Post-recurrence survival in patients with cervical cancer.

BACKGROUND: Up to 26% of patients with early-stage cervical cancer experience relapse after primary surgery. However, little is known about which factors influence prognosis following disease recurrence. Therefore, our aims were to determine post-recurrence disease-specific survival (PR-DSS) and to identify respective prognostic factors for PR-DSS. METHODS: Data from 528 patients with early-stage cervical cancer who relapsed after primary surgery performed between 2007 and 2016 were obtained from the SCANN study (Surveillance in Cervical CANcer). Factors related to the primary disease and recurrence were combined in a multivariable Cox proportional hazards model to predict PR-DSS. RESULTS: The 5-year PR-DSS was 39.1% (95% confidence interval [CI] 22.7%-44.5%), median disease-free interval between primary surgery and recurrence (DFI1) was 1.5 years, and median survival after recurrence was 2.5 years. Six significant variables were identified in the multivariable analysis and were used to construct the prognostic model. Two were related to primary treatment (largest tumour size and lymphovascular space invasion) and four to recurrence (DFI1, age at recurrence, presence of symptoms, and recurrence type). The C-statistic after 10-fold cross-validation of prognostic model reached 0.701 (95% CI 0.675-0.727). Three risk-groups with significantly differing prognoses were identified, with 5-year PR-DSS rates of 81.8%, 44.6%, and 12.7%. CONCLUSIONS: We developed the robust model of PR-DSS to stratify patients with relapsed cervical cancer according to risk profiles using six routinely recorded prognostic markers. The model can be utilised in clinical practice to aid decision-making on the strategy of recurrence management, and to better inform the patients.

Coarse Graining, Nonmaximal Entropy, and Power Laws.

We show that coarse graining produces significant and predictable effects on the entropy of states of equilibrium when the scale of coarse graining becomes comparable to that of density fluctuations. We demonstrate that a coarse-grained entropy typically evolves toward a state of effective equilibrium with a lower value than that of the state of maximum entropy theoretically possible. The finer the coarse graining, the greater the drop in effective entropy, and the more relevant the fluctuations around that. Fundamental considerations allow us to derive a remarkable power law that relates coarse graining to the effective entropy gap. Another power law is found that precisely relates the noise range of effective entropy fluctuations to coarse graining. We test both power laws with numerical simulations based on a well-studied two-dimensional lattice gas model. As expected, the effects of these power laws diminish as our description approaches a macroscopic level, eventually disappearing in the thermodynamic limit, where the maximum entropy principle is reasserted.

Role of environmental enrichment on social interaction, anxiety, locomotion, and memory in Wistar rats under chronic methylphenidate intake.

Introduction: Chronic use of various compounds can have long-lasting effects on animal behavior, and some of these effects can be influenced by the environment. Many environmental enrichment protocols have the potential to induce behavioral changes. Aim: The aim of the present study was to investigate how environmental enrichment can mitigate the effects of chronic methylphenidate consumption on the behavior of Wistar rats. Methods: The animals were housed for 20 days under either an environmental enrichment protocol (which included tubes of different shapes) or standard housing conditions. After seven days, half of the rats received 13 days of oral administration of methylphenidate (2 mg/kg). After seven days, the rats underwent behavioral tests, including the elevated plus maze (anxiety), open field (locomotion), object-in-place recognition test (spatial memory), and a test for social interaction (social behavior). Results: The results showed that the enriched environmental condition reversed the enhanced time in the open arms of the elevated plus maze induced by methylphenidate (F[1,43] = 4.275, p = 0.045). Methylphenidate also enhanced exploratory rearing in the open field (F[1,43] = 4.663, p = 0.036) and the time spent in the open area of the open field (H[3] = 8.786, p = 0.032). The enriched environment mitigated the inhibition of social interaction with peers induced by methylphenidate (H[3] = 16.755, p < 0.001) as well as the preference for single exploratory behavior (H[3] = 9.041, p = 0.029). Discussion: These findings suggest that environmental enrichment can counteract some of the effects of methylphenidate. These results are relevant for the clinical treatment of the long-lasting secondary effects associated with methylphenidate pharmacological treatment.

Providing Environmental Enrichment without Altering Behavior in Male and Female Wistar Rats (Rattus norvegicus).

In research using animal models, subjects are commonly maintained under standard housing conditions, mainly because of the idea that enhancing welfare conditions could alter experimental data. Another common practice in many laboratories relates to the preponderant use of males. Several reasons justifying this practice include the rapid hormonal and endocrine change in females, which may require a higher number of female animals to achieve more homogenous groups, thereby creating a dilemma with the reduction principle in animal research. In past decades, a relationship between enriched environments and enhanced cognitive functions has been reported in rats, but many of those enriched environmental protocols were not systematically or rigorously studied, leading to unexpected effects on behavior. Here we report the effects of 4 types of housing conditions (standard, structural changes, exercise, and foraging) in Wistar rats on anxiety (elevated plus maze), exploratory (open field), and stress vulnerability (forced swim test) responses. Sex was used as a blocking factor. Data show no effect of housing conditions on anxiety and exploratory behaviors, but do show an effect on stress responses. These results suggest the possibility of using a protocol for environmental enrichment without concern about altering experimental data. From this stand, new ways to enhance animal welfare in research laboratories could be designed and implemented.

Contribution of the parafascicular nucleus in the spontaneous object recognition task.

The parafascicular (PF) nucleus, a posterior component of the intralaminar nuclei of the thalamus, is considered to be an essential structure in the feedback systems of basal ganglia-thalamo-cortical circuits critically involved in cognitive processes. The specific role played by multimodal information encoded in PF neurons in learning and memory processes is still unclear. We conducted two experiments to investigate the role of the PF in the spontaneous object recognition (SOR) task. The behavioral effects of pretraining rats with bilateral lesions of PF with N-methyl-D-aspartate (NMDA) were compared to vehicle controls. In the first experiment, rats were tested on their ability to remember the association immediately after training trials and in the second experiment after a 24h delay. Our findings provide evidence that PF lesions critically affect both SOR tests and support its role in that non-spatial form of relational memory.

Cathodal transcranial direct current stimulation on the prefrontal cortex applied after reactivation attenuates fear memories and prevent reinstatement after extinction.

BACKGROUND: In the last decade, pharmacological strategies targeting reconsolidation after memory retrieval have shown promising efforts to attenuate persistent memories and overcome fear recovery. However, most reconsolidation inhibiting agents have not been approved for human testing. While non-invasive neuromodulation can be considered an alternative approach to pharmacological treatments, there is a lack of evidence about the efficacy of these technologies when modifying memory traces via reactivation/reconsolidation mechanism. OBJECTIVE: In this study, we evaluate the effect of cathodal (c-tDCS) and anodal (a-DCS) transcranial direct current stimulation applied after memory reactivation and extinction in rats. METHODS: Male Wistar rats were randomly assigned into three groups: one sham group, one anodal tDCS group, and one cathodal tDCS group (500 µA, 20 min). Reconsolidation and extinction of fear memories were evaluated using a contextual fear conditioning. RESULTS: Our results showed that c-tDCS and a-tDCS after memory reactivation can attenuate mild fear memories. However, only c-tDCS stimulation prevented both fear expression under strong fear learning and fear recovery after a reinstatement protocol without modification of learning rate or extinction retrieval. Nevertheless, the remote memories were resistant to modification through this type of neuromodulation. Our results are discussed considering the interaction between intrinsic excitability promoted by learning and memory retrieval and the electric field applied during tDCS. CONCLUSION: These results point out some of the boundary conditions influencing the efficacy of tDCS in fear attenuation and open new ways for the development of noninvasive interventions aimed to control fear-related disorders via reconsolidation.

Synaptic plasticity in Alzheimer's disease and healthy aging.

The strength and efficiency of synaptic connections are affected by the environment or the experience of the individual. This property, called synaptic plasticity, is directly related to memory and learning processes and has been modeled at the cellular level. These types of cellular memory and learning models include specific stimulation protocols that generate a long-term strengthening of the synapses, called long-term potentiation, or a weakening of the said long-term synapses, called long-term depression. Although, for decades, researchers have believed that the main cause of the cognitive deficit that characterizes Alzheimer's disease (AD) and aging was the loss of neurons, the hypothesis of an imbalance in the cellular and molecular mechanisms of synaptic plasticity underlying this deficit is currently widely accepted. An understanding of the molecular and cellular changes underlying the process of synaptic plasticity during the development of AD and aging will direct future studies to specific targets, resulting in the development of much more efficient and specific therapeutic strategies. In this review, we classify, discuss, and describe the main findings related to changes in the neurophysiological mechanisms of synaptic plasticity in excitatory synapses underlying AD and aging. In addition, we suggest possible mechanisms in which aging can become a high-risk factor for the development of AD and how its development could be prevented or slowed.

Distinct patterns of brain Fos expression in Carioca High- and Low-conditioned Freezing Rats.

BACKGROUND: The bidirectional selection of high and low anxiety-like behavior is a valuable tool for understanding the neurocircuits that are responsible for anxiety disorders. Our group developed two breeding lines of rats, known as Carioca High- and Low-conditioned Freezing (CHF and CLF), based on defensive freezing in the contextual fear conditioning paradigm. A random selected line was employed as a control (CTL) comparison group for both CHF and CLF lines of animals. The present study performed Fos immunochemistry to investigate changes in neural activity in different brain structures among CHF and CLF rats when they were exposed to contextual cues that were previously associated with footshock. RESULTS: The study indicated that CHF rats expressed high Fos expression in the locus coeruleus, periventricular nucleus of the hypothalamus (PVN), and lateral portion of the septal area and low Fos expression in the medial portion of the septal area, dentate gyrus, and prelimbic cortex (PL) compared to CTL animals. CLF rats exhibited a decrease in Fos expression in the PVN, PL, and basolateral nucleus of the amygdala and increase in the cingulate and perirhinal cortices compared to CTL animals. CONCLUSIONS: Both CHF and CLF rats displayed Fos expression changes key regions of the anxiety brain circuitry. The two bidirectional lines exhibit different pattern of neural activation and inhibition with opposing influences on the PVN, the main structure involved in regulating the hypothalamic-pituitary-adrenal neuroendocrine responses observed in anxiety disorders.

Fear Incubation Using an Extended Fear-Conditioning Protocol for Rats.

Emotional memory has been primarily studied with fear-conditioning paradigms. Fear conditioning is a form of learning through which individuals learn the relationships between aversive events and otherwise neutral stimuli. The most-widely utilized procedures for studying emotional memories entail fear conditioning in rats. In these tasks, the unconditioned stimulus (US) is a footshock presented once or several times across single or several sessions, and the conditioned response (CR) is freezing. In a version of these procedures, called cued fear conditioning, a tone (conditioned stimulus, CS) is paired with footshocks (US) during the training phase. During the first test, animals are exposed to the same context in which training took place, and freezing responses are tested in the absence of footshocks and tones (i.e., a context test). During the second test, freezing is measured when the context is changed (e.g., by manipulating the smell and walls of the experimental chamber) and the tone is presented in the absence of footshocks (i.e., a cue test). Most cued fear conditioning procedures entail few tone-shock pairings (e.g., 1-3 trials in a single session). There is a growing interest in less common versions involving an extensive number of pairings (i.e., overtraining) related to the long-lasting effect called fear incubation (i.e., fear responses increase over time without further exposure to aversive events or conditioned stimuli). Extended fear-conditioning tasks have been key to the understanding of fear incubation's behavioral and neurobiological aspects, including its relationship with other psychological phenomena (e.g., post-traumatic stress disorder). Here, we describe an extended fear-conditioning protocol that produces overtraining and fear incubation in rats. This protocol entails a single training session with 25 tone-shock pairings (i.e., overtraining) and a comparison of conditioned freezing responses during context and cue tests 48 h (short-term) and 6 weeks (long-term) after training.

A systematic review of brain functional connectivity patterns involved in episodic and semantic memory.

The study of functional connectivity and declarative memory has lately been focused on finding biomarkers of neuropsychological diseases. However, little is known about its patterns in healthy brains. Thus, in this systematic review we analyze and integrate the findings of 81 publications regarding functional connectivity (measured by fMRI during both task and resting-state) and semantic and episodic memory in healthy adults. Moreover, we discriminate and analyze the main areas and links found in specific memory phases (encoding, storage or retrieval) based on several criteria, such as time length, depth of processing, rewarding value of the information, vividness and amount or kind of details retrieved. There is a certain degree of overlap between the networks of episodic and semantic memory and between the encoding and retrieval stages. Although several differences are pointed out during the article, this calls to attention the need for further empirical studies that actively compare both types of memory, particularly using other baseline conditions apart from the traditional resting state. Indeed, the active involvement of the default mode network in both declarative memory and resting condition suggests the possibility that during rest there is an on-going memory processing. We find support for the 'attention to memory' hypothesis, the memory differentiation model and the appropriate transfer hypothesis, but some evidence is inconsistent with the traditional hub-and-spoke model.

Running wheel training does not change neurogenesis levels or alter working memory tasks in adult rats.

BACKGROUND: Exercise can change cellular structure and connectivity (neurogenesis or synaptogenesis), causing alterations in both behavior and working memory. The aim of this study was to evaluate the effect of exercise on working memory and hippocampal neurogenesis in adult male Wistar rats using a T-maze test. METHODS: An experimental design with two groups was developed: the experimental group (n = 12) was subject to a forced exercise program for five days, whereas the control group (n = 9) stayed in the home cage. Six to eight weeks after training, the rats' working memory was evaluated in a T-maze test and four choice days were analyzed, taking into account alternation as a working memory indicator. Hippocampal neurogenesis was evaluated by means of immunohistochemistry of BrdU positive cells. RESULTS: No differences between groups were found in the behavioral variables (alternation, preference index, time of response, time of trial or feeding), or in the levels of BrdU positive cells. DISCUSSION: Results suggest that although exercise may have effects on brain structure, a construct such as working memory may require more complex changes in networks or connections to demonstrate a change at behavioral level.

Behavioral Effects of Systemic, Infralimbic and Prelimbic Injections of a Serotonin 5-HT2A Antagonist in Carioca High- and Low-Conditioned Freezing Rats.

The role of serotonin (5-hydroxytryptamine [5-HT]) and 5-HT2A receptors in anxiety has been extensively studied, mostly without considering individual differences in trait anxiety. Our laboratory developed two lines of animals that are bred for high and low freezing responses to contextual cues that are previously associated with footshock (Carioca High-conditioned Freezing [CHF] and Carioca Low-conditioned Freezing [CLF]). The present study investigated whether ketanserin, a preferential 5-HT2A receptor blocker, exerts distinct anxiety-like profiles in these two lines of animals. In the first experiment, the animals received a systemic injection of ketanserin and were exposed to the elevated plus maze (EPM). In the second experiment, these two lines of animals received microinjections of ketanserin in the infralimbic (IL) and prelimbic (PL) cortices and were exposed to either the EPM or a contextual fear conditioning paradigm. The two rat lines exhibited bidirectional effects on anxiety-like behavior in the EPM and opposite responses to ketanserin. Both systemic and intra-IL cortex injections of ketanserin exerted anxiolytic-like effects in CHF rats but anxiogenic-like effects in CLF rats. Microinjections of ketanserin in the PL cortex also exerted anxiolytic-like effects in CHF rats but had no effect in CLF rats. These results suggest that the behavioral effects of 5-HT2A receptor antagonism might depend on genetic variability associated with baseline reactions to threatening situations and 5-HT2A receptor expression in the IL and PL cortices. Highlights -CHF and CLF rats are two bidirectional lines that are based on contextual fear conditioning.-CHF rats have a more "anxious" phenotype than CLF rats in the EPM.-The 5-HT2A receptor antagonist ketanserin had opposite behavioral effects in CHF and CLF rats.-Systemic and IL injections either decreased (CHF) or increased (CLF) anxiety-like behavior.-PL injections either decreased (CHF) anxiety-like behavior or had no effect (CLF).

Racial and ethnic differences in unmet need for vision care among children with special health care needs.

OBJECTIVE: To examine racial and ethnic differences in unmet need for vision care among children with special health care needs. METHODS: Cross-sectional data from the National Survey of Children with Special Health Care Needs were analyzed. The analytic sample was 14,070 children with special health care needs who needed eyeglasses or vision care in the previous year. Children who did not receive all the eyeglasses or vision care they needed were considered to have unmet need for vision care. RESULTS: Of the sample, 5.8%, representing approximately 198,600 children with special health care needs in the United States, had unmet need for vision care. Rates of unmet need ranged from 2.5% to 14.3% across the 7 racial and ethnic groups studied. Relative to whites, children of African American, Latino, and multiracial backgrounds had approximately twice the adjusted risk of unmet need, whereas American Indian or Alaskan Native children had a lower adjusted risk. Health care providers, school personnel, insurance coverage, and other factors also contributed to differences in the risk of unmet need, independently of child race/ethnicity. CONCLUSION: Further research is needed to explain and address the causes of racial and ethnic differences in unmet need for vision care among children with special health care needs.

Effect of Overcrowding on Hair Corticosterone Concentrations in Juvenile Male Wistar Rats.

In many species, chronic stress due to overcrowding during the juvenile period triggers several metabolic and behavioral pathologies in adulthood. The aim of this study was to determine whether a chronic stress condition (overcrowding) induces changes in plasma and hair corticosterone concentrations, overall growth, and organ weights in young Wistar rats. The experimental subjects were divided into 2 groups (control and overcrowded); the overcrowded subjects were exposed to overcrowding during days 38 through 65 after birth. Plasma and hair corticosterone concentrations were higher in overcrowded rats compared with control subjects. In addition, overcrowding reduced body and organ weight gains. These results demonstrate that measuring the concentration of corticosterone in hair samples is an effective, noninvasive method for monitoring chronic stress in rats.

Medial orbitofrontal cortex lesion prevents facilitatory effects of d-cycloserine during fear extinction.

Animal models of fear extinction have an important clinical relevance to pharmacological and exposure-based therapies for anxiety disorders. Lesions of prefrontal structures impair fear extinction. On the other hand, d-cycloserine is able to enhance this process. We hypothesize that the integrity of cortical structures involved in inhibitory control of emotional responses is crucial for the facilitatory effects of d-cycloserine. Here, we showed that medial orbitofrontal cortex lesion prevents d-cycloserine enhancement of fear extinction. These preliminary results suggest that effects of pharmacological treatments could be dependent on cortical activity state to promote fear memory reduction.

Effect of different illumination levels on rat behavior in the elevated plus-maze.

The present study addressed the role of environmental light intensity on the exploratory behavior of rats in the elevated plus-maze, with the specific goal of determining the light intensity threshold for triggering the aversion to the open arms. Male Wistar-derived rats were tested in the elevated plus-maze under different illumination levels: 0, 1, 3, 10, 30, 100 and 300 lx. Exploratory behavior occurring in the open arms (e.g., entries and time spent in these arms) was more intense under 0 and 1 lx than under the other illumination levels, which did not differ among themselves; on the other hand, locomotor behavior (as indicated by frequency of entries and distance run in the closed arms) was not altered under all illumination conditions. The data indicated that vision is important in triggering aversion to the open arms of the elevated plus-maze. They also indicated that the threshold of such aversion was found between 1 and 3 lx environmental illumination and that the phenomena is not intensity-dependent but rather of an all-or-none type. It should be emphasized that these conclusions only stand for unfamiliar environments. The role of light in familiar environments is currently under investigation in our laboratory.

The distribution of fos immunoreactivity in rat brain following freezing and escape responses elicited by electrical stimulation of the inferior colliculus.

Several sources of evidence indicate that the inferior colliculus also integrates acoustic information of an aversive nature besides its well-known role as a relay station for auditory pathways. Gradual increases of the electrical stimulation of this structure cause in a hierarchical manner alertness, freezing and escape behaviors. Independent groups of animals implanted with bipolar electrodes into the inferior colliculus received electrical stimulation at one of these aversive thresholds. Control animals were submitted to the same procedure but no current was applied. Next, analysis of Fos protein expression was used to map brain areas activated by the inferior colliculus stimulation at each aversive threshold and in the controls. Whereas alertness elicited by stimulation of the inferior colliculus did not cause any significant labeling in any structure studied in relation to the respective control, electrical stimulation applied at the freezing threshold increased Fos-like immunoreactivity in the central amygdaloid nucleus and entorhinal cortex. In contrast, escape response enhanced Fos-like immunoreactivity in the nucleus cuneiform and the dorsal periaqueductal gray matter of the mesencephalon. This evidence supports the notion that freezing and escape behaviors induced by electrical stimulation of the inferior colliculus activate different neural circuitries in the brain. Both defensive behaviors caused significant expression of c-fos in the frontal cortex, hippocampus and basolateral amygdaloid nucleus. This indistinct pattern of c-fos distribution may indicate a more general role for these structures in the modulation of fear-related behaviors. Therefore, the present data bring support to the notion that amygdala, dorsal hippocampus, entorhinal cortex, frontal cortex, dorsal periaqueductal gray matter and cuneiform nucleus altogether play a role in the integration of aversive states generated at the level of the inferior colliculus.

The role of vision and proprioception in the aversion of rats to the open arms of an elevated plus-maze.

The elevated plus-maze test is usually run with a short edge surrounding the open arms in order to prevent the rats from falling. The present experiment investigated the role of transparent edges differing in heights: 1 (used as control), 5, 10, 20 and 40 cm, the latter the same height as the closed arm walls. Additionally, this 40-cm high transparent edge was also studied covered by white translucent or black opaque paper. The data show that the time spent in the open arms was significantly greater when the edge height was 5, 10 or 40 cm covered by the white or black paper. However, there were no differences from the 1-cm control edge when the height was 40 cm transparent. A similar effect was observed when entries in the open arms and total entries were analyzed. The facts that there were no differences when the open arms were surrounded by 1- or 40-cm transparent edges (which allow thigmotaxis) and that the same 40-cm edge caused increases in exploratory behavior when covered by papers indicate that vision triggers aversion to open spaces.