental-suxamethonium combination for rapid sequence induction (p < 0.001).

The search for the definition, etiology, and effective diagnosis of upper urinary tract obstruction: the Whitaker test then and now.

INTRODUCTION: Robert Whitaker, inspired by Dr William W Scott at the Brady Institute at Johns Hopkins and by Sir David Innes Williams at Great Ormond Street Hospital for Children in the late 1960s, spent much of his career exploring the meaning of persistent dilatation of the upper urinary tract, in an attempt to define obstruction and to find a means of diagnosing it accurately. OBJECTIVE: This is a historical review of Bob Whitaker's journey from his definition of obstruction to the inception of his eponymous test. RESULTS: In 1975, he proposed a theory to explain the pathophysiology behind obstructive hydronephrosis and megaureter. He was among the first pediatric urologists to observe that 'it is wrong… to assume that dilatation necessarily indicates obstruction', a statement that was widely stated and even appeared in the textbooks at the time. He defined obstruction as 'an increased pressure in the pelvicalyceal system of the kidney at normal physiological flow rates such that the renal function is adversely affected'. This realization led to the development of a percutaneous pressure-measuring technique at controlled flows, later referred to as the Whitaker test. It predated and later assisted in the interpretation of diuretic renograms. DISCUSSION: Whitaker questioned the etiology of 'hydronephrosis' and challenged other hypotheses proposed at the time, which often included causes of mechanical occlusion at the ureteropelvic junction (UPJ) or ureterovesical junction (UVJ). Whitaker's hypothesis is that 'obstruction' at UPJ and UVJ levels is not mechanical but the result of a failure of normal peristalsis to form and propagate a bolus. This, in turn, depends on the potentially abnormal distensibility of the renal pelvic and ureteric wall whether it be congenital or acquired. The aim of this review is to recall the history of the development of a technique to evaluate dilated upper urinary tracts and to re-evaluate various theories that might explain the etiology of the dilatation in the light of more recent evidence. Robert (or Bob, to his colleagues) Whitaker was among the founder members of the British Association of Paediatric Urologists, which now has more than 50 members, in 1992. Together with his colleagues Philip Ransley and David Thomas, Whitaker established the annual pediatric urology course for pediatric surgery and urology trainees in Cambridge, U.K., which still runs to this day. He retired from his surgical practice in 1990 and up until the present time has taught clinical anatomy in the Cambridge University School of Medicine.

The aromatic amino acid pathway branches at L-arogenate in Euglena gracilis.

The recently characterized amino acid L-arogenate (Zamir et al., J. Am. Chem. Soc. 102:4499-4504, 1980) may be a precursor of either L-phenylalanine or L-tyrosine in nature. Euglena gracilis is the first example of an organism that uses L-arogenate as the sole precursor of both L-tyrosine and L-phenylalanine, thereby creating a pathway in which L-arogenate rather than prephenate becomes the metabolic branch point. E. gracilis ATCC 12796 was cultured in the light under myxotrophic conditions and harvested in late exponential phase before extract preparation for enzymological assays. Arogenate dehydrogenase was dependent upon nicotinamide adenine dinucleotide phosphate for activity. L-Tyrosine inhibited activity effectively with kinetics that were competitive with respect to L-arogenate and noncompetitive with respect to nicotinamide adenine dinucleotide phosphate. The possible inhibition of arogenate dehydratase by L-phenylalanine has not yet been determined. Beyond the latter uncertainty, the overall regulation of aromatic biosynthesis was studied through the characterization of 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase and chorismate mutase. 3-Deoxy-D-arabino-heptulosonate 7-phosphate synthase was subject to noncompetitive inhibition by L-tyrosine with respect to either of the two substrates. Chorismate mutase was feedback inhibited with equal effectiveness by either L-tyrosine or L-phenylalanine. L-Tryptophan activated activity of chorismate mutase, a pH-dependent effect in which increased activation was dramatic above pH 7.8 L-Arogenate did not affect activity of 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase or of chorismate mutase. Four species of prephenate aminotransferase activity were separated after ion-exchange chromatography. One aminotransferase exhibited a narrow range of substrate specificity, recognizing only the combination of L-glutamate with prephenate, phenylpyruvate, or 4-hydroxyphenylpyruvate. Possible natural relationships between Euglena spp. and fungi previously considered in the literature are discussed in terms of data currently available to define enzymological variation in the shikimate pathway.

Clonal origin of epithelial ovarian carcinoma: analysis by loss of heterozygosity, p53 mutation, and X-chromosome inactivation.

BACKGROUND: It has been suggested that multiple sites of epithelial ovarian carcinoma on the peritoneal surface reflect polyclonal disease arising from multiple primary tumors in the peritoneal mesothelium, rather than monoclonal disease spread by metastases from one primary ovarian cancer. PURPOSE: The purpose of this study was to investigate whether ovarian cancer has a monoclonal or polyclonal origin. METHODS: DNA specimens were obtained from peripheral blood lymphocytes (normal DNA) and from multiple tumor deposits of 17 women with epithelial ovarian carcinoma: primary tumors, metastatic deposits, and ascites. The clonal origin of each tumor was determined by performing (a) analysis to detect loss of heterozygosity at five loci on chromosomes 5, 11, 13, and 17; (b) sequencing of exons 5-8 of the p53 gene; and (c) X-chromosome inactivation analysis of the phosphoglycerate kinase (PGK) gene. RESULTS: In 15 of the 17 cases analyzed, there was clear evidence of monoclonal origin. The probability that the genetic events documented in these 15 cases occurred as independent events in each tumor deposit ranged from 2.5 x 10(-1) to 3.7 x 10(-16). In two cases, the pattern of allelic deletion and p53 gene mutation was compatible with either a monoclonal origin or origin from two primary ovarian tumors. CONCLUSIONS: The results did not support the hypothesis that ovarian cancer is a multifocal, polyclonal disease. Instead, the data suggest that sporadic epithelial ovarian carcinoma has either a monoclonal or a dual primary origin. IMPLICATIONS: These findings have important implications for understanding of the natural history of ovarian cancer and for clinical strategies aimed at prevention and early detection. Further studies will be required to determine the clonal origin of familial hereditary ovarian cancer.

Mucin gene expression in ovarian cancers.

Ovarian cancer is a highly lethal disease with metastases present in the majority of patients at the time of diagnosis. The molecular mechanisms underlying the metastatic process of this cancer are not well understood. One family of cell-associated and secreted glycoproteins, the mucin glycoproteins, has been implicated in events leading to metastasis of several epithelial cancers including gastrointestinal and lung cancers. The purpose of this study was to characterize mucin gene expression in ovarian cancers and relate expression to tumor histology, stage, and patient survival. RNA was isolated from 29 epithelial ovarian cancers, 1 neuroendocrine carcinoma, 3 mixed mesodermal tumors, and two transformed, yet nonmalignant, ovarian epithelial cell lines. The expression of mucin genes, MUC1, 2, 3, 4, 5AC and 5B, was determined by northern analyses. Epithelial ovarian cancers expressed several mucins including MUC1, 2, 4, and 5AC; MUC3 and 5B were rarely expressed. In contrast, the transformed nonmalignant ovarian epithelial cell lines expressed only MUC1 and 5AC. Although there was no correlation of mucin expression with tumor histology, there was a significant decrease in expression of MUC3 and MUC4 with increasing cancer stage (P < 0.05). In addition, a trend toward improved patient survival occurred with increased expression of MUC4. These observations suggest a relationship between mucin gene expression and the metastatic process in epithelial ovarian cancers. Additional investigation of MUC3 and MUC4 in ovarian cancers may lead to new approaches for early detection and therapy.

Overexpression of HER-2/neu is associated with poor survival in advanced epithelial ovarian cancer.

Previous studies have suggested that overexpression of HER-2/neu oncogene occurs in 15-40% of breast cancers and that overexpression is associated with poor prognosis. In the present report, we have used an immunohistochemical technique involving a monoclonal antibody specifically reactive with the external domain of HER-2/neu to study expression of HER-2/neu in frozen sections of normal ovary and advanced epithelial ovarian cancer. The intensity of staining for HER-2neu was always moderate or less (0-2+) in normal ovarian epithelium. Among 73 ovarian cancers, 50 (68%) had staining similar to that for normal ovarian epithelium (0-2+) while 23 (32%) stained heavily (3+). Survival of the 23 patients with high HER-2/neu expression (median, 15.7 months) was significantly worse (P = 0.001) than that of the 50 patients (median, 32.8 months) with normal HER-2/neu expression. In addition, patients whose tumors had high HER-2/neu expression were significantly less likely to have a complete response to primary therapy (P less than 0.05) or have a negative second-look laparotomy when serum CA 125 levels were normal preoperatively (P less than 0.05). These findings suggest that HER-2/neu deserves further evaluation as a prognostic marker in epithelial ovarian cancer.

Regulation of apoptosis in normal and malignant ovarian epithelial cells by transforming growth factor beta.

Previously, we found that transforming growth factor beta (TGF-beta) inhibits proliferation of normal human ovarian epithelial cells. In addition, although only 1 of 5 immortalized ovarian cancer cell lines was inhibited, TGF-beta inhibited proliferation of 19 of 20 primary epithelial ovarian cancers. In this study, we examined whether TGF-beta induces apoptosis in normal and malignant ovarian epithelial cells. Among 5 immortalized cell lines, only OVCA 420 is markedly growth inhibited by TGF-beta, and this was the only cell line in which TGF-beta elicited DNA fragmentation characteristic of apoptosis. Induction of apoptosis in OVCA 420 was time and concentration dependent and could be partially inhibited by concurrent treatment with an anti-TGF-beta mAb. Although apoptosis was not seen in normal ovarian epithelial cells (n = 7), [3H]thymidine incorporation was inhibited in all cases [mean = 61.2 +/- 7.2% (SD) of untreated control; P < 0.01]. Similarly, TGF-beta inhibited [3H]thymidine incorporation in all 10 primary ovarian cancers (mean = 40.4 +/- 7.1% of control; P < 0.01), but only 3 of 10 (30%) were found to undergo apoptosis when treated with TGF-beta. There was no relationship between p53 status of the ovarian cancers and the ability of TGF-beta to elicit apoptosis. In conclusion, TGF-beta inhibits proliferation but does not induce apoptosis in normal human ovarian epithelial cells. In contrast, some ovarian cancers that are growth inhibited by TGF-beta also undergo apoptosis. These data are consistent with the hypothesis that malignant cells are more susceptible to apoptosis than their normal nontransformed counterparts.

Tumor necrosis factor alpha as an autocrine and paracrine growth factor for ovarian cancer: monokine induction of tumor cell proliferation and tumor necrosis factor alpha expression.

Ovarian tumor cells produce macrophage colony stimulating factor, a potent chemoattractant for monocytes. Monocytes and macrophages produce tumor necrosis factor alpha (TNF-alpha) and interleukin 1 alpha or interleukin 1 beta (IL-1 beta) that can stimulate ovarian tumor cell growth. The present study has explored whether paracrine stimulation by monocyte derived cytokines might induce autocrine growth stimulation of normal and malignant ovarian epithelial cells. Endogenous expression of TNF-alpha mRNA was detected in ascites ovarian cancer cells isolated directly from patients, but not in established cultures of normal or malignant ovarian epithelial cells. When ascites tumor cells were cultured for 7 days, TNF-alpha expression ceased but could be reinduced by treatment with TNF-alpha or IL-1 beta. Ascites fluid contained concentrations of the cytokines that could mediate these effects. Similarly, treatment of normal or malignant ovarian epithelial cells with purified recombinant IL-1 beta or TNF-alpha induced transcription of TNF-alpha mRNA within 1 h. TNF-alpha protein could be detected by enzyme-linked immunosorbent assay in conditioned medium from IL-1 beta treated ovarian cancer cells. [3H]thymidine incorporation by normal or malignant ovarian epithelial cells was stimulated by a 24-h incubation with IL-1 beta or TNF-alpha. Stimulation of proliferation by IL-1 beta could be partially blocked by an antibody against TNF-alpha or by soluble TNF-alpha-receptor. Thus, TNF-alpha may function as both an autocrine and a paracrine growth factor in ovarian cancer.

A mutant of BamHI restriction endonuclease which requires N6-methyladenine for cleavage.

Amino acid residues Asn116 and Ser118 of the restriction endonuclease BamHI make several sequence-specific and water-bridged contacts to the DNA bases. An in vivo selection was used to isolate BamHI variants at position 116, 118 and 122 which maintained sequence specificity to GGATCC sites. Here, the variants N116H, N116H/S118G and S118G were purified and characterized. The variants N116H and N116H/S118G were found to have lost their ability to cleave unmethylated GGATCC sequences by more than two orders of magnitude, while maintaining nearly wild-type levels of activity on the N6-methyladenine-containing sequence, GGmATCC. In contrast, wild-type BamHI and variant S118G have only a three- to fourfold lower activity on unmethylated GGATCC sequences compared with GGmATCC sequences. The N116 to H116 mutation has effectively altered the specificity of BamHI from an endonuclease which recognizes and cleaves GGATCC and GGmATC, to an endonuclease which only cleaves GGmATCC. The N116H change of specificity is due to the lowered binding affinity for the unmethylated sequence because of the loss of two asparagine-DNA hydrogen bonds and the introduction of a favorable van der Waals contact between the imidazole group of histidine and the N6-methyl group of adenine.

Genetic analysis of the base-specific contacts of BamHI restriction endonuclease.

Here, we investigate the highly specific interaction of the BamHI endonuclease with its cognate recognition sequence GGATCC by determining which amino acid residues can be substituted at the DNA interface while maintaining specificity. Mutational studies, together with the structural determination of the restriction endonuclease BamHI have revealed the amino acid residues which are involved in DNA catalysis and those which play a role in the specific binding of the enzyme to its cognate DNA recognition sequence. Amino acid residues N116, S118, R122, D154 and R155 are involved in DNA sequence recognition and are located in the major groove in close proximity to the nucleotide bases comprising the recognition sequence. Cassette mutagenesis of these amino acids, together with in vivo transcriptional interference selection, was used to identify an array of substitutions which maintain site-specific binding to the cognate GGATCC sequence. This approach has demonstrated the extent of acceptable variation among amino acid residues which are directly involved in site-specific binding. One variant, double mutant N116H, S118G was found to cleave DNA only when the adenine base in the recognition site is methylated.

The prognostic significance of angiogenesis in epithelial ovarian carcinoma.

The molecular biology underlying the metastatic process in ovarian carcinoma remains poorly understood. For other neoplasms, the induction of angiogenesis by malignant cells has been shown to play a pivotal role in the process of tumor proliferation and metastasis. The purpose of this study was to characterize the degree of angiogenesis in epithelial ovarian malignancies and to determine whether the degree of neovascularization has prognostic significance for survival. Tissue sections obtained from 88 ovarian cancer patients were examined immunohistochemically for angiogenesis after staining with anti-human endothelial cell antibodies to von Willebrand factor and CD31. Light microscopy was performed, and individual microvessel counts were quantified at high power (x400). A chart review was completed, collating data regarding age, stage, grade, status of disease, and survival. Statistical exploratory methods were used to find potentially useful prognostic cutpoints for marker values of angiogenesis. Of the total 88 patients, tissue microvessel counts from 85 were evaluated via antibodies to von Willebrand factor and 87 for CD31. Overall, median survival was 2.7 years in women with cancers containing high microvessel counts versus 7.9 years in those with low microvessel counts (P = 0.03). A low microvessel count was associated with better 5-year survival in both early stage (I and II) and advanced stage (III and IV) disease. Our data suggest that the degree of neovascularization may have prognostic significance in epithelial ovarian carcinoma, especially for women with early-stage disease. In this group of women, the degree of angiogenesis may allow the selection of women at high risk for recurrence who may benefit from aggressive adjuvant therapy.

Heregulin and agonistic anti-p185(c-erbB2) antibodies inhibit proliferation but increase invasiveness of breast cancer cells that overexpress p185(c-erbB2): increased invasiveness may contribute to poor prognosis.

Overexpression of p185(c-erbB2) (p185/NEU/HER2) by tumor cells is associated with a poor prognosis in many but not all studies of breast and ovarian cancer. The poor prognosis associated with overexpression of p185(c-erbB2) could result from an increased growth rate or increased invasive potential. The p185(c-erbB2) tyrosine kinase receptor can be activated with agonistic antibodies directed against p185(c-erbB2) or with the ligand heregulin through a combinatorial interaction with erbB3 or erbB4. Consequently, we have asked whether heregulin or agonistic antibodies increase anchorage-independent growth or invasiveness of the SKBr3 breast cancer cell line, which overexpresses p185(c-erbB2). Incubation of SKBr3 breast cancer cells with heregulin inhibited anchorage-independent growth while enhancing tyrosine phosphorylation of p185(c-erbB2). Heregulin treatment also increased adhesion of SKBr3 cells to plastic and increased invasiveness of tumor cells into Matrigel membranes while increasing expression of the CD44 (HCAM) and CD54 (ICAM-1) adhesion molecules. Tumor cell invasion of Matrigel membranes was partially blocked by either anti-CD44 or anti-CD54 antibodies, indicating a role for these adhesion molecules in the invasion process. Compatible with the increased invasiveness, heregulin increased expression of the matrix metalloproteinase 9. In contrast, the agonistic anti-p185(c-erbB2) antibody ID5 induced only a subset of the responses induced by heregulin. ID5 induced tyrosine phosphorylation of p185(c-erbB2), increased invasiveness, and increased expression of CD44. Despite the similarity of effects of ID5 and heregulin on some outcomes, the ID5 antibody failed to increase adhesion to plastic, expression of CD54, or production of matrix metalloproteinase 9. Thus, the ID5 agonistic anti-p185(c-erbB2) antibody mimics rather than antagonizes some but not all of the actions of heregulin. Moreover, the poor prognosis of breast and ovarian cancers that overexpress p185(c-erbB2) could relate in part to enhanced invasiveness rather than to increased proliferative capacity.

Evaluation of a pediatric hospitalist service: impact on length of stay and hospital charges.

OBJECTIVES: Inpatient medical services supervised by pediatric hospitalist physicians are a new development in academic medical centers in the United States. In a large pediatric teaching hospital, we compared length of stay, readmission rates, and hospital charges for children admitted to medical services with and without a hospitalist system of care. DESIGN: This retrospective observational study compared a baseline year of a traditional ward service (TS) with a subsequent year of a new hospitalist system of care called the Generalist Inpatient Service (GIS). Data were obtained from the hospital's clinical, demographic, and financial databases and from selected record review. All hospitalizations were at least 24 hours long and did not involve a stay in an intensive care unit. RESULTS: The average length of stay was longer for the 627 TS hospitalizations than for the 813 GIS hospitalizations (2.7 +/- 2.0 vs 2.4 +/- 1.7 days). Total hospital charges were significantly lower on the GIS ($3002 +/- $2160 vs $2720 +/- $1933) because of lower room and respiratory therapy charges. Three readmissions to the TS and 8 to the GIS occurred within 24 hours of hospital discharge and were, therefore, considered potentially preventable by a longer initial hospital stay. CONCLUSIONS: In a large pediatric teaching hospital, a system of inpatient care provided by hospitalists can reduce length of stay. This model has the potential to control hospital charges in a period of increasing health care costs.