A unified theory of bone healing and nonunion: BHN theory.

This article presents a unified clinical theory that links established facts about the physiology of bone and homeostasis, with those involved in the healing of fractures and the development of nonunion. The key to this theory is the concept that the tissue that forms in and around a fracture should be considered a specific functional entity. This 'bone-healing unit' produces a physiological response to its biological and mechanical environment, which leads to the normal healing of bone. This tissue responds to mechanical forces and functions according to Wolff's law, Perren's strain theory and Frost's concept of the "mechanostat". In response to the local mechanical environment, the bone-healing unit normally changes with time, producing different tissues that can tolerate various levels of strain. The normal result is the formation of bone that bridges the fracture - healing by callus. Nonunion occurs when the bone-healing unit fails either due to mechanical or biological problems or a combination of both. In clinical practice, the majority of nonunions are due to mechanical problems with instability, resulting in too much strain at the fracture site. In most nonunions, there is an intact bone-healing unit. We suggest that this maintains its biological potential to heal, but fails to function due to the mechanical conditions. The theory predicts the healing pattern of multifragmentary fractures and the observed morphological characteristics of different nonunions. It suggests that the majority of nonunions will heal if the correct mechanical environment is produced by surgery, without the need for biological adjuncts such as autologous bone graft. Cite this article: Bone Joint J 2016;98-B:884-91.

Runx2 association with progression of prostate cancer in patients: mechanisms mediating bone osteolysis and osteoblastic metastatic lesions.

Runx2, a bone-specific transcriptional regulator, is abnormally expressed in highly metastatic prostate cancer cells. Here, we identified the functional activities of Runx2 in facilitating tumor growth and osteolysis. Our studies show that negligible Runx2 is found in normal prostate epithelial and non-metastatic LNCaP prostate cancer cells. In the intra-tibial metastasis model, high Runx2 levels are associated with development of large tumors, increased expression of metastasis-related genes (MMP9, MMP13, VEGF, Osteopontin) and secreted bone-resorbing factors (PTHrP, IL8) promoting osteolytic disease. Runx2 siRNA treatment of PC3 cells decreased cell migration and invasion through Matrigel in vitro, and in vivo shRunx2 expression in PC3 cells blocked their ability to survive in the bone microenvironment. Mechanisms of Runx2 function were identified in co-culture studies showing that PC3 cells promote osteoclastogenesis and inhibit osteoblast activity. The clinical significance of these findings is supported by human tissue microarray studies of prostate tumors at stages of cancer progression, in which Runx2 is expressed in both adenocarcinomas and metastatic tumors. Together these findings indicate that Runx2 is a key regulator of events associated with prostate cancer metastatic bone disease.

Yes/no recognition, forced-choice recognition, and the human hippocampus.

Two recent studies reported that yes/no recognition can be more impaired by hippocampal lesions than forced-choice recognition when the targets and foils are highly similar. This finding has been taken in support of two fundamental proposals: (1) yes/no recognition tests depend more on recollection than do forced-choice tests; and (2) the hippocampus selectively supports the recollection process. Using the same stimulus materials as in the earlier studies, we tested five memory-impaired patients with circumscribed hippocampal lesions and 15 controls. As in the earlier studies, participants studied 12 pictures of objects and then took either a 12-item forced-choice test with four alternatives or a 60-item yes/no test. Patients were impaired on both tests but did more poorly on the yes/no test. However, a yes/no test based on 12 study items would conventionally involve only 24 test items (i.e., 12 study items and 12 foil items). When we scored only the first 24 test items, the patients performed identically on the yes/no and forced-choice tests. Examination of the data in blocks of 12 trials indicated that the scores of the patients declined as testing continued. We suggest that a yes/no test of 60 items is difficult relative to a 12-item forced-choice test due to the increased study-test delay and due to increased interference, not because of any fundamental difference between the yes/no and forced-choice formats. We conclude that hippocampal lesions impair yes/no and forced-choice recognition to the same extent.

On the nature of associative information in recognition memory.

In a typical associative-recognition task, participants must distinguish between intact word pairs (both words previously studied together) and rearranged word pairs (both words previously studied but as part of different pairs). The familiarity of the individual items on this task is uninformative because all of the items were seen before, so the only way to solve the task is to rely on associative information. Prior research suggests that associative information is recall-like in nature and may therefore be an all-or-none variable. The present research reports several experiments in which some pairs were strengthened during list presentation. The resulting hit rates and false alarm rates, and an analysis of the corresponding receiver operating characteristic plots, suggest that participants rely heavily on item information when making an associative-recognition decision (to no avail) and that associative information may be best thought of as a some-or-none variable.

Relation between confidence in yes-no and forced-choice tasks.

Yes-no and forced-choice tasks are common in psychology, but the empirical relation between reported confidence in the 2 tasks has been unclear. The authors examined this relation with 2 experiments. The general experimental method had participants first report confidence in the truth of each of many general knowledge statements (a yes-no task) then report confidence in them again when the statements were put into pairs where it was known that one statement was true and one was false (a forced-choice task). At issue was how confidence in the statements changed between the yes-no task and the forced-choice task. Two models, including the normative one, were ruled out as descriptive models. A linear model and a multiplicative model remain viable contenders.

The case against a criterion-shift account of false memory.

M. B. Miller and G. L. Wolford (1999) argued that the high false-alarm rate associated with critical lures in the Roediger-McDermott (H. L. Roediger & K. B. McDermott, 1995) paradigm results from a criterion shift and therefore does not reflect false memory. This conclusion, which is based on new data reported by Miller and Wolford, overlooks the fact that Roediger and McDermott's false-memory account is as compatible with the new findings as the criterion-shift account is. Furthermore, a consideration of prior work concerned with investigating the conditions under which participants are and are not inclined to adjust the decision criterion suggests that the criterion-shift account of false memory is unlikely to be correct.

The disparate effects of Alzheimer's disease and Huntington's disease on semantic memory.

Alzheimer's disease (AD) and Huntington's disease (HD) impair performance on semantic memory tasks, but researchers disagree on whether AD and HD cause these impairments in the same manner. According to one view, AD disrupts the storage of semantic memories, whereas HD disrupts the retrieval of semantic memories. Dissenters argue that AD, like HD, disrupts retrieval. In this study, participants generated category exemplars (e.g., kinds of fruits) for 1 min, and response latencies were examined. Relative to healthy controls, the 12 AD patients produced a larger proportion of responses earlier in the recall period, consistent with the view that AD patients quickly exhaust their limited supply of items in storage. By contrast, the 12 HD patients produced a larger proportion of their responses late in the recall period, consistent with the view that HD slows retrieval.

Psychophysics of remembering.

We present a new model of remembering in the context of conditional discrimination. For procedures such as delayed matching to sample, the effect of the sample stimuli at the time of remembering is represented by a pair of Thurstonian (normal) distributions of effective stimulus values. The critical assumption of the model is that, based on prior experience, each effective stimulus value is associated with a ratio of reinforcers obtained for previous correct choices of the comparison stimuli. That ratio determines the choice that is made on the basis of the matching law. The standard deviations of the distributions are assumed to increase with increasing retention-interval duration, and the distance between their means is assumed to be a function of other factors that influence overall difficulty of the discrimination. It is a behavioral model in that choice is determined by its reinforcement history. The model predicts that the biasing effects of the reinforcer differential increase with decreasing discriminability and with increasing retention-interval duration. Data from several conditions using a delayed matching-to-sample procedure with pigeons support the predictions.

On the difference between strength-based and frequency-based mirror effects in recognition memory.

A mirror effect can be produced by manipulating word class (e.g., high vs. low frequency) or by manipulating strength (e.g., short vs. long study time). The results of 5 experiments reported here suggest that a strength-based mirror effect is caused by a shift in the location of the decision criterion, whereas a frequency-based mirror effect occurs although the criterion remains fixed with respect to word frequency. Evidence supporting these claims is provided by a series of studies in which high frequency (HF) words were differentially strengthened (and sometimes differentially colored) during list presentation. That manipulation increased the HF hit rate above that for low frequency (LF) words without selectively decreasing the HF false alarm rate, just as a fixed-criterion account of the word-frequency mirror effect predicts.

Decision rules for recognition memory confidence judgments.

According to the standard signal-detection model of recognition memory, confidence judgments for recognition responses are reached in much the same way that old-new decisions are reached (i.e., on the basis of criteria situated along the strength-of-evidence axis). The question investigated here is how the confidence criteria shift when recognition accuracy is manipulated across conditions. Although several theories assume that the old-new decision criterion shifts when recognition accuracy changes, less is known about how the confidence criteria move. An analysis of data previously reported by R. Ratcliff, G. McKoon, and M. Tindall (1994) and some new data reported here suggest that the confidence criteria fan out on the decision axis as d' decreases. This result is qualitatively consistent with the predictions of a likelihood ratio model, although the data did not support the stronger quantitative predictions of this account.

Same-different texture discrimination in pigeons: testing competing models of discrimination and stimulus integration.

The choice behavior of 6 pigeons performing a mulltidimensional same-different texture discrimination was examined. On each trial, they had to choose among 2 choice hoppers depending on whether a color, shape, or redundant (color and shape) target signal was present or not in a textured stimulus. Receiver operating characteristic (ROC) curves were produced by variations in the priori signal presentation probabilities across conditions. Quantitative analyses of these ROC curves were used to evaluate different competing theories of discrimination (signal detection vs. high-threshold-default response models) and information integration (independent observations, additive integration, unidimensional models). The results suggested the structure of the pigeons' choice behavior in this same-different discrimination was best described by an unequal variance signal detection model involving a unidimensional evidence variable (e.g., degree of difference).

Genuine power curves in forgetting: a quantitative analysis of individual subject forgetting functions.

Wixted and Ebbesen (1991) showed that forgetting functions produced by a variety of procedures are often well described by the power function, at-b, where a and b are free parameters. However, all of their analyses were based on data arithmetically averaged over subjects. R. B. Anderson and Tweney (1997) argue that the power law of forgetting may be an artifact of arithmetically averaging individual subject forgetting functions that are truly exponential in form and that geometric averaging would avoid this potential problem. We agree that researchers should always be cognizant of the possibility of averaging artifacts, but we also show that our conclusions about the form of forgetting remain unchanged (and goodness-of-fit statistics are scarcely affected by) whether arithmetic or geometric averaging is used. In addition, an analysis of individual subject forgetting functions shows that they, too, are described much better by a power function than by an exponential.

Timing and amplitude of saccades during predictive saccadic tracking in schizophrenia.

Schizophrenia patients have ocular motor abnormalities. It has been hypothesized that these abnormalities are associated with frontal eye field pathology. If so, schizophrenia patients should have difficulties decreasing saccadic reaction times in response to predictably moving targets. To evaluate the frontal eye field hypothesis, 25 schizophrenic and 26 nonpsychiatric subjects completed predictive saccadic tracking tasks. The groups demonstrated equivalent decreases in saccadic reaction times over consecutive trials. Schizophrenia patients, however, had faster reaction times and shorter amplitude saccades than nonpsychiatric subjects. The shorter amplitude saccades were made regardless of reaction time, perhaps an antipsychotic medication effect. The reaction time results are unlikely to be an effect of treatment with antipsychotic medication and are inconsistent with the hypothesis that schizophrenia patients have frontal eye field pathology.

Detecting a nonevent: Delayed presence-versus-absence discrimination in pigeons.

Eight pigeons were trained on a delayed presence-versus-absence discrimination paradigm in which a sample stimulus was presented on some trials but not on others. If a sample was presented, then a response to one choice key produced food. If no sample was presented, a response to the other choice key produced food. The basic finding was that performance remained constant and well above 50% correct on no-sample trials as the retention interval increased, whereas performance dropped precipitously (to below 50% correct) on sample trials. In the second phase of the experiment, all of the trials were no-sample trials, and reinforcers were delivered probabilistically for one group of pigeons and according to time-based schedules for the other group. The exact reinforcement probabilities used in Phase 2 were those calculated to be in effect on no-sample trials in Phase 1 (according to a discrete-state model of performance). Subjects did not show exclusive preference for the richer alternative on no-sample trials in the first phase, but those in the probabilistic group developed near-exclusive preference for the richer alternative during the second phase. These data are inconsistent with the predictions of the discrete-state model, but are easily accommodated by an account based on signal detection theory, which also can be applied effectively to discrimination of event duration and the "subjective shortening" effect.

Retrieval from semantic memory and its implications for Alzheimer's disease.

In 3 experiments, participants generated category exemplars (e.g., kinds of fruits) while a voice key and computer recorded each response latency relative to the onset of responding. In Experiment 1, mean response latency was faster when participants generated exemplars from smaller categories, suggesting that smaller mental search sets result in faster mean latencies. In Experiment 2, a concurrent secondary task increased mean response latency, suggesting that slowed mental processing results in slower mean latencies. In Experiment 3, the mean response latency of Alzheimer's participants was faster than that of elderly controls, which is consistent with the idea that the semantic memory impairments of Alzheimer's disease patients stem primarily from a reduction in available items (as in Experiment 1) rather than retrieval slowing (as in Experiment 2).

An analysis of latency and interresponse time in free recall.

In four experiments, subjects freely recalled previously studied items while a voice key and computer recorded each item's recall latency relative to the onset of the recall period. The measures of recall probability and mean recall latency were shown to be empirically independent, demonstrating that there exists no a priori relationship between the two. In all four experiments, latency distributions were fit well by the ex-Gaussian, suggesting that retrieval includes a brief normally distributed initiation stage followed by a longer exponentially distributed search stage. Further, the variation in mean latency stemmed from the variation in the duration of the search stage, not the initiation stage. Interresponse times (IRTs), the time elapsed between two successive item recalls, were analyzed as well. The growth of mean IRTs, plotted as a function of output position, was shown to be a simple function of the number of items not yet recalled. Finally, the mathematical nature of both free recall latency and IRT growth are shown to be consistent with a simple theoretical account of retrieval that depicts mean recall latency as a measure of the breadth of search.

Shortcomings of the behavioral competition theory of contrast: Reanalysis of McLean (1992).

McLean (1992) presented significant data showing that the occurrence of behavioral contrast in a multiple schedule was correlated with shifts in the frequency of reinforcers from a second source between components of the schedule, and interpreted his results as showing that contrast was due to changes in the degree of response competition within the constant component of the multiple schedule. Reanalysis of his data shows that there was an effect of reinforcement in the alternative component of the schedule independent of the shifts in reinforcers between components. Thus, the effect of relative rate of reinforcement cannot be ascribed, at least entirely, to the mechanisms proposed by the behavioral competition theory of contrast.

Analyzing the dynamics of free recall: An integrative review of the empirical literature.

Relatively few experiments have measured the time course of free recall from episodic or semantic memory. Of those that have, most report that cumulative recall is a negatively accelerated exponential (or hyperbolic) function that is characterized by two properties: asymptotic recall and rate of approach to asymptote. The most common measure of free recall performance (viz., the number of items recalled) provides a reasonably good estimate of asymptotic recall if a relatively long recall period is used (which is rare), but the effect of experimental manipulations on the rate of approach to asymptote cannot be determined without timing when recall responses occur. The research reviewed herein suggests that the rate of approach to asymptote may offer an estimate of the breadth of search through long-term memory. The search in question, unlike most of those investigated in the memory literature, is unique in that it requires minutes rather than milliseconds to complete.