Late toxicity and five year outcomes after high-dose-rate brachytherapy as a monotherapy for localized prostate cancer

BACKGROUND To determine the 5-year outcome after high-dose-rate brachytherapy (HDR-BT) as a monotherapy. METHODS Between 10/2003 and 06/2006, 36 patients with low (28) and intermediate (8) risk prostate cancer were treated by HDR-BT monotherapy. All patients received one implant and 4 fractions of 9.5 Gy within 48 hours for a total prescribed dose (PD) of 38 Gy. Five patients received concomitant androgen deprivation therapy (ADT). Toxicity was scored according to the common terminology criteria for adverse events from the National Cancer Institute (CTCAE) version 3.0. Biochemical recurrence was defined according to the Phoenix criteria and analyzed using the Kaplan Meier method. Predictors for late grade 3 GU toxicity were analyzed using univariate and multivariate Cox regression analyses. RESULTS The median follow-up was 6.9 years (range, 1.5-8.0 years). Late grade 2 and 3 genitourinary (GU) toxicity was observed in 10 (28%) and 7 (19%) patients, respectively. The actuarial proportion of patients with late grade 3 GU toxicity at 5 years was 17.7%. Late grade 2 and 3 gastrointestinal (GI) toxicities were not observed. The crude erectile function preservation rate in patients without ADT was 75%. The 5 year biochemical recurrence-free survival (bRFS) rate was 97%. Late grade 3 GU toxicity was associated with the urethral volume (p = 0.001) and the urethral V120 (urethral volume receiving ≥120% of the PD; p = 0.0005) after multivariate Cox regression. CONCLUSIONS After HDR-BT monotherapy late grade 3 GU was observed relatively frequently and was associated with the urethral V120. GI toxicity was negligible, the erectile function preservation rate and the bRFS rate was excellent.

Specialized managed care for children with cystic fibrosis: Resource use patterns and rate design for a high cost Medicaid population

Objective. This research study had two goals: (1) to describe resource consumption patterns for Medi-Cal children with cystic fibrosis, and (2) to explore the feasibility from a rate design perspective of developing specialized managed care plans for such a special needs population.^ Background. Children with special health care needs (CSHN) comprise about 2% of the California Medicaid pediatric population. CSHN have rare but serious health problems, such as cystic fibrosis. Medicaid programs, including Medi-Cal, are enrolling more and more beneficiaries in managed care to control costs. CSHN, however, do not fit the wellness model underlying most managed care plans. Child health advocates believe that both efficiency and quality will suffer if CSHN are removed from regionalized special care centers and scattered among general purpose plans. They believe that CSHN should be "carved out" from enrollment in general plans. One alternative is the Specialized Managed Care Plan, tailored for CSHN.^ Methods. The study population consisted of children under age 21 with CF who were eligible for Medi-Cal and California Children's Services program (CCS) during 1991. Health Care Financing Administration (HCFA) Medicaid Tape-to-Tape data were analyzed as part of a California Children's Hospital Association (CCHA) project.^ Results. Mean Medi-Cal expenditures per month enrolled were $2,302 for 457 CF children, compared to about \$1,270 for all 47,000 CCS special needs children and roughly $60 for almost 2.6 million ``regular needs'' children. For CF children, inpatient care (80\%) and outpatient drugs (9\%) were the major cost drivers, with {\it all\/} outpatient visits comprising only 2\% of expenditures. About one-third of CF children were eligible due to AFDC (Aid to Families with Dependent Children). Age group explained about 17\% of all expenditure variation. Regression analysis was used to select the best capitation rate structure (rate cells by age and eligibility group). Sensitivity analysis estimated moderate financial risk for a statewide plan (360 enrollees), but severe risk for single county implementation due to small numbers of children.^ Conclusions. Study results support the carve out of CSHN due to unique expenditure patterns. The Specialized Managed Care Plan concept appears feasible from a rate design perspective given sufficient enrollees. ^

DEVELOPMENT AND IMPLEMENTATION OF A REMOTE AUDIT TOOL FOR HIGH DOSE RATE (HDR) 192IR BRACHYTHERAPY USING OPTICALLY STIMULATED LUMINESCENCE DOSIMETRY

This work aimed to create a mailable and OSLD-based phantom with accuracy suitable for RPC audits of HDR brachytherapy sources at institutions participating in NCI-funded cooperative clinical trials. An 8 × 8 × 10 cm3 prototype with two slots capable of holding nanoDot Al2O3:C OSL dosimeters (Landauer, Glenwood, IL) was designed and built. The phantom has a single channel capable of accepting all 192Ir HDR brachytherapy sources in current clinical use in the United States. Irradiations were performed with an 192Ir HDR source to determine correction factors for linearity with dose, dose rate, and the combined effect of irradiation energy and phantom construction. The uncertainties introduced by source positioning in the phantom and timer resolution limitations were also investigated. It was found that the linearity correction factor was where dose is in cGy, which differed from that determined by the RPC for the same batch of dosimeters under 60Co irradiation. There was no significant dose rate effect. Separate energy+block correction factors were determined for both models of 192Ir sources currently in clinical use and these vendor-specific correction factors differed by almost 2.6%. For Nucletron sources, this correction factor was 1.026±0.004 (99% Confidence Interval) and for Varian sources it was 1.000±0.007 (99% CI). Reasonable deviations in source positioning within the phantom and the limited resolution of the source timer had insignificant effects on the ability to measure dose. Overall measurement uncertainty of the system was estimated to be ±2.5% for both Nucletron and Varian source audits (95% CI). This uncertainty was sufficient to establish a ±5% acceptance criterion for source strength audits under a formal RPC audit program. Trial audits of eight participating institutions resulted in an average RPC-to-institution dose ratio of 1.000 with a standard deviation of 0.011.

CHARACTERIZATION OF THE COUNT RATE PERFORMANCE AND EVALUATION OF THE EFFECTS OF HIGH COUNT RATES ON MODERN GAMMA CAMERAS

CHARACTERIZATION OF THE COUNT RATE PERFORMANCE AND EVALUATION OF THE EFFECTS OF HIGH COUNT RATES ON MODERN GAMMA CAMERAS Michael Stephen Silosky, B.S. Supervisory Professor: S. Cheenu Kappadath, Ph.D. Evaluation of count rate performance (CRP) is an integral component of gamma camera quality assurance and measurement of system dead time (τ) is important for quantitative SPECT. The CRP of three modern gamma cameras was characterized using established methods (Decay and Dual Source) under a variety of experimental conditions. For the Decay method, input count rate was plotted against observed count rate and fit to the paralyzable detector model (PDM) to estimate τ (Rates method). A novel expression for observed counts as a function of measurement time interval was derived and the observed counts were fit to this expression to estimate τ (Counts method). Correlation and Bland-Altman analysis were performed to assess agreement in estimates of τ between methods. The dependencies of τ on energy window definition and incident energy spectrum were characterized. The Dual Source method was also used to estimate τ and its agreement with the Decay method under identical conditions and the effects of total activity and the ratio of source activities were investigated. Additionally, the effects of count rate on several performance metrics were evaluated. The CRP curves for each system agreed with the PDM at low count rates but deviated substantially at high count rates. Estimates of τ for the paralyzable portion of the CRP curves using the Rates and Counts methods were highly correlated (r=0.999) but with a small (~6%) difference. No significant difference was observed between the highly correlated estimates of τ using the Decay or Dual Source methods under identical experimental conditions (r=0.996). Estimates of τ increased as a power-law function with decreasing ratio of counts in the photopeak to the total counts and linearly with decreasing spectral effective energy. Dual Source method estimates of τ varied as a quadratic with the ratio of the single source to combined source activities and linearly with total activity used across a large range. Image uniformity, spatial resolution, and energy resolution degraded linearly with count rate and image distorting effects were observed. Guidelines for CRP testing and a possible method for the correction of count rate losses for clinical images have been proposed.

Long term low latitude and high elevation cosmogenic 3He production rate inferred from a 107 ka-old lava flow in northern Chile; 22°S-3400 m a.s.l

Available geological calibration sites used to estimate the rate at which cosmogenic 3He is produced at the Earth’s surface are mostly clustered in medium to high latitudes. Moreover, most of them have exposure histories shorter than tens of thousands of years. This lack of sites prevents a qualitative assessment of available production models used to convert cosmogenic 3He concentrations into exposure ages and/or denudation rates. It thus limits our ability to take into account the atmospheric, geomagnetic and solar modulation conditions that might have affected the production of cosmogenic nuclides in the past for longer exposure histories and in low latitude regions. We present the cosmogenic 3He production rate inferred from a new geological calibration site located in northern Chile. Five samples were collected on the surface of the largest and best-preserved lava flow of the San Pedro volcano (21.934°S-68.510°W- 3390 m a.s.l), which displays pristine crease-structure features. 40Ar/39Ar dating yield a reliable plateau age of 107±12 ka for the eruption of this lava flow. Eight pyroxene aliquots separated from the surface samples yield a weighted average cosmogenic 3He concentration of 99.3±1.2 Mat.g-1 from which a local cosmogenic 3He production rate of 928±101 at.g-1.yr-1 is calculated. The local production rate is then scaled to a sea level high latitude (SLHL) reference position using different combinations of geographic spatialization schemes, atmosphere models and geomagnetic field reconstructions, yielding SLHL production rates between 103±11 and 130±14 at.g-1.yr-1 consistent with the most recent estimates available from the literature. Finally, we use the same scaling frameworks to re-evaluate the mean global-scale cosmogenic 3He production rate in olivine and pyroxene minerals at 120±16 at.g-1.yr-1 from the compilation of previously published calibration datasets.

Sea urchins in a high CO2 world: partitioned effects of body-size, ocean warming and acidification on metabolic rate

Body-size and temperature are the major factors explaining metabolic rate, and the additional factor of pH is a major driver at the biochemical level. These three factors have frequently been found to interact, complicating the formulation of broad models predicting metabolic rates and hence ecological functioning. In this first study of the effects of warming and ocean acidification, and their potential interaction, on metabolic rate across a broad body-size range (two-to-three orders of magnitude difference in body mass) we addressed the impact of climate change on the sea urchin Heliocidaris erythrogramma in context with climate projections for east Australia, an ocean warming hotspot. Urchins were gradually introduced to two temperatures (18 and 23 °C) and two pH (7.5 and 8.0), and maintained for two months. That a new physiological steady-state had been reached, otherwise know as acclimation, was validated through identical experimental trials separated by several weeks. The relationship between body-size, temperature and acidification on the metabolic rate of H. erythrogramma was strikingly stable. Both stressors caused increases in metabolic rate; 20% for temperature and 19% for pH. Combined effects were additive; a 44% increase in metabolism. Body-size had a highly stable relationship with metabolic rate regardless of temperature or pH. None of these diverse drivers of metabolism interacted or modulated the effects of the others, highlighting the partitioned nature of how each influences metabolic rate, and the importance of achieving a full acclimation state. Despite these increases in energetic demand there was very limited capacity for compensatory modulating of feeding rate; food consumption increased only in the very smallest specimens, and only in response to temperature, and not pH. Our data show that warming, acidification and body-size all substantially affect metabolism and are highly consistent and partitioned in their effects, and for H. erythrogramma near-future climate change will incur a substantial energetic cost.

Exchange Rate Stabilization and IMF High Interest Rate Policy: A Critical Reconsideration Using a Dynamic Model

This paper examines whether the IMF high interest rate policy was suitable for crisis-ridden East Asian economies. Using an "overshoot" model similar to that of Dornbusch's (1976), it shows that this sort of policy might cause an unnecessary deflationary adjusting process and have no effect on containing the real depreciation of exchange rates in the long run. The study also demonstrates that Thai economic data coincides quite well with the model presented here. Finally, it points out that the high interest policy itself might provoke high risk-premium, the existence of which, in turn, justifies the policy. This means that the policy has a self-fulfilling property. In conclusion, a "one-size-fits-all" adaptation of high interest rate policy in a currency crisis is very dangerous in general, and was inappropriate for East Asia. The desirable policy would have been to let currencies depreciate and keep interest rates stable.

Influence of cement properties in the reaction rate and mechanical behavior of concrete with high fl y ash content

The use of fly ash (FA) as an admixture to concrete is broadly extended for two main reasons: the reduction of costs that supposes the substitution of cement and the micro structural changes motivated by the mineral admixture. Regarding this second point, there is a consensus that considers that the ash generates a more compact concrete and a reduction in the size of the pore. However, the measure in which this contributes to the pozzolanic activity or as filler is not well defined. There is also no justification to the influence of the physical parameters, fineness of the grain and free water, in its behavior. This work studies the use of FA as a partial substitute of the cement in concretes of different workability (dry and wet) and the influence in the reactivity of the ash. The concrete of dry consistency which serves as reference uses a cement dose of 250 Kg/m 3 and the concrete of fluid consistency utilized a dose of cement of 350 Kg/m 3 . Two trademark of Portland Cement Type 1 were used. The first reached the resistant class for its fineness of grain and the second one for its composition. Moreover, three doses of FA have been used, and the water/binder ratio was constant in all the mixtures. We have studied the mechanical properties and the micro-structure of the concretes by means of compressive strength tests, mercury intrusion porosimetry (MIP) and thermal analysis (TA). The results of compressive strength tests allow us to observe that concrete mixtures with cements of the same classification and similar dosage of binder do not present the same mechanical behavior. These results show that the effective water/binder ratio has a major role in the development of the mechanical properties of concrete. The study of different dosages using TA, thermo-gravimetry and differential thermal analysis, revealed that the portlandite content is not restrictive in any of the dosages studied. Again, this proves that the rheology of the material influences the reaction rate and content of hydrated cement products. We conclude that the available free water is determinant in the efficiency of pozzolanic reaction. It is so that in accordance to the availability of free water, the ashes can react as an active admixture or simply change the porous distribution. The MIP shows concretes that do not exhibit significant changes in their mechanical behavior, but have suffered significant variation in their porous structure

High data rate modulation of high power 1060-nm DBR tapered lasers with separate contacts

Direct optical modulation at 2.5 Gb/s with amplitude of more than 0.5 W has been demonstrated in single longitudinal mode distributed Bragg reflector tapered lasers emitting at 1060 nm with separated injection of the ridge waveguide and tapered sections. The modulating signal of ~110 mA peak to peak was applied to the ridge waveguide section, yielding a high modulation efficiency of ~5 W/A. The large-signal frequency response of the experimental set-up was limited by the bandwidth of the electrical amplifier rather than by the internal dynamics of the laser, indicating that higher bit rates could be achieved with improved driving electronics.

Design and optimization of optical, fiber based PSK demodulators for high-bit-rate optical networks

El objetivo principal de esta tesis ha sido el diseño y la optimización de receptores implementados con fibra óptica, para ser usados en redes ópticas de alta velocidad que empleen formatos de modulación de fase. En los últimos años, los formatos de modulación de fase (Phase Shift keying, PSK) han captado gran atención debido a la mejora de sus prestaciones respecto a los formatos de modulación convencionales. Principalmente, presentan una mejora de la eficiencia espectral y una mayor tolerancia a la degradación de la señal causada por la dispersión cromática, la dispersión por modo de polarización y los efectos no-lineales en la fibra óptica. En este trabajo, se analizan en detalle los formatos PSK, incluyendo sus variantes de modulación de fase diferencial (Differential Phase Shift Keying, DPSK), en cuadratura (Differential Quadrature Phase Shift Keying, DQPSK) y multiplexación en polarización (Polarization Multiplexing Differential Quadrature Phase Shift Keying, PM-DQPSK), con la finalidad de diseñar y optimizar los receptores que permita su demodulación. Para ello, se han analizado y desarrollado nuevas estructuras que ofrecen una mejora en las prestaciones del receptor y una reducción de coste comparadas con las actualmente disponibles. Para la demodulación de señales DPSK, en esta tesis, se proponen dos nuevos receptores basados en un interferómetro en línea Mach-Zehnder (MZI) implementado con tecnología todo-fibra. El principio de funcionamiento de los MZI todo-fibra propuestos se asienta en la interferencia modal que se produce en una fibra multimodo (MMF) cuando se situada entre dos monomodo (SMF). Este tipo de configuración (monomodo-multimodo-monomodo, SMS) presenta un buen ratio de extinción interferente si la potencia acoplada en la fibra multimodo se reparte, principal y equitativamente, entre dos modos dominantes. Con este objetivo, se han estudiado y demostrado tanto teórica como experimentalmente dos nuevas estructuras SMS que mejoran el ratio de extinción. Una de las propuestas se basa en emplear una fibra multimodo de índice gradual cuyo perfil del índice de refracción presenta un hundimiento en su zona central. La otra consiste en una estructura SMS con las fibras desalineadas y donde la fibra multimodo es una fibra de índice gradual convencional. Para las dos estructuras, mediante el análisis teórico desarrollado, se ha demostrado que el 80 – 90% de la potencia de entrada se acopla a los dos modos dominantes de la fibra multimodo y se consigue una diferencia inferior al 10% entre ellos. También se ha demostrado experimentalmente que se puede obtener un ratio de extinción de al menos 12 dB. Con el objeto de demostrar la capacidad de estas estructuras para ser empleadas como demoduladores de señales DPSK, se han realizado numerosas simulaciones de un sistema de transmisión óptico completo y se ha analizado la calidad del receptor bajo diferentes perspectivas, tales como la sensibilidad, la tolerancia a un filtrado óptico severo o la tolerancia a las dispersiones cromática y por modo de polarización. En todos los casos se ha concluido que los receptores propuestos presentan rendimientos comparables a los obtenidos con receptores convencionales. En esta tesis, también se presenta un diseño alternativo para la implementación de un receptor DQPSK, basado en el uso de una fibra mantenedora de la polarización (PMF). A través del análisi teórico y del desarrollo de simulaciones numéricas, se ha demostrado que el receptor DQPSK propuesto presenta prestaciones similares a los convencionales. Para complementar el trabajo realizado sobre el receptor DQPSK basado en PMF, se ha extendido el estudio de su principio de demodulación con el objeto de demodular señales PM-DQPSK, obteniendo como resultado la propuesta de una nueva estructura de demodulación. El receptor PM-DQPSK propuesto se basa en la estructura conjunta de una única línea de retardo junto con un rotador de polarización. Se ha analizado la calidad de los receptores DQPSK y PM-DQPSK bajo diferentes perspectivas, tales como la sensibilidad, la tolerancia a un filtrado óptico severo, la tolerancia a las dispersiones cromática y por modo de polarización o su comportamiento bajo condiciones no-ideales. En comparación con los receptores convencionales, nuestra propuesta exhibe prestaciones similares y además permite un diseño más simple que redunda en un coste potencialmente menor. En las redes de comunicaciones ópticas actuales se utiliza la tecnología de multimplexación en longitud de onda (WDM) que obliga al uso de filtros ópticos con bandas de paso lo más estrechas posibles y a emplear una serie de dispositivos que incorporan filtros en su arquitectura, tales como los multiplexores, demultiplexores, ROADMs, conmutadores y OXCs. Todos estos dispositivos conectados entre sí son equivalentes a una cadena de filtros cuyo ancho de banda se va haciendo cada vez más estrecho, llegando a distorsionar la forma de onda de las señales. Por esto, además de analizar el impacto del filtrado óptico en las señales de 40 Gbps DQPSK y 100 Gbps PM-DQPSK, este trabajo de tesis se completa estudiando qué tipo de filtro óptico minimiza las degradaciones causadas en la señal y analizando el número máximo de filtros concatenados que permiten mantener la calidad requerida al sistema. Se han estudiado y simulado cuatro tipos de filtros ópticos;Butterworth, Bessel, FBG y F-P. ABSTRACT The objective of this thesis is the design and optimization of optical fiber-based phase shift keying (PSK) demodulators for high-bit-rate optical networks. PSK modulation formats have attracted significant attention in recent years, because of the better performance with respect to conventional modulation formats. Principally, PSK signals can improve spectrum efficiency and tolerate more signal degradation caused by chromatic dispersion, polarization mode dispersion and nonlinearities in the fiber. In this work, many PSK formats were analyzed in detail, including the variants of differential phase modulation (Differential Phase Shift Keying, DPSK), in quadrature (Differential Quadrature Phase Shift Keying, DQPSK) and polarization multiplexing (Polarization Multiplexing Differential Quadrature Phase Shift Keying, PM-DQPSK), in order to design and optimize receivers enabling demodulations. Therefore, novel structures, which offer good receiver performances and a reduction in cost compared to the current structures, have been analyzed and developed. Two novel receivers based on an all-fiber in-line Mach-Zehnder interferometer (MZI) were proposed for DPSK signal demodulation in this thesis. The operating principle of the all-fiber MZI is based on the modal interference that occurs in a multimode fiber (MMF) when it is located between two single-mode fibers (SMFs). This type of configuration (Single-mode-multimode-single-mode, SMS) can provide a good extinction ratio if the incoming power from the SMF could be coupled equally into two dominant modes excited in the MMF. In order to improve the interference extinction ratio, two novel SMS structures have been studied and demonstrated, theoretically and experimentally. One of the two proposed MZIs is based on a graded-index multimode fiber (MMF) with a central dip in the index profile, located between two single-mode fibers (SMFs). The other one is based on a conventional graded-index MMF mismatch spliced between two SMFs. Theoretical analysis has shown that, in these two schemes, 80 – 90% of the incoming power can be coupled into the two dominant modes exited in the MMF, and the power difference between them is only ~10%. Experimental results show that interference extinction ratio of 12 dB could be obtained. In order to demonstrate the capacity of these two structures for use as DPSK signal demodulators, numerical simulations in a completed optical transmission system have been carried out, and the receiver quality has been analyzed under different perspectives, such as sensitivity, tolerance to severe optical filtering or tolerance to chromatic and polarization mode dispersion. In all cases, from the simulation results we can conclude that the two proposed receivers can provide performances comparable to conventional ones. In this thesis, an alternative design for the implementation of a DQPSK receiver, which is based on a polarization maintaining fiber (PMF), was also presented. To complement the work made for the PMF-based DQPSK receiver, the study of the demodulation principle has been extended to demodulate PM-DQPSK signals, resulting in the proposal of a novel demodulation structure. The proposed PM-DQPSK receiver is based on only one delay line and a polarization rotator. The quality of the proposed DQPSK and PM-DQPSK receivers under different perspectives, such as sensitivity, tolerance to severe optical filtering, tolerance to chromatic dispersion and polarization mode dispersion, or behavior under non-ideal conditions. Compared with the conventional receivers, our proposals exhibit similar performances but allow a simpler design which can potentially reduce the cost. The wavelength division multiplexing (WDM) technology used in current optical communications networks requires the use of optical filters with a passband as narrow as possible, and the use of a series of devices that incorporate filters in their architecture, such as multiplexers, demultiplexers, switches, reconfigurable add-drop multiplexers (ROADMs) and optical cross-connects (OXCs). All these devices connected together are equivalent to a chain of filters whose bandwidth becomes increasingly narrow, resulting in distortion to the waveform of the signals. Therefore, in addition to analyzing the impact of optical filtering on signal of 40 Gbps DQPSK and 100 Gbps PM-DQPSK, we study which kind of optical filter minimizes the signal degradation and analyze the maximum number of concatenated filters for maintaining the required quality of the system. Four types of optical filters, including Butterworth, Bessel, FBG and FP, have studied and simulated.

Rate-Adaptive LDPC-based key reconciliation for high performance quantum key distribution

The postprocessing or secret-key distillation process in quantum key distribution (QKD) mainly involves two well-known procedures: information reconciliation and privacy amplification. Information or key reconciliation has been customarily studied in terms of efficiency. During this, some information needs to be disclosed for reconciling discrepancies in the exchanged keys. The leakage of information is lower bounded by a theoretical limit, and is usually parameterized by the reconciliation efficiency (or inefficiency), i.e. the ratio of additional information disclosed over the Shannon limit. Most techniques for reconciling errors in QKD try to optimize this parameter. For instance, the well-known Cascade (probably the most widely used procedure for reconciling errors in QKD) was recently shown to have an average efficiency of 1.05 at the cost of a high interactivity (number of exchanged messages). Modern coding techniques, such as rate-adaptive low-density parity-check (LDPC) codes were also shown to achieve similar efficiency values exchanging only one message, or even better values with few interactivity and shorter block-length codes.

The high spontaneous mutation rate: Is it a health risk?*

The human mutation rate for base substitutions is much higher in males than in females and increases with paternal age. This effect is mainly, if not entirely, due to the large number of cell divisions in the male germ line. The mutation-rate increase is considerably greater than expected if the mutation rate were simply proportional to the number of cell divisions. In contrast, those mutations that are small deletions or rearrangements do not show the paternal age effect. The observed increase with the age of the father in the incidence of children with different dominant mutations is variable, presumably the result of different mixtures of base substitutions and deletions. In Drosophila, the rate of mutations causing minor deleterious effects is estimated to be about one new mutation per zygote. Because of a larger number of genes and a much larger amount of DNA, the human rate is presumably higher. Recently, the Drosophila data have been reanalyzed and the mutation-rate estimate questioned, but I believe that the totality of evidence supports the original conclusion. The most reasonable way in which a species can cope with a high mutation rate is by quasi-truncation selection, whereby a number of mutant genes are eliminated by one “genetic death.”

The cellulose-binding domain of the major cellobiohydrolase of Trichoderma reesei exhibits true reversibility and a high exchange rate on crystalline cellulose.

Cellulose-binding domains (CBDs) bind specifically to cellulose, and form distinct domains of most cellulose degrading enzymes. The CBD-mediated binding of the enzyme has a fundamental role in the hydrolysis of the solid cellulose substrate. In this work we have investigated the reversibility and kinetics of the binding of the CBD from Trichoderma reesei cellobiohydrolase I on microcrystalline cellulose. The CBD was produced in Escherichia coli, purified, and radioactively labeled by reductive alkylation with 3H. Sensitive detection of the labeled CBD allowed more detailed analysis of its behavior than has been possible before, and important novel features were resolved. Binding of the CBD was found to be temperature sensitive, with an increased affinity at lower temperatures. The interaction of the CBD with cellulose was shown to be fully reversible and the CBD could be eluted from cellulose by simple dilution. The rate of exchange measured for the CBD-cellulose interaction compares well with the hydrolysis rate of cellobiohydrolase I, which is consistent with its proposed mode of action as a processive exoglucanase.