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Discusses examples of scaling laws in economics and finance. Importance of regularities in data for disciplining theory formation; Primary goal of econometric work; Challenges that face emprirical and theoretical researchers who wish to make use of scaling law type regularities.

Cultural learning represents a novel problem in that an optimal decision depends not only on intrinsic utility of the decision/behavior but also on transparency of costs and benefits, the degree of social versus individual learning, and the relative popularity of each possible choice in a population. In terms of a fitness-landscape function, this recursive relationship means that multiple equilibria can exist. Here we use discrete-choice theory to construct a fitness-landscape function for a bi-axial decision-making map that plots the magnitude of social influence in the learning process against the costs and payoffs of decisions. Specifically, we use econometric and statistical methods to estimate not only the fitness function but also movements along the map axes. To search for these equilibria, we employ a hill-climbing algorithm that leads to the expected values of optimal decisions, which we define as peaks on the fitness landscape. We illustrate how estimation of a measure of transparency, a measure of social influence, and the associated fitness landscape can be accomplished using panel data sets., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Discrete choice, coupled with social influence, plays a significant role in evolutionary studies of human fertility, as investigators explore how and why reproductive decisions are made. We have previously proposed that the relative magnitude of social influence can be compared against the transparency of pay-off, also known as the transparency of a decision, through a heuristic diagram that maps decision-making along two axes. The horizontal axis represents the degree to which an agent makes a decision individually versus one that is socially influenced, and the vertical axis represents the degree to which there is transparency in the pay-offs and risks associated with the decision the agent makes. Having previously parametrized the functions that underlie the diagram, we detail here how our estimation methods can be applied to real-world datasets concerning sexual health and contraception., (© 2016 The Author(s).)

Variable flows of food, water, or other ecosystem services complicate planning. Management strategies that decrease variability and increase predictability may therefore be preferred. However, actions to decrease variance over short timescales (2-4 y), when applied continuously, may lead to long-term ecosystem changes with adverse consequences. We investigated the effects of managing short-term variance in three well-understood models of ecosystem services: lake eutrophication, harvest of a wild population, and yield of domestic herbivores on a rangeland. In all cases, actions to decrease variance can increase the risk of crossing critical ecosystem thresholds, resulting in less desirable ecosystem states. Managing to decrease short-term variance creates ecosystem fragility by changing the boundaries of safe operating spaces, suppressing information needed for adaptive management, cancelling signals of declining resilience, and removing pressures that may build tolerance of stress. Thus, the management of variance interacts strongly and inseparably with the management of resilience. By allowing for variation, learning, and flexibility while observing change, managers can detect opportunities and problems as they develop while sustaining the capacity to deal with them.

Studies of the evolution of collective behavior consider the payoffs of individual versus social learning. We have previously proposed that the relative magnitude of social versus individual learning could be compared against the transparency of payoff, also known as the "transparency" of the decision, through a heuristic, two-dimensional map. Moving from west to east, the estimated strength of social influence increases. As the decision maker proceeds from south to north, transparency of choice increases, and it becomes easier to identify the best choice itself and/or the best social role model from whom to learn (depending on position on east-west axis). Here we show how to parameterize the functions that underlie the map, how to estimate these functions, and thus how to describe estimated paths through the map. We develop estimation methods on artificial data sets and discuss real-world applications such as modeling changes in health decisions.

Recent human population increase has been enabled by a massive expansion of global agricultural production. A key component of this "Green Revolution" has been application of inorganic fertilizers to produce and maintain high crop yields. However, the long-term sustainability of these practices is unclear given the eutrophying effects of fertilizer runoff as well as the reliance of fertilizer production on finite non-renewable resources such as mined phosphate- and potassium-bearing rocks. Indeed, recent volatility in food and agricultural commodity prices, especially phosphate fertilizer, has raised concerns about emerging constraints on fertilizer production with consequences for its affordability in the developing world. We examined 30 years of monthly prices of fertilizer commodities (phosphate rock, urea, and potassium) for comparison with three food commodities (maize, wheat, and rice) and three non-agricultural commodities (gold, nickel, and petroleum). Here we show that all commodity prices, except gold, had significant change points between 2007-2009, but the fertilizer commodities, and especially phosphate rock, showed multiple symptoms of nonlinear critical transitions. In contrast to fertilizers and to rice, maize and wheat prices did not show significant signs of nonlinear dynamics. From these results we infer a recent emergence of a scarcity price in global fertilizer markets, a result signaling a new high price regime for these essential agricultural inputs. Such a regime will challenge on-going efforts to establish global food security but may also prompt fertilizer use practices and nutrient recovery strategies that reduce eutrophication.

A number of ecosystems can exhibit abrupt shifts between alternative stable states. Because of their important ecological and economic consequences, recent research has focused on devising early warning signals for anticipating such abrupt ecological transitions. In particular, theoretical studies show that changes in spatial characteristics of the system could provide early warnings of approaching transitions. However, the empirical validation of these indicators lag behind their theoretical developments. Here, we summarize a range of currently available spatial early warning signals, suggest potential null models to interpret their trends, and apply them to three simulated spatial data sets of systems undergoing an abrupt transition. In addition to providing a step-by-step methodology for applying these signals to spatial data sets, we propose a statistical toolbox that may be used to help detect approaching transitions in a wide range of spatial data. We hope that our methodology together with the computer codes will stimulate the application and testing of spatial early warning signals on real spatial data.

The behavioral sciences have flourished by studying how traditional and/or rational behavior has been governed throughout most of human history by relatively well-informed individual and social learning. In the online age, however, social phenomena can occur with unprecedented scale and unpredictability, and individuals have access to social connections never before possible. Similarly, behavioral scientists now have access to "big data" sets - those from Twitter and Facebook, for example - that did not exist a few years ago. Studies of human dynamics based on these data sets are novel and exciting but, if not placed in context, can foster the misconception that mass-scale online behavior is all we need to understand, for example, how humans make decisions. To overcome that misconception, we draw on the field of discrete-choice theory to create a multiscale comparative "map" that, like a principal-components representation, captures the essence of decision making along two axes: (1) an east-west dimension that represents the degree to which an agent makes a decision independently versus one that is socially influenced, and (2) a north-south dimension that represents the degree to which there is transparency in the payoffs and risks associated with the decisions agents make. We divide the map into quadrants, each of which features a signature behavioral pattern. When taken together, the map and its signatures provide an easily understood empirical framework for evaluating how modern collective behavior may be changing in the digital age, including whether behavior is becoming more individualistic, as people seek out exactly what they want, or more social, as people become more inextricably linked, even "herdlike," in their decision making. We believe the map will lead to many new testable hypotheses concerning human behavior as well as to similar applications throughout the social sciences.

In a recent New York Times column (April 15, 2013), David Brooks discussed how the big-data agenda lacks a coherent framework of social theory – a deficiency that the Bentley, O'Brien, and Brock (henceforth BOB) model was meant to overcome. Or, stated less pretentiously, the model was meant as a first step in that direction – a map that hopefully would serve as a minimal, practical, and accessible framework that behavioral scientists could use to analyze big data. Rather than treating big data as a record of, and also a predictor of, where and when certain behaviors might take place, the BOB model is interested in what big data reveal about how decisions are being made, how collective behavior evolves from daily to decadal time scales, and how this varies across communities.

The variability in radiosensitivity across the human population is governed in part by genetic factors. The ability to predict therapeutic response, identify individuals at greatest risk for adverse clinical responses after therapeutic radiation doses, or identify individuals at high risk for carcinogenesis from environmental or medical radiation exposures has a medical and economic impact on both the individual and society at large. As radiotherapy incorporates particles, particularly particles larger than protons, into therapy, the need for such discriminators, (i.e., biomarkers) will become ever more important. Cellular assays for survival, DNA repair, or chromatid/chromosomal analysis have been used to identify at-risk individuals, but they are not clinically applicable. Newer approaches, such as genome-wide analysis of gene expression or single nucleotide polymorphisms and small copy number variations within chromosomes, are examples of technologies being applied to the discovery process. Gene expression analysis of primary or immortalized human cells suggests that there are distinct gene expression patterns associated with radiation exposure to both low and high linear energy transfer radiations and that those most radiosensitive are discernible by their basal gene expression patterns. However, because the genetic alterations that drive radio response may be subtle and cumulative, the need for large sample sizes of specific cell or tissue types is required. A systems biology approach will ultimately be necessary. Potential biomarkers from cell lines or animal models will require validation in a human setting where possible and before being considered as a credible biomarker some understanding of the molecular mechanism is necessary.

Many dynamical systems, including lakes, organisms, ocean circulation patterns, or financial markets, are now thought to have tipping points where critical transitions to a contrasting state can happen. Because critical transitions can occur unexpectedly and are difficult to manage, there is a need for methods that can be used to identify when a critical transition is approaching. Recent theory shows that we can identify the proximity of a system to a critical transition using a variety of so-called 'early warning signals', and successful empirical examples suggest a potential for practical applicability. However, while the range of proposed methods for predicting critical transitions is rapidly expanding, opinions on their practical use differ widely, and there is no comparative study that tests the limitations of the different methods to identify approaching critical transitions using time-series data. Here, we summarize a range of currently available early warning methods and apply them to two simulated time series that are typical of systems undergoing a critical transition. In addition to a methodological guide, our work offers a practical toolbox that may be used in a wide range of fields to help detect early warning signals of critical transitions in time series data.

Abrupt changes in dynamics of an ecosystem can sometimes be detected using monitoring data. Using nonparametric methods that assume minimal knowledge of the underlying structure, we compute separate estimates of the drift (deterministic) and diffusion (stochastic) components of a general dynamical process, as well as an indicator of the conditional variance. Theory and simulations show that nonparametric conditional variance rises prior to critical transition. Nonparametric diffusion rises also, in cases where the true diffusion function involves a critical transition (sometimes called a noise-induced transition). Thus it is possible to discriminate noise-induced transitions from other kinds of critical transitions by comparing time series for the conditional variance and the diffusion function. Monte Carlo analysis shows that the indicators generally increase prior to the transition, but uncertainties of the indicators become large as the ecosystem approaches the transition point.

As public and political debates often demonstrate, a substantial disjoint can exist between the findings of science and the impact it has on the public. Using climate-change science as a case example, we reconsider the role of scientists in the information-dissemination process, our hypothesis being that important keywords used in climate science follow "boom and bust" fashion cycles in public usage. Representing this public usage through extraordinary new data on word frequencies in books published up to the year 2008, we show that a classic two-parameter social-diffusion model closely fits the comings and goings of many keywords over generational or longer time scales. We suggest that the fashions of word usage contributes an empirical, possibly regular, correlate to the impact of climate science on society.

The tools for predicting clinical outcome after radiotherapy are not yet optimal. To improve on this, we applied the COXEN informatics approach to in vitro radiation sensitivity data of transcriptionally profiled human cells and gene expression data from untreated head and neck squamous cell carcinoma (HNSCC) and bladder tumors to generate a multigene predictive model that is independent of histologic findings and reports on tumor radiosensitivity. The predictive ability of this 41-gene model was evaluated in patients with HNSCC and was found to stratify clinical outcome after radiotherapy. In contrast, this model was not useful in stratifying similar patients not treated with radiation. This led us to hypothesize that expression of some of the 41 genes contributes to tumor radioresistance and clinical recurrence. Hence, we evaluated the expression the 41 genes as a function of in vitro radioresistance in the NCI-60 cancer cell line panel and found cyclophilin B (PPIB), a peptidylprolyl isomerase and target of cyclosporine A (CsA), had the strongest direct correlation. Functional inhibition of PPIB by small interfering RNA depletion or CsA treatment leads to radiosensitization in cancer cells and reduced cellular DNA repair. Immunohistochemical evaluation of PPIB expression in patients with HNSCC was found to be associated with outcome after radiotherapy. This work demonstrates that a novel 41-gene expression model of radiation sensitivity developed in bladder cancer cell lines and human skin fibroblasts predicts clinical outcome after radiotherapy in head and neck cancer patients and identifies PPIB as a potential target for clinical radiosensitization.

Early warning signals (EWS) of regime shifts are challenging in cases where the true natural data-generating process is uncertain. Nonparametric drift-diffusion-jump models address this problem by fitting a general model that can approximate a wide range of data-generating processes. Drift measures the local rate of change. Diffusion measures relatively small shocks that occur at each time step. Jumps are large intermittent shocks. Total variance combines the contributions of diffusion and jumps. Nonparametric methods are well suited to emerging technology for automated, high-frequency sensors. Total variance is the most precisely measured indicator. Jump intensity appears to be a useful EWS. Estimates of the drift are highly uncertain unless long time series with many regime shifts are available. EWS computed from drift estimates (such as autocorrelation coefficients or return rates) have low precision and should be used with caution. Nonetheless, in the current state of knowledge, it is premature to disregard any potential EWS.

Catastrophic ecological regime shifts may be announced in advance by statistical early warning signals such as slowing return rates from perturbation and rising variance. The theoretical background for these indicators is rich, but real-world tests are rare, especially for whole ecosystems. We tested the hypothesis that these statistics would be early warning signals for an experimentally induced regime shift in an aquatic food web. We gradually added top predators to a lake over 3 years to destabilize its food web. An adjacent lake was monitored simultaneously as a reference ecosystem. Warning signals of a regime shift were evident in the manipulated lake during reorganization of the food web more than a year before the food web transition was complete, corroborating theory for leading indicators of ecological regime shifts.

Complex dynamical systems, ranging from ecosystems to financial markets and the climate, can have tipping points at which a sudden shift to a contrasting dynamical regime may occur. Although predicting such critical points before they are reached is extremely difficult, work in different scientific fields is now suggesting the existence of generic early-warning signals that may indicate for a wide class of systems if a critical threshold is approaching.

Ecological regime shifts are large, abrupt, long-lasting changes in ecosystems that often have considerable impacts on human economies and societies. Avoiding unintentional regime shifts is widely regarded as desirable, but prediction of ecological regime shifts is notoriously difficult. Recent research indicates that changes in ecological time series (e.g., increased variability and autocorrelation) could potentially serve as early warning indicators of impending shifts. A critical question, however, is whether such indicators provide sufficient warning to adapt management to avert regime shifts. We examine this question using a fisheries model, with regime shifts driven by angling (amenable to rapid reduction) or shoreline development (only gradual restoration is possible). The model represents key features of a broad class of ecological regime shifts. We find that if drivers can only be manipulated gradually management action is needed substantially before a regime shift to avert it; if drivers can be rapidly altered aversive action may be delayed until a shift is underway. Large increases in the indicators only occur once a regime shift is initiated, often too late for management to avert a shift. To improve usefulness in averting regime shifts, we suggest that research focus on defining critical indicator levels rather than detecting change in the indicators. Ideally, critical indicator levels should be related to switches in ecosystem attractors; we present a new spectral density ratio indicator to this end. Averting ecological regime shifts is also dependent on developing policy processes that enable society to respond more rapidly to information about impending regime shifts.

Regime shifts are large, long-lasting changes in ecosystems. They are often hard to predict but may have leading indicators which are detectable in advance. Potential leading indicators include wider swings in dynamics of key ecosystem variables, slower return rates after perturbation and shift of variance towards lower frequencies. We evaluated these indicators using a food web model calibrated to long-term whole-lake experiments. We investigated whether impending regime shifts driven by gradual increase in exploitation of the top predator can create signals that cascade through food webs and be discerned in phytoplankton. Substantial changes in standard deviations, return rates and spectra occurred near the switch point, even two trophic levels removed from the regime shift in fishes. Signals of regime shift can be detected well in advance, if the driver of the regime shift changes much more slowly than the dynamics of key ecosystem variables which can be sampled frequently enough to measure the indicators. However, the regime shift may occur long after the driver has passed the critical point, because of very slow transient dynamics near the critical point. Thus, the ecosystem can be poised for regime shift by the time the signal is discernible. Field tests are needed to evaluate these indicators.

We consider panacea formation in the framework of adaptive learning and decision for social-ecological systems (SESs). Institutions for managing such systems must address multiple timescales of ecological change, as well as features of the social community in which the ecosystem policy problem is embedded. Response of the SES to each candidate institution must be modeled and treated as a stochastic process with unknown parameters to be estimated. A fundamental challenge is to design institutions that are not vulnerable to capture by subsets of the community that self-organize to direct the institution against the overall social interest. In a world of episodic structural change, such as SESs, adaptive learning can lock in to a single institution, model, or parameter estimate. Policy diversification, leading to escape from panacea traps, can come from monitoring indicators of episodic change on slow timescales, minimax regret decision making, active experimentation to accelerate model identification, mechanisms for broadening the set of models or institutions under consideration, and processes for discovery of new institutions and technologies for ecosystem management. It is difficult to take all of these factors into account, but the discipline that comes with the attempt to model the coupled social-ecological dynamics forces policy makers to confront all conceivable responses. This process helps induce the modesty needed to avoid panacea traps while supporting systematic effort to improve resource management in the public interest.

Background and Purpose: We previously determined that the density of a rapidly migrating DNA end-binding complex (termed 'band-A') predicts radiosensitivity of human normal and tumor cells. The goal of this study was first to identify the protein components of band-A and to determine if the protein levels of band-A components would correlate with band-A density and radiosensitivity., Patients and Methods: DNA end-binding protein complex (DNA-EBC) protein components were identified by adding antibodies specific for a variety of DNA repair-associated proteins to the DNA-EBC reaction and then noting which antibodies super-shifted various DNA-EBC bands. Band-A levels were correlated with SF2 for a panel of primary human fibroblasts heterozygous for sequence-proven mutations in BRCA1 or BRCA2. The nuclear protein levels of band-A components were determined in each BRCA1 heterozygote by western hybridization., Results: DNA-EBC analysis of human nuclear proteins revealed 10 identifiable bands. The density of the most rapidly migrating DNA-EBC band correlated closely with both BRCA-mutation status and radiosensitivity (r(2)=0.85). This band was absent in cells with homozygous mutations in their ataxia-telangiectasia-mutated protein (ATM) genes. This band was also completely supershifted by the addition of antibodies to ATM, Ku70, DNA ligase III, Rpa32, Rpa14, DNA ligase IV, XRCC4, WRN, BLM, RAD51 and p53. However, the intranuclear concentrations of these proteins did not correlate with either the SF2 or DNA-EBC density. Neither BRCA1 or BRCA2 could be detected in band-A., Conclusions: DNA-EBC analysis of human nuclear extracts resulted in 10 bands, at least six of which contained ATM. The density of one of the DNA-EBCs predicted the radiosensitization caused by BRCA haploinsufficiency, and this band contains Ku70, ATM, DNA ligase III, Rpa32, Rpa14, DNA ligase IV, XRCC4, WRN, BLM, RAD51 and p53 but not BRCA 1 or 2. The density of band-A was independent of the nuclear concentration of any of its known component.

Point mutations and deletions in mitochondrial DNA (mtDNA) accumulate as a result of oxidative stress, including ionizing radiation. As a result, dysfunctional mitochondria suffer from a decline in oxidative phosphorylation and increased release of superoxides and other reactive oxygen species (ROS). Through this mechanism, mitochondria have been implicated in a host of degenerative diseases. Associated with this type of damage, and serving as a marker of total mtDNA mutations and deletions, the accumulation of a specific 4977-bp deletion, known as the common deletion (Delta-mtDNA(4977)), takes place. The Delta-mtDNA(4977) has been reported to increase with age and during the progression of mitochondrial degeneration. The purpose of this study was to investigate whether ionizing radiation induces the formation of the common deletion in a variety of human cell lines and to determine if it is associated with cellular radiosensitivity. Cell lines used included eight normal human skin fibroblast lines, a radiosensitive non-transformed and an SV40 transformed ataxia telangiectasia (AT) homozygous fibroblast line, a Kearns Sayre Syndrome (KSS) line known to contain mitochondrial deletions, and five human tumor lines. The Delta-mtDNA(4977) was assessed by polymerase chain reaction (PCR). Significant levels of Delta-mtDNA(4977) accumulated 72 h after irradiation doses of 2, 5, 10 or 20 Gy in all of the normal lines with lower response in tumor cell lines, but the absolute amounts of the induced deletion were variable. There was no consistent dose-response relationship. SV40 transformed and non-transformed AT cell lines both showed significant induction of the deletion. However, the five tumor cell lines showed only a modest induction of the deletion, including the one line that was deficient in DNA damage repair. No relationship was found between sensitivity to radiation-induced deletions and sensitivity to cell killing by radiation.

Inhibition of poly(ADP-ribose) polymerase (PARP) by a novel, potent inhibitor, INO-1001, was examined in two rodent and one human fibroblast cell lines, after single and fractionated radiation treatments. Since PARP plays a role in the early events following DNA damage and influences the effectiveness of DNA repair, its inhibition has been proposed to constitute a drug target for the development of novel radiosensitizers. We found that INO-1001 effectively inhibited PARP activity at non-cytotoxic concentrations. Combination treatment of 10 microM INO-1001 and a single dose of radiation resulted in significant radiosensitization of all three cells lines (enhancement ratios 1.4-1.6). This radioenhancement was even greater when the drug and radiation were given as fractionated treatments (enhancement ratio 8.0). Apoptosis (as evaluated by TUNEL staining) was not enhanced by the treatments, suggesting that inhibiting PARP enzyme activity by INO-1001 enhanced radiation-induced cell killing by interfering with DNA repair mechanisms, resulting in necrotic cell death. INO-1001 therefore, appears to have potential as a potent enhancer of radiation sensitivity, without any intrinsic cytotoxicity from the drug alone.

Previous reports have suggested that measuring radiosensitivity of normal and tumor cells would have significant clinical relevance for the practice of radiation oncology. We hypothesized that radiosensitivity might be predicted by analyzing DNA end-binding complexes (DNA-EBCs), which form at DNA double-strand breaks, the most important cytotoxic lesion caused by radiation. To test this hypothesis, the DNA-EBC pattern of 21 primary human fibroblast cultures and 15 tumor cell lines were studied. DNA-EBC patterns were determined using a modified electrophoretic mobility shift assay and were correlated with radiosensitivity, as measured by SF2. DNA-EBC analysis identified a rapidly migrating ATM-containing band (identified as "band-A") of which the density correlated with SF2 (0.02

It has been suggested that the technique for measuring repair fidelity of radiation-induced DNA double-strand breaks (DSBs) using Southern blotting and hybridization to defined regions of the genome could be compromised by broken or poorly-digested DNA. Since misrepair of DNA DSBs is an important aspect of radiation-induced chromosome aberrations, mutations, and cell killing, we checked for such a supposition in non-transformed human fibroblasts. DSB misrepair was assessed in a NotI-cleavable DNA fragment of 3.2 Mbp located on the long arm of chromosome 21 and detected by D21S1 probe. We hypothesized that the suggested DNA degradation, whether spurious in nature or the results of irradiation-induced phenomena such as apoptosis and/or necrosis, should be detectable with or without NotI restriction enzyme treatment. When the DNA embedded in agarose plugs was separated by electrophoresis without prior NotI restriction, no significant difference was observed in the relative amount of migrating DNA between the control (no irradiation) and 24 h of repair following 80 Gy irradiation. Furthermore, only about 10% of the total signal was located below the 3.2 Mbp band. This suggests that the amount of DNA fragmentation due to biological (apoptosis or necrosis) or technical processes was negligible. The Tunel assay supported these results, as there was little to no apoptosis detectable in these fibroblasts up to 24 h after irradiation. We conclude that in primary human fibroblasts, the NotI method for measuring radiation-induced misrepair is not compromised by DNA degradation.

Beside a few known radiosensitive syndromes, a patient's reaction to radiotherapy is difficult to predict. In this report we describe the management of a pediatric cancer patient presented with a family history of radiosensitivity and cancer proneness. Laboratory investigations revealed a chromosomal fragility syndrome and an increased cellular radiosensitivity in vitro. AT gene sequencing revealed no mutations. The patient was treated with reduced radiation doses to avoid the presumed increased risks of toxicity to normal tissues. The patient tolerated well the treatment with no significant acute or late radiation sequelae. Five years later, the patient remains both disease and complications free. While an accurate laboratory test for radiosensitivity is still lacking, assessments of chromosomal fragility, cell survival and clinical medicine will continue to be useful for a small number of patients.

Purpose: In older children the spontaneous resolution rate of low grade vesicoureteral reflux is low and currently its management is controversial in regard to surgery versus prophylaxis versus observation alone. Bladder dysfunction in children with neurogenic bladders and to a less declarative degree in neurologically intact children has a role in the etiology or persistence of reflux. We determine the impact of biofeedback therapy on neurologically intact children with vesicoureteral reflux and detrusor-sphincter dyssynergia., Materials and Methods: Vesicoureteral reflux was detected by voiding cystourethrography in children evaluated for urinary tract infections. Children with breakthrough infections or dysfunctional voiding based on history underwent uroflowmetry with concomitant patch electromyography of the external sphincter. Dyssynergia was defined as increased or steady electromyography activity during micturition. Biofeedback was initially performed weekly and the interval increased as indicated. The goals were to eliminate dyssynergia and reduce or eliminate post-void residual urine. Voiding cystourethrography was performed 1 year later to determine the status of the reflux. Ureteral reimplantation was performed during the period of biofeedback when indicated., Results: From February 1997 to March 2001, 25 children 6 to 10 years old (mean age 9) with vesicoureteral reflux and detrusor-sphincter dyssynergia were treated with biofeedback therapy. There were 31 units (5 bilateral) with reflux, which was grade I in 10, II in 15, III in 5 and IV in 1. Children underwent an average of 7 sessions of biofeedback (range 2 to 20). On followup voiding cystourethrography, vesicoureteral reflux resolved in 17 units (55%), grade improved in 5 (16%) and reflux remained unchanged in 9 (29%). All cured vesicoureteral reflux was grade I (8 cases) or II (9). Four children (5 renal units) underwent reimplantation. In cured children there were no breakthrough infections during or since therapy and post-void residual urine decreased from an average of 40% before to 10% after therapy. Symptoms of urgency, daytime wetting and hoarding of urine improved or were eliminated in all children with resolved vesicoureteral reflux., Conclusions: Treating external detrusor-sphincter dyssynergia in older children with low grade vesicoureteral reflux, with biofeedback results in 1-year resolution rates that are considerably greater than historical resolution rates. External detrusor-sphincter dyssynergia should be screened for in children when surgery or discontinuation of chemoprophylaxis is considered so that biofeedback can be started.

The BRCA1 and BRCA2 gene products are thought to play important roles in the processing of DNA damage. To assess whether heterozygous mutations in these genes are associated with cellular radiosensitivity, we performed an in vitro radiation clonogenic survival assay on dermal fibroblasts obtained from 8 sequence-proven BRCA heterozygotes (6 BRCA1, 2 BRCA2). These data were compared to results obtained from a previous set of 17 prospectively studied cancer patients who had a negligible risk for a BRCA mutation. In addition, results from radiation-induced chromatid break assay performed on lymphocytes obtained from 9 BRCA heterozygotes (8 BRCA1, 1 BRCA2) were compared to results from a control group of 18 women with no cancer history. Results from both assays suggested that cells containing a heterozygous mutation in BRCA1 or BRCA2 were more radiosensitive than controls. For the fibroblast studies, the mean surviving fraction at 2 Gy (SF2) for carriers was 0.279 vs. 0.348 for the control set (p = 0.007). For the lymphocyte studies, the mean number of chromatid breaks after 125 cGy of radiation was 0.79 breaks per cell for the carriers vs. 0.45 for the controls (p = 0.0005). There was no apparent difference in the radiosensitivity between cells with BRCA1 vs. BRCA2 mutations (p = 0.769), although the small sample size minimizes the certainty of this observation. These preliminary results are consistent with a relationship between a germline mutation in BRCA1 or BRCA2 and a hypersensitivity to radiation. This phenotype could possibly predispose to an increased risk of radiation-induced mutagenesis and carcinogenesis., (Copyright 2001 Wiley-Liss, Inc.)

Purpose: Laparoscopic orchiopexy is extremely effective for treating patients with nonpalpable testis. However, despite the high dissection and wide mobilization it allows in some cases, vessel length prevents the testis from reaching the scrotum. There have been only incidental cases reported in which laparoscopy has been used for vessel transection and testicular mobilization orchiopexy. We reviewed our cases treated with the Fowler-Stephens orchiopexy performed laparoscopically in 1 or 2 stages., Materials and Methods: We reviewed the records of all boys who underwent laparoscopy for a nonpalpable testis at our institutions since 1992. Patients who underwent testicular vessel transection and orchiopexy performed laparoscopically in 1 or 2 stages were selected for evaluation. Office charts and operative reports were reviewed in detail., Results: Of the 126 nonpalpable testes in 108 patients 51 (40%) were intra-abdominal, including 18 (35%) in 14 patients in whom the Fowler-Stephens procedure was performed laparoscopically. Five testes were treated with a 2-stage procedure, while 11 were managed by laparoscopic mobilization followed by laparoscopic vessel clipping and orchiopexy in 1 stage. In 2 additional patients nearly all dissection was performed laparoscopically but due to extenuating circumstances inguinal incision was required as well. Thus, 13 testes were managed by 1-stage Fowler-Stephens orchiopexy, including all cases since August 1996 which required vessel transection. Two patients were hospitalized postoperatively for prolonged ileus after the second stage. All other 2-stage and all 1-stage cases were managed on an outpatient basis. There were no complications. At a mean followup of 6 months all cases without previous surgery that were managed by laparoscopic orchiopexy are without atrophy and the testes are in a scrotal position. Two testes in which previous surgery had been done atrophied postoperatively., Conclusions: Laparoscopic transection of the testicular vessels is safe in boys with high abdominal testes that do not reach the scrotum after laparoscopic high retroperitoneal dissection. The magnification and wide mobilization of laparoscopy likely allow better preservation of the collateral vascular supply than open exploration. Previous surgery is a risk factor for atrophy. The success rate of 89% overall and 100% in patients who did not previously undergo testicular surgery equals or exceeds that of open orchiopexy in patients with abdominal testes. The 1-stage procedure avoids repeat anesthesia and the extensive, sometimes tedious, dissection that is occasionally required during reoperation.

The genetic determinants for most breast cancer cases remain elusive. However, a mutation in a tumor suppressor gene, such as p53, BRCA1, BRCA2, or ATM, has been determined to be one mechanism of breast carcinogenesis. It has been established that inherited mutations in p53, BRCA1, and BRCA2 significantly contribute to breast cancer risk, although the importance of an inherited ATM mutation is controversial. Sporadic mutations in p53 are also common in breast cancer cells. The precise deficiencies that result from these genetic mutations have yet to be fully described. Although the functions of these genes are different, they are all involved in the maintenance of genomic stability after DNA damage. Mutations that impair the function of these four genes may adversely affect the manner in which DNA damage is processed. It is likely that the risk of breast cancer development is increased through this mechanism. In this article, we review the relevancy of p53, BRCA1, BRCA2, and ATM mutations to breast cancer development, and review the in vitro, in vivo, and clinical data exploring the mechanisms by which these mutations affect genomic integrity and DNA damage repair.

Purpose: Conventional techniques result in chordee correction in the majority of patients. However, some with extensive chordee require further treatment to correct persistent extraordinary penile curvature. Our practice has been to treat this condition with interpositional dermal grafting. We review our experience with this procedure., Materials and Methods: During a 5-year period dermal grafts harvested from the nonhair-bearing inguinal skin fold were placed in 51 patients with a mean age of 29 months. The primary diagnosis was penoscrotal or perineal hypospadias in 36 patients (hypospadias cripple in 4), the exstrophy-epispadias complex in 3, mid shaft or distal hypospadias with severe chordee in 10 and chordee without hypospadias in 2. A total of 49 patients (96%) underwent staged urethroplasty., Results: One graft was placed in 29 patients (57%), 9 (18%) received 1 graft and underwent a Nesbit plication, (14%) received 2 grafts, 5 (10%) received 2 grafts and underwent dorsal plication, and 1 (2%) received 3 grafts. Second stage urethral reconstruction was done using a Thiersch-Duplay tube in the majority of cases. In 5 patients mild residual chordee was easily corrected at the time of second stage repair., Conclusions: In a staged repair the first priority of the initial stage is to achieve a straight phallus. While our experience indicates that a single dermal graft is sufficient in approximately 57% of cases, when it does not result in complete straightening, we have had success with placing additional graft(s) and/or performing dorsal plication. We believe that the additional penile length achieved with dermal grafting results in a dependent phallus and cosmesis preferable to that of plication only.

Purpose: Multiple approaches exist for the management of the nonpalpable testis. With the use of diagnostic laparoscopy widely accepted in the setting of the nonpalpable testis we have found laparoscopic orchiopexy to be an efficient and logical extension. To evaluate its use we report our experience with laparoscopic orchiopexy to treat 44 nonpalpable testes in 36 patients., Materials and Methods: We retrospectively reviewed the medical records of all patients who underwent laparoscopic orchiopexy for a 2 1/2-year period. Modifications of the surgical technique are described., Results: The left testis was affected in 18 boys, the right in 9 and both in 9. At laparoscopy 8 testes were at the internal ring or were peeping and the remainder were intra-abdominal. One patient underwent a unilateral 1-stage Fowler-Stephens orchiopexy, and 3 unilateral and 1 bilateral 2-stage Fowler-Stephens orchiopexy. Two patients underwent laparoscopically assisted orchiectomy. The remaining 31 patients underwent laparoscopic orchiopexy without division of the spermatic vessels. At followup (mean 6 months) all testes are without atrophy, and 39 of 42 (93%) are in an acceptable scrotal position. There are 3 testes (7%) high in the scrotum., Conclusions: Laparoscopic orchiopexy is a logical extension of diagnostic laparoscopy for the evaluation and treatment of the nonpalpable testis. The low incidence of complications and 93% success rate underscore the feasibility of this procedure. It is our procedure of choice for the treatment of nonpalpable testis.

Mechanical ventilation is one of the most common medical therapies administered within ICUs. Similarly, the "weaning" or "liberation" of patients from mechanical ventilation is a common and extremely important task performed in ICUs and specialized ventilator units within hospitals. Various methods exist for assessing a patient's readiness to be liberated from mechanical ventilation and for conducting the weaning process. Clinicians working in ICUs frequently develop their own personal preferences regarding the best approach to weaning patients from ventilatory support. Therefore, variability in the practice of weaning patients from mechanical ventilation is frequently demonstrated, even within a single ICU. Recently, several randomized clinical trials have produced conflicting results regarding the best technique for carrying out the weaning process (e.g., spontaneous breathing trials, intermittent mandatory ventilation, pressure-support ventilation). Such conflicting findings have further illustrated the complexity of the weaning process and the difficulties in identifying the "best" medical practices for carrying out this endeavor. However, other investigations have suggested that the selection of an individual technique for weaning patients from mechanical ventilation may not be as important as employing a systematic approach to this medical process. Protocol-guided weaning of mechanical ventilation in the ICU setting, often performed by nonphysicians, has gained in acceptance as a result of these investigations. We describe the recent experiences of three ICUs which have demonstrated significant improvements in patient outcomes (e.g., shorter durations of mechanical ventilation, lower incidence of ventilator-associated pneumonia, fewer patient complications) as a result of implementing formal weaning protocols. Our hope is that these data will assist other hospitals in developing their own systematic guidelines and protocols for weaning patients from mechanical ventilation.

Objectives: To better characterize intrarenal neuroblastoma., Methods: We retrospectively reviewed the records of 5 children with neuroblastoma initially diagnosed as Wilms' tumor., Results: Five patients, aged 11 months to 3.5 years, were preoperatively diagnosed as having intrarenal Wilms' tumor, prior to operative or histopathologic diagnosis of neuroblastoma. In 3 children the diagnosis of neuroblastoma involving the kidney was confirmed; in the fourth child subcutaneous metastatic disease precluded biopsy confirmation of the intrarenal tumor; and in the fifth child the kidney was severely displaced but not actually involved by neuroblastoma. All patients were hypertensive and 4 patients had elevated urinary catechol levels. Molecular genetic studies showed N-myc amplification in both patients who were evaluated. All patients had poorly differentiated histopathology. One patient is presently alive at 8 months with recurrent disease and another patient is free of disease 13 years after diagnosis. The remaining 3 patients died of the malignancy., Conclusions: Intrarenal neuroblastoma is a rare entity that clinically and radiographically may resemble Wilms' tumor. Our limited experience indicates that intrarenal neuroblastoma is an aggressive malignancy, and long-term survival is rare.

Adapting practices that are described in the literature or used effectively in other critical care units provides an opportunity to improve the quality of critical care and reduce costs. Described in the literature are different techniques for the gradual withdrawal of mechanical ventilator support from patients during weaning from the ventilator. Phoebe Putney Memorial Hospital in Albany, GA used a systematic approach to adapt these techniques to improve the weaning process. This resulted in a reduction in the number of days patients were on a ventilator and a reduction in the ICU length of stay for patients with acute respiratory failure requiring mechanical ventilation.

Fludarabine, an effective repair inhibitor of radiation-induced chromosome breaks, and indomethacin, an inhibitor of prostaglandin synthesis, were shown previously to improve the therapeutic ratio of radiotherapy for murine tumors. The purpose of this study was to determine whether the combination of these two radiosensitizers with different mechanisms of action could further increase the therapeutic ratio of radiotherapy in an FSA mouse sarcoma after single and fractionated irradiation. The effect of the combined treatment on tumors was assessed by the local tumor control assay (TCD50) in mice bearing an FSA sarcoma in the leg. The effect of the combination on normal tissues was assessed by skin desquamation, hair loss and leg contracture in the legs of non-tumor-bearing mice. For the TCD50 assay, after single irradiation, the radiation dose modification factor (DMF) reached 1.2 for both indomethacin (35 micrograms/ml in the drinking water for 10 days) and fludarabine (800 mg/kg intraperitoneally 3 h prior to irradiation). For both drugs combined, the DMF increased to 1.7. No significant increase in normal tissue toxicity was observed with any of the combinations. After fractionated irradiation (16 fractions over 4 days), the DMFs for local tumor control reached 1.3 for indomethacin and 1.8 for fludarabine darabine (400 mg/kg every day for 4 days). The combination of both drugs produced a DMF of 2.0. None of the combinations altered the effects of radiation on skin desquamation, hair loss or leg contracture significantly. The present study suggests that the therapeutic ratio of radiotherapy for a murine sarcoma can be improved by the combination of indomethacin and fludarabine, two agents differing in their mechanisms of radiopotentiation.

Background and Purpose: The usefulness of colony forming assays (CFA) has been established for almost 40 years (Puck and Marcus, J.Exp.Med. 103: 653-666, 1956). Although time-consuming and not successful for all cell lines, it is generally considered to be the gold standard of assays for testing the sensitivity of cell lines to ionizing radiation or other cytotoxic agents in vitro. We recently found for several cell lines that the plating efficiencies of both control and irradiated cells is dependent upon the density of cells seeded for colony formation; that is, increasing cell inoculum levels resulted in a non-linear relationship with colony formation, even at relatively low colony numbers., Material and Methods: All data from a human melanoma cell line, transfected with c-myc or N-ras, as well as from normal human diploid fibroblasts, were taken to see how this phenomenon influenced outcome and interpretation of clonogenic assays. Survival was recalculated using all data, or only data with a linear relationship between inoculum level and colony formation., Results: It is found that when data with a non-linear relationship between inoculum level and colony formation are included, survival can be underestimated due to inhibition of colony formation in treated cultures., Conclusion: For validity, colony forming assays must be standardized to assure a constant relationship between the cell density and colony forming efficiency. This usually requires a much lower density of colonies than has been typically published for many cell survival studies.

Clonogenic and non-clonogenic parameters of cell survival were compared in irradiated Chinese hamster cells. Clonogenic survival, chromatid break and repair kinetics, as well as DNA damage and repair, were assessed in synchronized cells in different parts of the cell cycle. C2 chromatid damage and repair was examined in metaphase chromosomes of cells irradiated during S and G2 phase, treated with or without inhibitors of DNA repair. Bromodeoxyuridine labelling of S phase cells starting at the time of irradiation made it possible to determine precisely, while scoring metaphase chromosomes, whether cells were irradiated in mid S, late S, or G2 phases of the cycle. The results showed that chromatid breaks induced in S phase are efficiently repaired until the moment cells progress into G2, when repair stops abruptly. Chromatid damage in G2 phase is not repaired. On the other hand, DNA double-strand breaks are repaired in all phases of the cycle, even during G2 phase which has no concurrent chromatid break repair. Finally, there is no consistent correlation between chromatid damage and repair, DNA damage and repair, and cell survival, thus indicating that the interaction of different parameters of radiosensitivity must be better understood for them to be useful predictors of cell survival.

Predictive assays are presently being developed to identify the patients at highest risk for developing severe late normal-tissue complications. If such patients could be identified prior to treatment, then the doses to those patients could be reduced to lower their complication rate. In addition, patients identified as being relatively radioresistant could receive higher doses without an increase in complications. The aim of the present study was to estimate the magnitude of the dose adjustments that could potentially be made if radiotherapy doses were tailored to the individual patient using a predictive assay of normal-tissue radiosensitivity. The dose adjustments were estimated by re-analyzing data from an earlier study [13] to determine the influence of dose and in vitro fibroblast radiosensitivity on the incidence of severe late normal-tissue complications. Although the dose estimates are preliminary and based on limited data, the results of this study support the concept that a significant therapeutic gain could be achieved for a subset of patients from the use of a predictive assay of normal-tissue radiosensitivity.

Purpose/objective: To determine if the radiosensitivity of normal human skin fibroblasts, measured in early passage cultures, is significantly correlated with the degree of acute or late normal skin damage in patients treated for breast cancer with radiotherapy., Methods and Materials: In the 1970s, a series of breast cancer patients was treated at the Department of Oncology in Gothenburg, Sweden with postoperative irradiation to the parasternal region. Patients were treated bilaterally using different fractionation schedules and doses to the right and left fields. Peak acute reactions were scored on a six-point scale, and skin erythema was measured by reflectance spectrophotometry. Telangiectasia was graded over time on a six-point scale. In April 1992, two small skin biopsies were obtained from 22 patients in two treatment groups (i.e., four dose-fractionation schedules) and, using either delayed or immediate plating, fibroblast radiosensitivity was measured in early passage cultures by clonogenic survival, after high and low dose-rate irradiations. Survival at 2.0 Gy (SF2) was calculated from complete survival curves., Results: To test assay reproducibility, SF2 values derived from paired biopsies of the same patient (12 cases) were compared. A reasonably good correlation (p = 0.075) was obtained for SF2s determined by high dose-rate irradiations with immediate plating, but not for delayed plating or low dose-rate treatments. The median coefficient of variation in the replicate SF2s after high dose-rate treatment and immediate plating was 13%, suggesting that the poor correlation in paired SF2 values is due to the magnitude of the uncertainty in SF2 relative to the overall spread in SF2 values between patients (CV = 28%). Individual SF2 values and averaged values from patients with data from two biopsies were compared with the acute and late clinical reactions. A significant negative correlation was found between SF2 and relative clinical response, but only when averaged high dose-rate SF2 values and telangiectasia scores were compared. There was no significant correlation between average SF2 values and acute responses or between individual SF2 measurements and either the acute or late clinical response., Conclusion: The results of this study suggest that the degree of late telangiectasia is at least partially dependent upon the intrinsic cellular radiosensitivity of normal fibroblasts, but the relationship is not clear cut. Multiple replicate assays are necessary to obtain reliable estimates of fibroblast SF2 values using current techniques.

The effect of fludarabine (9-beta-D-arabinosyl-2-fluoroadenine-5'- monophosphate), an adenine nucleoside analogue, on the tolerance of the spinal cord to fractionated irradiation was studied in a rat model. Anesthetized female Fisher 344 rats received irradiation to 2 cm of the cervical spine with a telecobalt unit (dose rate 1.14 Gy/min). Radiation was administered in two, four or eight fractions spread over a 48-h period with or without fludarabine. Animals assigned to combined therapy received two daily intraperitoneal injections of fludarabine (150 mg/kg) given 3 h prior to the first daily radiation fraction. It was found that fludarabine reduced the iso-effect dose required to induce leg paresis at 9 months after irradiation for all fractionation schedules. Dose modification factors of 1.23, 1.29 and greater than 1.27 were obtained for two, four and eight fractions, respectively. Fitting the data with the direct analysis method of Thames et al. with an incomplete repair model [18] showed that the potentiating effect of fludarabine may be mediated through reduction in the number of 'tissue-rescuing units' (InK). Alpha and beta values were slightly but not significantly decreased, whereas the alpha/beta ratio was unchanged. These features suggest that fludarabine did not significantly inhibit cellular repair processes but rather reduced the spinal cord tolerance by a fixed additive toxic effect on the same target cells. In rodent models, the combination of fludarabine and fractionated radiation has previously been found to yield a therapeutic gain, i.e., the drug enhanced tumor response to a greater extent than it reduced normal tissue tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)

Chinese hamster ovary cells were synchronized into purified populations of viable G1-, S-, G2-, and M-phase cells by a combination of methods, including growth arrest, aphidicolin block, cell cycle progression, mitotic shake-off, and centrifugal elutriation. The DNA content and bromodeoxyuridine (BrdUrd) labeling index were measured in each purified fraction by dual-parameter flow cytometry. The cell cycle distributions determined from the DNA measurements alone (single parameter) were compared with those calculated from both DNA and BrdUrd data (dual parameter). The results show that highly purified cells can be obtained using these methods, but the assessed purity depends on the method of cell cycle analysis. Using the single versus dual parameter measurement to determine cell cycle distributions gave similar results for most phases of the cell cycle, except for cells near the transition from G1- to S-phase and S- to G2-phase. There the BrdUrd labeling index determined by flow cytometry was more sensitive for detecting small amounts of DNA synthesis. As an alternative to flow cytometry, a simple method of measuring BrdUrd labeling index on cell smears was used and gave the same result as flow cytometry. Measuring both DNA content and DNA synthesis improves characterization of synchronized cell populations, especially at the transitions in and out of S-phase, when cells are undergoing dramatic shifts in biochemical activity.

We describe use of the posterior sagittal trans-anorectal approach to excise a prostatic utricle in a child. This alternative approach provides excellent exposure to the retrourethral space, permitting safe and functional reconstruction.

We have previously reported that fludarabine, an adenine nucleoside analogue, significantly enhances radiation-induced tumor regrowth delay and local cure in several mouse tumors. Although fludarabine potentiated tumor regrowth delay at various times from -36 h to +6 h in a SA-NH mouse sarcoma model, the greatest enhancement was observed when fludarabine was administered 24 h before irradiation. The purpose of this study was to understand the basis for in vivo enhancement of radiation efficacy by fludarabine. To examine the effect of fludarabine on DNA synthesis and cell cycle progression, tumor-bearing mice were given fludarabine by an i.p. route and then bromodeoxyuridine at various times up to 36 h, followed 0.5 h later by tumor harvest. Two-parameter flow cytometry analysis of the tumor cells using an anti-bromodeoxyuridine antibody demonstrated that an 800-mg/kg fludarabine dose stops DNA synthesis within 3 h with recovery starting at 12 h. By 24 h after fludarabine treatment, a synchronized wave of cycling tumor cells appeared in G2-M phase. The degree of DNA synthesis shutdown and the timing of the reinitiation of DNA synthesis and cell cycle progression were all fludarabine dose dependent. Interestingly, DNA synthesis reinitiated only at the G1-S boundary; cells in the S phase at the time of fludarabine administration appeared to disappear from the tumor population. To confirm these observations more directly, we pretreated tumor-bearing mice i.p. with chlorodeoxyuridine to mark the cells in the S phase, gave them fludarabine 0.5 h later, and then gave them iododeoxyuridine 0.5 h before tumor harvest. Flow cytometry analysis using antibodies specific for chlorodeoxyuridine- and iododeoxyuridined-labeled cells confirmed that cells in the S phase at the time of fludarabine administration never reinitiated DNA synthesis and disappeared from the tumor population. Immunohistological analysis of tumor sections obtained after fludarabine administration demonstrated that prelabeled S-phase cells took on an apoptotic appearance and gradually disappeared from the tumors. An in situ DNA end labeling assay demonstrated DNA fragmentation in these morphologically apoptotic cells. These results suggest that the mechanism of fludarabine enhancement of radiation response involves induced S-phase cell loss through an apoptotic pathway and subsequent synchronization of the remaining cells to a more radiosensitive cell cycle phase at the time of irradiation.