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Objectives: This study aimed to evaluate hemodynamic correlates of inducible blood pressure (BP) pulsatility with exercise in heart failure with preserved ejection fraction (HFpEF), to identify relationships to outcomes, and to compare this with heart failure with reduced ejection fraction (HFrEF)., Background: In HFpEF, determinants and consequences of exercise BP pulsatility are not well understood., Methods: We measured exercise BP in 146 patients with HFpEF who underwent invasive cardiopulmonary exercise testing. Pulsatile BP was evaluated as proportionate pulse pressure (PrPP), the ratio of pulse pressure to systolic pressure. We measured pulmonary arterial catheter pressures, Fick cardiac output, respiratory gas exchange, and arterial stiffness. We correlated BP changes to central hemodynamics and cardiovascular outcome (nonelective cardiovascular hospitalization) and compared findings with 57 patients with HFrEF from the same referral population., Results: In HFpEF, only age (standardized beta = 0.593; P < 0.001), exercise stroke volume (standardized beta = 0.349; P < 0.001), and baseline arterial stiffness (standardized beta = 0.182; P = 0.02) were significant predictors of peak exercise PrPP in multivariable analysis (R = 0.661). In HFpEF, lower PrPP was associated with lower risk of cardiovascular events, despite adjustment for confounders (HR:0.53 for PrPP below median; 95% CI: 0.28-0.98; P = 0.043). In HFrEF, lower exercise PrPP was not associated with arterial stiffness but was associated with lower peak exercise stroke volume (P = 0.013) and higher risk of adverse cardiovascular outcomes (P = 0.004)., Conclusions: In HFpEF, greater inducible BP pulsatility measured using exercise PrPP reflects greater arterial stiffness and higher risk of adverse cardiovascular outcomes, in contrast to HFrEF where inducible exercise BP pulsatility relates to stroke volume reserve and favorable outcome., Competing Interests: Funding Support and Author Disclosures Dr Namasivayam is supported by a Clinical and Research Fellowship from the Division of Cardiology, Massachusetts General Hospital, Harvard Medical School; and is a recipient of the St. Vincent’s Clinic Travelling Fellowship Award. Dr Lewis is supported by the American Heart Association Award 15GPSGC24800006 and by the National Heart, Lung and Blood Institute Awards R01-HL 131029 and R01-HL151841. Dr Nayor is supported by National Institutes of Health/National Heart, Lung, and Blood Institute K23-HL138260. Dr Ho is supported by National Institutes of Health/National Heart, Lung, and Blood Institute R01-HL134893 and R01-HL140224. Dr Malhotra is supported by Transformation Project Award 18TPA34230025 from the American Heart Association and grant R01-HL142809 from the National Heart, Lung, and Blood Institute. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022. Published by Elsevier Inc.)

Importance: Heart failure with preserved ejection fraction (HFpEF) is a joint metabolic and cardiovascular disorder with significant noncardiac contributions., Objective: To define and quantify the metabolic cost of initiating exercise in individuals with and without HFpEF and its functional consequences., Design, Setting, and Participants: This prospective cohort study included individuals with hemodynamically confirmed HFpEF from the Massachusetts General Hospital Exercise Study (MGH-ExS) and community-dwelling participants from the Framingham Heart Study (FHS). Analysis began April 2016 and ended November 2020., Exposures: Internal work (IW), a measure of work equivalents required to initiate movement., Main Outcomes and Measures: Using breath-by-breath oxygen uptake (V̇o2) measurements and V̇o2-work rate associations, cost of initiating exercise (IW) in patients with HFpEF (MGH-ExS) and in community-dwelling individuals (FHS) was quantified. Linear regression was used to estimate associations between IW and clinical/hemodynamic measures., Results: Of 3231 patients, 184 (5.7%) had HFpEF and were from MGH-ExS, and 3047 (94.3%) were community-dwelling individuals from FHS. In the MGH-ExS cohort, 86 (47%) were women, the median (interquartile range) age was 63 (53-72) years, and the median (interquartile range) peak V̇o2 level was 13.33 (11.77-15.62) mL/kg/min. In the FHS cohort, 1620 (53%) were women, the median (interquartile range) age was 54 (48-60) years, and the median (interquartile range) peak V̇o2 level was 22.2 (17.85-27.35) mL/kg/min. IW was higher in patients with HFpEF and accounted for 27% (interquartile range, 21%-39%) of the total work (IW + measured external workload on the cycle), compared with 15% (interquartile range, 12%-20%) of that in FHS participants. Body mass index accounted for greatest explained variance in patients with HFpEF from MGH-ExS and FHS participants (22% and 18%, respectively), while resting cardiac output and biventricular filling pressures were not significantly associated with variance in IW in patients with HFpEF. A higher IW in patients with HFpEF was associated with a greater increase in left- and right-sided cardiac filing pressure during unloaded exercise, despite similar resting hemodynamic measures across IW., Conclusions and Relevance: This study found that internal work, a new body mass index-related measure reflecting the metabolic cost of initiating movement, is higher in individuals with HFpEF compared with middle-aged adults in the community and is associated with steep, early increases in cardiac filling pressures. These findings highlight the importance of quantifying heterogeneous responses to exercise initiation when evaluating functional intolerance in individuals at risk for or with HFpEF.

Electron paramagnetic resonance (EPR) based distance measurements have been exploited to measure protein-protein docking, protein-DNA interactions, substrate binding and metal coordination sites. Here, we use EPR to locate a native paramagnetic metal binding site in a protein with less than 2 Å resolution. We employ a rigid Cu2+ binding motif, the double histidine (dHis) motif, in conjunction with double electron electron resonance (DEER) spectroscopy. Specifically, we utilize a multilateration approach to elucidate the native Cu2+ binding site in the immunoglobulin binding domain of protein G. Notably, multilateration performed with the dHis motif required only the minimum number of four distance constraints, whereas comparable studies using flexible nitroxide-based spin labels require many more for similar precision. This methodology demonstrates a significant increase in the efficiency of structural determinations via EPR distance measurements using the dHis motif.

Background: Single measurements of left ventricular filling pressure at rest lack sensitivity for identifying heart failure with preserved ejection fraction (HFpEF) in patients with dyspnea on exertion. We hypothesized that exercise hemodynamic measurements (ie, changes in pulmonary capillary wedge pressure [PCWP] indexed to cardiac output [CO]) may more sensitively differentiate HFpEF and non-HFpEF disease states, reflect aerobic capacity, and forecast heart failure outcomes in individuals with normal PCWP at rest., Methods and Results: We studied 175 patients referred for cardiopulmonary exercise testing with hemodynamic monitoring: controls (n=33), HFpEF with resting PCWP≥15 mm Hg (n=32), and patients with dyspnea on exertion with normal resting PCWP and left ventricular ejection fraction (DOE-nlrW; n=110). Across 1835 paired PCWP-CO measurements throughout exercise, we used regression techniques to define normative bounds of "PCWP/CO slope" in controls and tested the association of PCWP/CO slope with exercise capacity and composite cardiac outcomes (defined as cardiac death, incident resting PCWP elevation, or heart failure hospitalization) in the DOE-nlrW group. Relative to controls (PCWP/CO slope, 1.2±0.4 mm Hg/L/min), patients with HFpEF had a PCWP/CO slope of 3.4±1.9 mm Hg/L/min. We used a threshold (2 SD above the mean in controls) of 2 mm Hg/L/min to define abnormal. PCWP/CO slope >2 in DOE-nlrW patients was common (n=45/110) and was associated with reduced peak Vo 2 ( P <0.001) and adverse cardiac outcomes after adjustment for age, sex, and body mass index (hazard ratio, 3.47; P =0.03) at a median 5.3-year follow-up., Conclusions: Elevated PCWP/CO slope during exercise (>2 mm Hg/L/min) is common in DOE-nlrW and predicts exercise capacity and heart failure outcomes. These findings suggest that current definitions of HFpEF based on single measures during rest are insufficient and that assessment of exercise PCWP/CO slope may refine early HFpEF diagnosis., (© 2018 American Heart Association, Inc.)

Cu 2+ based distance measurements using the double-histidine (dHis) motif by pulsed ESR present an attractive strategy to obtain precise, narrow distance distributions that can be easily related to protein backbone structure (Cunningham et al., Angew. Chem., Int. Ed., 2015, 54, 633). The Cu 2+ -ion is introduced as a complex with the iminodiacetic acid (IDA) chelating agent, which enhances binding selectivity to the two histidine residues that are site-selectively placed on the protein through mutagenesis. However, initial results of this method produced weak dipolar modulations. To enhance applicability of the double histidine motif using IDA, we perform a systematic examination of the possible causes of these weak dipolar modulations. We examine the efficiency of the Cu 2+ -ion to form the Cu 2+ -IDA complex in solution. In addition, we analyze the selectivity of Cu 2+ -IDA binding to dHis sites at both α-helical and β-strand environments. Our results indicate that the dHis motif on the β-sheet sites have high affinity towards Cu 2+ -IDA while the dHis sites on α-helices show poor affinity for the metal-ion complex. We are able to use our new findings to optimize conditions to maximize dHis loading while minimizing both free Cu 2+ and unbound Cu 2+ -IDA complex in solution, allowing us to double the sensitivity of the Double Electron-Electron Resonance (DEER) experiment. Finally, we illustrate how Cu 2+ -based CW-ESR and DEER can be combined to obtain information on populations of different Cu 2+ -complexes in solution.

Measurements of distances in cells by pulsed ESR spectroscopy afford tremendous opportunities to study proteins in native environments that are irreproducible in vitro. However, the in-cell environment is harsh towards the typical nitroxide radicals used in double electron-electron resonance (DEER) experiments. A systematic examination is performed on the loss of the DEER signal, including contributions from nitroxide decay and nitroxide side-chain cleavage. In addition, the possibility of extending the lifetime of the nitroxide radical by use of an oxidizing agent is investigated. Using this oxidizing agent, DEER distance measurements are performed on doubly nitroxide-labeled GB1, the immunoglobulin-binding domain of protein G, at varying incubation times in the cellular environment. It is found that, by comparison of the loss of DEER signal to the loss of the CW spectrum, cleavage of the nitroxide side chain contributes to the loss of DEER signal, which is significantly greater in cells than in cell extracts. Finally, local spin concentrations are monitored at varying incubation times to show the time required for molecular diffusion of a small globular protein within the cellular milieu., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Protein spin labeling to yield the nitroxide-based R1 side chain is a powerful method to measure protein dynamics and structure by electron spin resonance. However, R1 measurements are complicated by the flexibility of the side chain. While analysis approaches for solvent-exposed α-helical environment have been developed to partially account for flexibility, similar work in β-sheets is lacking. The goal of this study is to provide the first essential steps for understanding the conformational preferences of R1 within edge β-strands using X-ray crystallography and double electron electron resonance (DEER) distance measurements. Crystal structures yielded seven rotamers for a non-hydrogen-bonded site and three rotamers for a hydrogen-bonded site. The observed rotamers indicate contextual differences in R1 conformational preferences compared to other solvent-exposed environments. For the DEER measurements, each strand site was paired with the same α-helical site elsewhere on the protein. The most probable distance observed by DEER is rationalized based on the rotamers observed in the crystal structure. Additionally, the appropriateness of common molecular modeling methods that account for R1 conformational preferences are assessed for the β-sheet environment. These results show that interpretation of R1 behavior in β-sheets is difficult and indicate further development is needed for these computational methods to correctly relate DEER distances to protein structure at edge β-strand sites., (© 2016 The Protein Society.)

The development of ESR methods that measure long-range distance distributions has advanced biophysical research. However, the spin labels commonly employed are highly flexible, which leads to ambiguity in relating ESR measurements to protein-backbone structure. Herein we present the double-histidine (dHis) Cu(2+)-binding motif as a rigid spin probe for double electron-electron resonance (DEER) distance measurements. The spin label is assembled in situ from natural amino acid residues and a metal salt, requires no postexpression synthetic modification, and provides distance distributions that are dramatically narrower than those found with the commonly used protein spin label. Simple molecular modeling based on an X-ray crystal structure of an unlabeled protein led to a predicted most probable distance within 0.5 Å of the experimental value. Cu(2+) DEER with the dHis motif shows great promise for the resolution of precise, unambiguous distance constraints that relate directly to protein-backbone structure and flexibility., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Double electron electron resonance (DEER) is an attractive technique that is utilized for gaining insight into protein structure and dynamics via nanometer-scale distance measurements. The most commonly used paramagnetic tag in these measurements is a nitroxide spin label, R1. Here, we present the application of two types of high-affinity Cu(2+) chelating tags, based on the EDTA and cyclen metal-binding motifs as alternative X-band DEER probes, using the B1 immunoglobulin-binding domain of protein G (GB1) as a model system. Both types of tags have been incorporated into a variety of protein secondary structure environments and exhibit high spectral sensitivity. In particular, the cyclen-based tag displays distance distributions with comparable distribution widths and most probable distances within 1-3 Å when compared to homologous R1 distributions. The results display the viability of the cyclen tag as an alternative to the R1 side chain for X-band DEER distance measurements in proteins.

Electron spin resonance (ESR) spectroscopy in combination with site-directed spin labeling has been widely used to determine the structure and dynamics of proteins and other biomolecules. The most popular spin label is a nitroxide-based radical which can be attached to a protein via a site-specific reaction with either native cysteines or cysteines engineered into the system via site-directed mutagenesis. Paramagnetic transition metals, including Cu(2+), often serve as cofactors of metalloproteins, and have already been realized as ESR probes to report structural information in these proteins. This chapter summarizes recent methodological development from our laboratory in utilizing Cu(2+) as an ESR spin probe to determine distance information. We focus on detailed experimental procedures, optimized instrumental parameters, and data analysis approaches in order to guide one who is new to the field. Theory and applications of metal ESR have been reviewed in literature and are not the focus of this chapter. A few examples of applications of the methods are listed in the end., (© 2015 Elsevier Inc. All rights reserved.)

Paramagnetic relaxation enhancements (PREs) are a rich source of structural information in protein solid-state NMR spectroscopy. Here we demonstrate that PRE measurements in natively diamagnetic proteins are facilitated by a thiol-reactive compact, cyclen-based, high-affinity Cu(2+) binding tag, 1-[2-(pyridin-2-yldisulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (TETAC), that overcomes the key shortcomings associated with the use of larger, more flexible metal-binding tags. Using the TETAC-Cu(2+) K28C mutant of B1 immunoglobulin-binding domain of protein G as a model, we find that amino acid residues located within ~10 Å of the Cu(2+) center experience considerable transverse PREs leading to severely attenuated resonances in 2D (15)N-(13)C correlation spectra. For more distant residues, electron-nucleus distances are accessible via quantitative measurements of longitudinal PREs, and we demonstrate such measurements for (15)N-Cu(2+) distances up to ~20 Å.

College students searched for either h or the in prose passages in which every h occurred in the test word the. In Experiment 1, passage versions differed in that the critical noun phrases were either the alone (i.e., in citation form as a noun referring to itself) or "the definite article." Many more detection errors occurred for letter than word target items, especially with "the definite article." In Experiment 2, passage versions differed in that a given noun phrase containing the test word the occurred as a subject in one version and an object in the other. Again, many more detection errors occurred when the target item was the letter h than when it was the letter sequence the. Also, with letter but not letter sequence targets, more detection errors occurred for object than subject noun phrases. In Experiment 3, passages were presented either in regular format or with all capital letters. Students made more detection errors with the regular than with the capitals format, many more errors occurred when participants searched for letters than for letter sequences, and the effect of target item was larger with regular than with capitals format. These findings suggest that accounts of detection errors in reading must include the influence of unitization and processing time or attentional allocation.

X-ray crystallography has been a useful tool in the development of site-directed spin labeling by resolving rotamers of the nitroxide spin-label side chain in a variety of α-helical environments. In this work, the crystal structure of a doubly spin-labeled N8C/K28C mutant of the B1 immunoglobulin-binding domain of protein G (GB1) was solved. The double mutant formed a domain-swapped dimer under crystallization conditions. Two rotameric states of the spin-label were resolved at the solvent-exposed α-helical site, at residue 28; these are in good agreement with rotamers previously reported for helical structures. The second site, at residue 8 on an interior β-strand, shows the presence of three distinct solvent-exposed side-chain rotamers. One of these rotamers is rarely observed within crystal structures of R1 sites and suggests that the H(α) and S(δ) hydrogen bond that is common to α-helical sites is absent at this interior β-strand residue. Variable temperature continuous wave (CW) experiments of the β-strand site showed two distinct components that were correlated to the rotameric states observed in crystallography. Interestingly, the CW data at room temperature could be fit without the use of an order parameter, which is consistent with the lack of the H(α) and S(δ) interaction. Additionally, double electron electron resonance (DEER) spectroscopy was performed on the GB1 double mutant in its monomeric form and yielded a most probable interspin distance of 25 ± 1 Å. In order to evaluate the accuracy of the measured DEER distance, the rotamers observed in the crystal structure of the domain-swapped GB1 dimer were modeled into a high-resolution structure of the wild type monomeric GB1. The distances generated in the resulting GB1 structural models match the most probable DEER distance within ~2 Å. The results are interesting as they indicate by direct experimental measurement that the rotameric states of R1 found in this crystal provide a very close match to the most probable distance measured by DEER.

Building on our recently introduced library-based Monte Carlo (LBMC) approach, we describe a flexible protocol for mixed coarse-grained (CG)/all-atom (AA) simulation of proteins and ligands. In the present implementation of LBMC, protein side chain configurations are pre-calculated and stored in libraries, while bonded interactions along the backbone are treated explicitly. Because the AA side chain coordinates are maintained at minimal run-time cost, arbitrary sites and interaction terms can be turned on to create mixed-resolution models. For example, an AA region of interest such as a binding site can be coupled to a CG model for the rest of the protein. We have additionally developed a hybrid implementation of the generalized Born/surface area (GBSA) implicit solvent model suitable for mixed-resolution models, which in turn was ported to a graphics processing unit (GPU) for faster calculation. The new software was applied to study two systems: (i) the behavior of spin labels on the B1 domain of protein G (GB1) and (ii) docking of randomly initialized estradiol configurations to the ligand binding domain of the estrogen receptor (ERα). The performance of the GPU version of the code was also benchmarked in a number of additional systems.

Herein, we identify the coordination environment of Cu²(+) in the human α1-glycine receptor (GlyR). GlyRs are members of the pentameric ligand-gated ion channel superfamily (pLGIC) that mediate fast signaling at synapses. Metal ions like Zn²(+) and Cu²(+) significantly modulate the activity of pLGICs, and metal ion coordination is essential for proper physiological postsynaptic inhibition by GlyR in vivo. Zn²(+) can either potentiate or inhibit GlyR activity depending on its concentration, while Cu²(+) is inhibitory. To better understand the molecular basis of the inhibitory effect we have used electron spin resonance to directly examine Cu²(+) coordination and stoichiometry. We show that Cu²(+) has one binding site per α1 subunit, and that five Cu²(+) can be coordinated per GlyR. Cu²(+) binds to E192 and H215 in each subunit of GlyR with a 40 μM apparent dissociation constant, consistent with earlier functional measurements. However, the coordination site does not include several residues of the agonist/antagonist binding site that were previously suggested to have roles in Cu²(+) coordination by functional measurements. Intriguingly, the E192/H215 site has been proposed as the potentiating Zn²(+) site. The opposing modulatory actions of these cations at a shared binding site highlight the sensitive allosteric nature of GlyR., (Copyright © 2010 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

We examined the influence of encoding and generation processes on distinctiveness, isolation, and background effects in short-term recall of order information. Adults recalled the order of letters in one of two segments following a distractor task, knowing in advance the identity of the letters. A distinctive letter was one that was either in red or absent and replaced with a red dash, thereby requiring generation. On trials with a distinctive letter, the letter was primed in advance. A negative generation effect was found; in addition, there was a positive distinctiveness effect but a negative background effect on trials in which generation was required. These effects can be explained in terms of the extra processing given to distinctive items when they need to be generated.

College students searched for the letter "a" in prose passages typed normally, with an asterisk (Experiments 1 and 2) or the letter "x" (Experiment 3) replacing every interword space, or with asterisks replacing only some of the interword spaces (Experiment 2). Contrary to predictions based on masking through lateral interference but consistent with predictions based on studies of eye movement monitoring and unitization, asterisks or instances of the letter "x" surrounding the word "a" actually made the letter "a" easier to detect in that word, but generally not in other words in the text. It is concluded that for very common words, reading units may extend beyond the word boundary to include the surrounding interword spaces.

Adults recalled the order of the letters in one of two four-letter segments following a distractor task. They knew in advance the identity of the letters in each segment. A letter was made distinctive by replacing it with a red dash. This unusual form of distinctiveness generally had negative effects on recall of both the segment containing the missing letter and the absent letter within the segment. Encoding and output processes were manipulated by varying precue information and recall order instructions, respectively. Informing participants in advance whether or not a trial would contain a distinctive (i.e., missing) letter depressed recall. Constraining output order eliminated the disadvantage for the absent letter. The results are discussed in terms of encoding and output order processes in short-term recall of order information.

In two experiments, we examined short-term recall of order information using a partial-report distractor task. We manipulated the characteristics of a single letter in one of two four-letter segments. Participants knew in advance the identity of the letters in each segment. We made a single letter distinctive at presentation either by printing it in red or by replacing it with a red dash. Presenting the letter in red did not affect overall recall of the positions of the letters in the segment but did facilitate specific recall of the position of the distinct letter. Replacing the letter with a red dash inhibited overall recall as well as specific recall of the distinct letter. Participants were also less likely to respond in the regular output order when there was a dash replacing a letter in the segment. These effects of distinctiveness are explained in terms of output order processes in recent versions of the perturbation model.

In two experiments, subjects recalled one of two letter segments following a digit-filled retention interval. In Experiment 1, recall expectancy was manipulated by using precues that correctly informed or misinformed subjects concerning which letter segment would be tested for recall. In Experiment 2, item importance was varied by precuing one segment as important but requiring that the uncued segment be recalled first. Recall performance was very low under conditions of low expectancy and low segment importance, but the slopes of the retention functions did not demonstrate more rapid forgetting than under standard conditions. The previous observations of very rapid forgetting from primary memory may be a function of an elevated initial recall level in the earlier studies. Our retention functions were compared with predictions of the Estes perturbation model. The findings suggested that when secondary memory processes were reduced, forgetting order information from primary memory occurred at the same rate as that estimated on the basis of previous studies using the standard distractor task.

Fourth- and seventh-grade children and college-age adults proofread passages typed either in lowercase or in all capital letters. Words were misspelled by deleting one of four letters, s, c, k, or p, that have similar features in lowercase and uppercase. Proofreading errors decreased with age and increasing reading ability, but all of the subjects were sensitive to changes in word shape--they missed more words with deletions of s or c than k or p in the lowercase passage but not in the all-capitals passage. These findings indicate that word shape is an important variable in recognizing familiar words, even for young readers.

In Experiments 1 and 2 first-, third-, and seventh-grade children and college subjects circled the letter a while reading passages constructed of words familiar to first graders. First graders made more errors on the letter a embedded in a word than on the word a, whereas the converse was true of the other age groups. In Experiments 3 and 4 first-, second-, fourth-, and seventh-grade children and college students read passages and circled the letter t, making more errors on the common word the than on other words and on correctly spelled than on misspelled words. The effect of misspelling the other words increased with age and reading skill. Our combined results suggest that reading unit size increases with age and reading ability and that, whereas younger children, like adults, unitize common words, the unitization of less common words increases as word configurations become more familiar.

In two experiments, subjects recalled one of two letter sequences following a digit-filled retention interval. Recall performance was increased by precues informing subjects which letter sequence would be tested, and the cuing advantage remained throughout 60-digit retention intervals. No improvement was found, however, for cues occurring after the letters but before the digits. The cuing effects were attributed to encoding, not rehearsal, processes and were explained by a version of the Estes perturbation model, which included a long-term storage component and a fixed perturbation probability.

A small number of patients manifest wound infections several months to several years after their operations. A study was undertaken to delineate the clinical characteristics of patients whose infections became apparent after a prolonged time interval from surgery. Twenty-six patients were admitted to the New York Hospital-Cornell University Medical Center, with wound infections that occurred more than six months postoperatively. There were three distinct groups. The first group consisted of patients with Staphylococcus aureus infections related to superficial stitch abscesses. The second group comprised patients with pacemaker infections; S epidermidis was the most frequently recovered organism. The third group consisted of patients with more clinically significant infections. These infectious complications followed genitourinary, gastrointestinal, and biliary surgery. The findings of this study suggest that most of these infections are caused by organisms introduced into the wound at the time of surgery; these organisms may become active because of alterations in the host's resistance.

Two experiments examined the effects of repetition on the short-term retention of order information. A partial report procedure was coupled with the distractor paradigm to vary which one of two 4-letter sequences was tested after a digit-filled retention interval. Repeatedly presenting the stimulus but not its testing did not increase recall, but recall did increase when both presentation and testing were repeated. Recall was also improved by precues that informed subjects in advance which sequence was to be recalled. The perturbation model of Estes (1972; Lee & Estes, 1981) was able to account for the qualitative and quantitative aspects of the results by making an explicit distinction between two types of rehearsal: the reactivation process, which corresponds to a passive, automatic rehearsal process; and an active, conscious rehearsal process that crystallizes the memory structure and makes perturbations less likely.

The hypothesis that familial sinistrality (FS) might be a useful variable for differentiating between pathological and natural left-handers was explored. A comparison of the incidence of FS in mentally retarded and nonretarded samples indicated that a positive history of familial sinistrality (FS+) was significantly more likely to occur in mildly retarded individuals. In addition, left-handed retarded people, in general, were significantly more likely to be FS+ than were right-handed retarded people.