High discordance between punch biopsy and excision in establishing basal cell carcinoma subtype: analysis of 500 cases.

BACKGROUND: Basal cell carcinoma (BCC) is the most frequently occurring cancer in humans. Worldwide incidences rise about 10% each year, increasing the burden on dermatologists, general practitioners and pathologists as well as increasing costs for the health care system. Increasingly non-surgical treatment options are used in the treatment of BCC, without histological confirmation of BCC subtype, potentially resulting in under-treatment. OBJECTIVE: We evaluated the diagnostic accuracy of a punch biopsy for the BCC histological subytpe in a primary BCC and the prevalence of biopsy-based under-diagnosis of aggressive subtypes. Accuracy of a punch biopsy was defined as concordance of the diagnosis of subtype of BCC at punch biopsy and excision. METHODS: A retrospective chart-review was performed of primary BCC, which were proven by punch biopsy and subsequently treated by excision. The first 100 consecutive BCCs per year during the years 2004-2009 were included, yielding a total of 500 evaluated BCCs. RESULTS: The overall accuracy of punch biopsy for BCC subtype at excision was 69%, in single-type BCC 83% (n = 343) and in mixed-type BCC 37% (n = 157). Accuracy varied substantially according to BCC subtype, being highest in the superficial subtype (84%) and subsequently in infiltrative (69%), nodular (63%) and micronodular subtype (38%). In 11% of all cases, an unsuspected more aggressive subtype was present. CONCLUSION: Punch biopsy has a high accuracy in single-type BCCs and a considerably lower accuracy in mixed-type BCCs for establishing BCC subtype compared to excision. The presence of an unsuspected aggressive subtype could explain therapy failure of non-surgical treatments like imiquimod or photodynamic therapy.

Development of an in vitro model for bovine placentation: a comparison of the in vivo and in vitro expression of integrins and components of extracellular matrix in bovine placental cells.

BACKGROUND/AIMS: Interaction of trophoblastic integrins with the extracellular matrix plays a role in embryo implantation and trophoblast invasion. The phenomenon of restricted trophoblast invasion, observed in the bovine epitheliochorial placenta offers intriguing conditions to study invasive processes. The migration of bovine trophoblast giant cells is accompanied by the expression of specific integrins and corresponding extracellular matrix ligands. METHODS: Primary cultures of different cell populations from cow placentomes were established and characterized, and in vitro phenotypes were compared with in vivo conditions by immunofluorescence. RESULTS: Propagated epithelial cells were positive for cytokeratin and vimentin, while fibroblasts contained alpha-smooth muscle actin, desmin and vimentin. Epithelial cells coexpressed integrin subunits alpha(6) and beta(1) with laminin, and fibroblast cells were positive for alpha(v), beta(3), fibronectin and laminin. In contrast to cells in vivo, cultured epithelial cells secreted fibronectin, while collagen IV was not detected. The occurrence of integrin subunits was confirmed at mRNA level by RT-PCR. CONCLUSION: We have established cell cultures isolated from maternal and fetal components of bovine placentomes expressing typical cytoskeletal filaments and integrin receptors also present in their in vivo counterparts. These bovine placentomal cells provide a suitable in vitro model for the study of cell-cell interactions.

BK-virus nephropathy in renal transplants-tubular necrosis, MHC-class II expression and rejection in a puzzling game.

We review BK-virus nephropathy (BKN) as a new complication that increasingly affects renal allografts and causes dysfunction. Since starting in 1996, we have seen 11 cases. Currently, the prevalence of BKN is 3% in our graft biopsies. The diagnosis can only be made histologically. The virus affects tubular epithelial cells that show characteristic intranuclear inclusion bodies. The major reason for impaired graft function and a possible way for viral particles to gain access to the blood via peritubular capillaries is necrosis of infected epithelial cells. BK-virus DNA in the plasma, which can be detected by PCR, is closely associated with nephropathy. BK-virus does not stimulate tubular MHC-class II expression as judged by immunofluorescence double labelling. The inflammatory response is inconsistent and the frequency of rejection episodes is not increased during disease. Clinical manifestation of viral nephropathy evolves in several stages. (i) Initial, asymptomatic and reversible activation of the virus, judged by the presence of inclusion bearing cells in the urine. (ii) High dose immunosuppressive drug regimens, often including tacrolimus. (iii) Tubular injury and viraemia as additional promoting conditions. BKN nephropathy was associated with graft loss in 45% of our patients. The remaining patients with persistent viral nephropathy showed renal dysfunction (serum creatinine levels on average 150% above baseline readings). Currently, no established antiviral therapy is available. We discuss attempts to lower immunosuppression as a means to control viral replication. We propose a diagnostic algorithm for screening and monitoring the disease.

On sundials, springs, and atoms.

The orderly behavior that occurs when animals are required to deal with time requirements suggests the possibility that they have an internal clock that provides information about the duration of events. After discussing questions inherent in the concept of an internal clock and suggesting criteria that such a device should meet if it exists, data are reviewed involving several different types of experimental procedures. Every procedure produced different conclusions about the nature of timing. Such results, together with observations of behavior outside of the laboratory, suggest that an internal clock has not evolved and, furthermore, is not even necessary for animals to display temporal regularities in their behavior or to respond to temporal demands.

ET-1 excretion is urine flow-dependent in kidney donors and transplant recipients.

Urinary endothelin-1 excretion (uET-1/min) has been reported to be elevated under cyclosporin A (CsA) therapy in kidney transplant recipients (KR). The possible flow-dependence of uET-1/min was not considered. Therefore, we studied the effect of water diuresis on uET-1/min in KR 1 year after transplantation and used kidney donors (KD) as controls. Urinary ET-1/min and urine flow (uFlow) were measured in 25 KR and in 21 KD before and 27 KD 1 year after surgery (KD-Nx) during water diuresis induced by oral hydration in a 12 h overnight collection. uET-1/min was correlated with uFlow. uET-1/min in 12-h overnight collection was similar in KD, KD-Nx, and KR (127 +/- 55, 110 +/- 42, and 122 +/- 53 pg/min respectively). Urine flow did not differ significantly among the three groups (range 0.6-3.7 ml/min). uET-1/min correlated significantly with urine flow in KD, KD-Nx, and KR (r = 0.59, r = 0.42, and r = 0.53, p < 0.03, respectively). The slope of the three regression lines was not different. There was no correlation of uET-1/min with CsA trough level or dose. uET-1/min is urine flow-dependent during water diuresis. Because NaCl diuresis has been reported to have no influence on uET-1/min, we hypothesize that uET-1/min is linked to the state of diuresis or antidiuresis in the distal nephron. CsA therapy does not influence uET-1/min in a 12-h urine collection.

Plasma creatinine for the evaluation of recovery of glomerular filtration rate after discontinuation of cyclosporine A in bone marrow transplantation: results of a prospective study.

In clinical practice p-creatinine is used to estimate changes of GFR. Generally, it is believed that recovery of p-creatinine within 10% of initial baseline allows exclusion of relevant nephrotoxic changes. We evaluated whether recovery of GFR after discontinuation of CyA therapy can be adequately predicted by measuring p-creatinine alone. Fifty-four allogenic BMT patients were followed up by p-creatinine and classical inulin clearance (GFR) before BMT and 1, 3, 6, 12, 18, 24 months after BMT. A total of 10 patients fulfilled following three criteria: (1) 24 months total follow-up time; (2) at least 12 months follow-up after discontinuation of CyA therapy (3) no trimethoprim or cimetidine comedication at time of clearance measurement. Time after CyA withdrawal varied between 13 and 21 months (mean +/- standard deviation, 17 +/- 2 months); mean duration of CyA therapy was 8 +/- 2 months (minimum: 3 months, maximum: 11 months). After at least 12 months of CyA stop mean p-creatinine returned to baseline values. In contrast, mean GFR remained about 20% below baseline (paired sample Wilcoxon-test P < .02). Neither creatinine excretion nor body weight nor creatinine clearance changed significantly between baseline and 24 months after BMT. Follow-up of p-creatinine after CyA stop can overestimate the recovery of GFR. A 20% loss of GFR may remain unrecognized. We speculate that this phenomenon is due to tubular hypertrophy in the recovery phase.

Temporal control in fixed-interval schedules.

The peak procedure was used to study temporal control in pigeons exposed to seven fixed-interval schedules ranging from 7.5 to 480 s. The focus was on behavior in individual intervals. Quantitative properties of temporal control depended on whether the aspect of behavior considered was initial pause duration, the point of maximum acceleration in responding, the point of maximum deceleration, the point at which responding stopped, or several different statistical derivations of a point of maximum responding. Each aspect produced different conclusions about the nature of temporal control, and none conformed to what was known previously about the way ongoing responding was controlled by time under conditions of differential reinforcement. Existing theory does not explain why Weber's law so rarely fit the results or why each type of behavior seemed unique. These data fit with others suggesting that principles of temporal control may depend on the role played by the particular aspect of behavior in particular situations.

To wait or to respond?

Emitting a certain response and waiting for a specified time without making that response had the same consequence. In Experiment 1, food-deprived pigeons were as likely to wait as to respond only if waiting provided food at a much higher frequency than did pecking. In Experiment 2, the consequence for humans was a brief light flash and tone. People were not biased for responding over waiting. Instead, their choices suggested crude payoff maximization. In Experiment 3, pigeons again obtained food, but they were not food deprived and could eat freely at each opportunity. Their behavior was more like that of the humans of Experiment 2 than that of food-deprived pigeons given small quantities of food at each feeding opportunity. The three experiments together showed that biases for responding over waiting were neither inherent characteristics of species nor inevitable outcomes of particular schedules. Choice between active search and waiting depended on ecological-motivational factors even when species and schedules were held constant.

On immediate function.

Behavior is a property of living organisms, not of inanimate matter. The problems of physical science are to understand how a phenomenon works; biological science adds the questions of what a phenomenon does and how something that does such things came to be. Exclusive dedication to cause-effect explanations ignores how behavior helps creatures cope with their internal and external environments. Laws of causation describe the precursors to behavior; laws of function describe the effects of behavior. The numerous instances of learning reflect the many ways that selective pressure for altering behavior on the basis of experience has been manifested. Little basis exists for assuming that the various forms of learning reflect either common functions or common processes. Instead, it seems that evolutionary processes have resulted in domain-specific learning. The rules of learning must be understood in terms of the function that the particular manifestation of learning serves for the organism. Evolutionary theory provides the framework for understanding function as well as relations between function and causal mechanisms.

Temporal reproduction.

A signal appeared for a certain time period. After the period elapsed, pigeons had to begin and complete a sequence of 15 responses in a time window ranging from the signal duration to 50% longer. Sessions involved as many as 10 different signal durations occurring in a random sequence. The times produced by pigeons often were in the same ranges as those that have been found with adult human subjects. The average times were described equally well as linear or power functions of signal duration. However, instead of the overestimation of durations usually found when animals have timed the duration of antecedent stimuli, the linear functions suggested that the pigeons underestimated the durations of their own behavior. The birds showing the strongest control when the conditions involved eight or 10 different duration requirements revealed the constant coefficients of variation that support Weber's law and scalar timing theory. Scalar timing in temporal differentiation appears to depend on non-ambiguous information about the duration required for reinforcement and on a high degree of sensitivity to the duration requirement.

Optimal temporal differentiation.

In order to illuminate a light signaling a correct response, adult humans had to space their button presses according to a range of time requirements. In some conditions, the spacing needed only to exceed a minimum duration; in others, it had to fall between lower and upper bounds. Mean interresponse times always exceeded the lower limit, and decreased the more stringent were the upper bounds. Variability of interresponse times increased with larger lower bounds, but was unaffected by the size of the upper bound. Feedback about the direction of errors in conditions involving both upper and lower bounds did not affect the means, but it did reduce variability. Predictions were derived from optimality theory, based on the assumption that the critical factor was minimization of the time between correct responses. Without upper bounds, the theory overestimated the mean interresponse times by about 10%; with upper bounds, the theoretical predictions corresponded closely to the actual data. The results did not appear to reflect a scalar timing process. Optimality theory, in contrast to Weber's law, correctly predicted the variety of curves relating sensitivity to duration requirements.

Pure timing in temporal differentiation.

Temporal control appears to depend on whether the critical durations are those of stimuli or those of responses. Stimulus timing (temporal discrimination) supports Weber's law, whereas response timing (temporal differentiation) indicates decreasing relative sensitivity with longer time intervals. The two types of procedure also yield different conclusions in scaling experiments designed to study the functional midpoint of two or more durations (temporal bisection procedures). In addition, the fractional-exponent power relation between emitted and required duration usually found with animals in differentiation experiments conflicts with deductions from formal analyses. The experiment reported here derived from considering differentiation arrangements as schedules of reinforcement. When analyzed from this perspective, the procedures are tandem schedules involving a required pause followed by a response, and it is the pause alone that involves temporal control. A choice procedure separated timing from responding, and enabled observations of pause timing in isolation. Pure temporal control in differentiation consisted of linear overestimation of the standard duration, and Weber's law described sensitivity. These results indicate that the two problems, the fractional-exponent power relations and the apparently different nature of sensitivity in differentiation and discrimination, disappear when temporal control is observed alone in differentiation.

The sleeping giant: Reinforcement schedules.

Schedule research has been the core of operant conditioning, but it is no longer an active area, at least with respect to its traditional focus of describing and explaining moment-to-moment behavior. Yet schedules are central in psychology: Not only do they establish lawful behavior, but they also play a major role in determining the effects of other variables. The reason for the decline appears to be primarily theoretical, in that the work seems not to have led to meaningful integration. The search for controlling variables brought into play by schedule specification has proven unsuccessful, and a catalog of all possible schedule effects is of limited interest. The paper reviews the reasons for the contemporary state of affairs. One prediction about future developments is that instead of revealing component variables and their modes of interaction, schedule effects will be treated as basic empirical laws. Theory will take the form of abstract statements that integrate these separate laws by reference to higher-order principles rather than by reduction to supposedly simpler component variables.

Choice between response units: The rate constancy model.

In a conjoint schedule, reinforcement is available simultaneously on two or more schedules for the same response. The present experiments provided food for key pecking on both a random-interval and a differential-reinforcement-of-low-rate (DRL) schedule. Experiment 1 involved ordinary DRL schedules; Experiment 2 added an external stimulus to indicate when the required interresponse time had elapsed. In both experiments, the potential reinforcer frequency from each component was varied by means of a second-order fixed-ratio schedule, and the DRL time parameter was changed as well. Response rates were described by a model stating that time allocation to each component matches the relative frequency of reinforcement for that component. When spending time in a given component, the subject is assumed to respond at the rate characteristic of baseline performance. This model appeared preferable to the absolute-rate version of the matching law. The model was shown to be applicable to multiple-response concurrent schedules as well as to conjoint schedules, and it described some of the necessary conditions for response matching, undermatching, and bias. In addition, the pigeons did not optimize reinforcer frequency.

Responses and pauses: discrimination and a choice catastrophe.

Pigeons produced a stimulus change either by responding or by not responding for a specified time period (by pausing). They then had to choose between two responses to obtain food. One choice was correct if the first component had been completed by a response; the other was correct if the component had been completed by a pause. The pigeons usually chose correctly, thereby indicating that they used their own prior behavior as a discriminative stimulus. Fixed pause requirements did not produce equal first component completions by a response and by a pause. To obtain equality, the pause requirement was titrated as a function of current performance. Titration resulted in equal completions and also produced accurate discrimination. In addition to showing that pigeons discriminated whether they had responded or paused, the data displayed and discontinuous functions predicted by catastrophe theory. Another procedure used forced choice rather than titration to produce equal completions by pausing and responding and also showed accurate discrimination of behavior.