Reconfiguration of Behavioral Signals in the Anterior Cingulate Cortex Based on Emotional State.

Behaviors and their execution depend on the context and emotional state in which they are performed. The contextual modulation of behavior likely relies on regions such as the anterior cingulate cortex (ACC) that multiplex information about emotional/autonomic states and behaviors. The objective of the present study was to understand how the representations of behaviors by ACC neurons become modified when performed in different emotional states. A pipeline of machine learning techniques was developed to categorize and classify complex, spontaneous behaviors in male rats from the video. This pipeline, termed Hierarchical Unsupervised Behavioural Discovery Tool (HUB-DT), discovered a range of statistically separable behaviors during a task in which motivationally significant outcomes were delivered in blocks of trials that created three unique "emotional contexts." HUB-DT was capable of detecting behaviors specific to each emotional context and was able to identify and segregate the portions of a neural signal related to a behavior and to emotional context. Overall, ∼10× as many neurons responded to behaviors in a contextually dependent versus a fixed manner, highlighting the extreme impact of emotional state on representations of behaviors that were precisely defined based on detailed analyses of limb kinematics. This type of modulation may be a key mechanism that allows the ACC to modify the behavioral output based on emotional states and contextual demands.

Persistent Valence Representations by Ensembles of Anterior Cingulate Cortex Neurons.

The anterior cingulate cortex (ACC) responds to outcomes of a positive or negative valence, but past studies typically focus on one valence or the other, making it difficult to know how opposing valences are disambiguated. We recorded from ACC neurons as rats received tones followed by aversive, appetitive or null outcomes. The responses to the different tones/outcomes were highly inter-mixed at the single neuron level but combined to produce robust valence-specific representations at the ensemble level. The valence-specific patterns far outlasted the tones and outcomes, persisting throughout the long inter-trial intervals (ITIs) and even throughout trial blocks. When the trials were interleaved, the valence-specific patterns abruptly shifted at the start of each new trial. Overall the aversive trials had the greatest impact on the neurons. Thus within the ACC, valence-specificity is largely an emergent property of ensembles and valence-specific representations can appear quickly and persist long after the initiating event.

How Much Does Movement and Location Encoding Impact Prefrontal Cortex Activity? An Algorithmic Decoding Approach in Freely Moving Rats.

Specialized brain structures encode spatial locations and movements, yet there is growing evidence that this information is also represented in the rodent medial prefrontal cortex (mPFC). Disambiguating such information from the encoding of other types of task-relevant information has proven challenging. To determine the extent to which movement and location information is relevant to mPFC neurons, tetrodes were used to record neuronal activity while limb positions, poses (i.e., recurring constellations of limb positions), velocity, and spatial locations were simultaneously recorded with two cameras every 200 ms as rats freely roamed in an experimental enclosure. Regression analyses using generalized linear models revealed that more than half of the individual mPFC neurons were significantly responsive to at least one of the factors, and many were responsive to more than one. On the other hand, each factor accounted for only a very small portion of the total spike count variance of any given neuron (<20% and typically <1%). Machine learning methods were used to analyze ensemble activity and revealed that ensembles were usually superior to the sum of the best neurons in encoding movements and spatial locations. Because movement and location encoding by individual neurons was so weak, it may not be such a concern for single-neuron analyses. Yet because these weak signals were so widely distributed across the population, this information was strongly represented at the ensemble level and should be considered in population analyses.

Effect of pulmonary hyperinflation on central blood volume: An MRI study.

Pulmonary hyperinflation attained by glossopharyngeal insufflation (GPI) challenges the circulation by compressing the heart and pulmonary vasculature. Our aim was to determine the amount of blood translocated from the central blood volume during GPI. Cardiac output and cardiac chamber volumes were assessed by magnetic resonance imaging in twelve breath-hold divers at rest and during apnea with GPI. Pulmonary blood volume was determined from pulmonary blood flow and transit times for gadolinium during first-pass perfusion after intravenous injection. During GPI, the lung volume increased by 0.8±0.6L (11±7%) above the total lung capacity. All cardiac chambers decreased in volume and despite a heart rate increase of 24±29 bpm (39±50%), pulmonary blood flow decreased by 2783±1820mL (43±20%). The pulmonary transit time remained unchanged at 7.5±2.2s and pulmonary blood volume decreased by 354±176mL (47±15%). In total, central blood volume decreased by 532±248mL (46±14%). Voluntary pulmonary hyperinflation leads to ∼50% decrease in pulmonary and central blood volume.

Dietary patterns, food groups and telomere length: a systematic review of current studies.

Telomere length (TL) is recognized as a biomarker of aging and shorter telomeres are linked with shorter lifespan. Inter-individual variability in telomere length is highly heritable. However, there has been a resurgence of interest in the controversial relationship between diet and TL. Evaluating the impact of diet at the food group and dietary pattern level will provide greater insight into the effect of diet on TL dynamics, which are of significant importance in health and longevity. This article reports the first systematic review of the relation between food groups, dietary patterns and TL in human populations based on PRISMA guidelines. DESIGN: PubMed, Science Direct, The Cochrane Library and Google Scholar databases were electronically searched for all relevant studies, up to November 2015. Among the 17 included studies, 3 and 10 of them were regarding the effect of dietary patterns and various food groups on TL, respectively. Also, in 4 studies, both dietary patterns and different food groups were assessed in relation to TL. Mediterranean dietary pattern was related to longer TL in 3 studies. Five studies indicated beneficial effect of fruits or vegetables on TL. In 7 studies, a reverse association between TL and intake of cereals, processed meat, and fats and oils was reported. Our systematic review supports the health benefits of adherence to Mediterranean diet on TL. Except for the fruits and vegetables, which showed positive association with TL, results were inconsistent for other dietary factors. Also, certain food categories including processed meat, cereals and sugar-sweetened beverages may be associated with shorter TLs. However, additional epidemiological evidence and clinical trials should be considered in future research in order to develop firm conclusions in this regard.

Fish consumption is inversely associated with the metabolic syndrome.

BACKGROUND/OBJECTIVES: Although fish consumption has inversely been associated with several metabolic abnormalities, limited and inconsistent data have reported the relationship between fish consumption and metabolic syndrome. The aim of this study was to identify the association between fish consumption and metabolic syndrome and its components. SUBJECTS/METHODS: In a cross-sectional study conducted on 420 Iranian female adults, usual fish consumption was assessed using a dish-based semiquantitative food frequency questionnaire (FFQ). Fasting blood samples were taken for biochemical assessment. Anthropometric and blood pressure measurements were carried out according to standard protocols. Metabolic syndrome was defined based on the National Cholesterol Education Program Adult Treatment Panel III guidelines. Multivariate logistic regression adjusted for lifestyle and dietary variables was applied to assess fish-metabolic syndrome association. RESULTS: The prevalence of metabolic syndrome was 8.2%. Mean daily intake of fish was 14.4 g per day. Individuals in the highest tertile of fish intake were 65% less likely to have the metabolic syndrome than those in the lowest tertile (odds ratio: 0.35; 95% confidence interval (CI): 0.14-0.88). Controlling for potential confounders and dietary variables strengthened this association (odds ratio: 0.05; 95% CI: 0.004-0.64). After adjustment for potential cofounders, high fish intake was inversely associated with hypertriglyceridemia (odds ratio: 0.11; 95% CI: 0.01-0.85), low high-density lipoprotein cholesterol (odds ratio: 0.57; 95% CI: 0.19-0.89) and elevated blood pressure (odds ratio: 0.23; 95% CI: 0.14-0.89). CONCLUSIONS: We found that increased fish intake was independently related to the lower odds of metabolic syndrome and its features. Further prospective investigations are warranted to confirm this association.

Abrupt changes in the patterns and complexity of anterior cingulate cortex activity when food is introduced into an environment.

Foraging typically involves two distinct phases, an exploration phase where an organism explores its local environment in search of needed resources and an exploitation phase where a discovered resource is consumed. The behavior and cognitive requirements of exploration and exploitation are quite different and yet organisms can quickly and efficiently switch between them many times during a foraging bout. The present study investigated neural activity state dynamics in the anterior cingulate sub-region of the rat medial prefrontal cortex (mPFC) when a reliable food source was introduced into an environment. Distinct and largely independent states were detected using a Hidden Markov Model (HMM) when food was present or absent in the environment. Measures of neural entropy or complexity decreased when rats went from exploring the environment to exploiting a reliable food source. Exploration in the absence of food was associated with many weak activity states, while bouts of food consumption were characterized by fewer stronger states. Widespread activity state changes in the mPFC may help to inform foraging decisions and focus behavior on what is currently most prominent or valuable in the environment.

Size of metastatic lymph nodes.

We present a case and review of the literature of well-differentiated sigmoid adenocarcinoma with numerous metastases into pericolic lymph nodes. All positive lymph nodes were small. The authors concluded that there is no clear correlation between nodal size and the likelihood of metastasis in the lymph node, and the status of small lymph nodes must receive special attention by clinicians and pathologists.

Temporal pattern of recurrence of stage I endometrial cancer in relation to histological risk factors.

OBJECTIVE: To study the temporal pattern of endometrial cancer recurrence in relation to histological risk factors in a large multicenter setting. METHODS: 843 patients with apparent stage I endometrial cancer were followed for a median time of 38 months, documenting all recurrences. Patients were stratified as high risk based on the presence of at least one of the established histological risk factors: high tumor grade, penetration to the outer half of the myometrium, lymphvascular space involvement, lower uterine segment involvement and non endometroid histology. Survival analysis, including Kaplan-Meier curves, log-rank tests and multi-variate Cox proportional hazard regression were used to evaluate the equality of recurrence-free distributions for different levels of risk. RESULTS: Recurrence was documented in 66 cases. The presence of one or more of the histological risk factors was associated with significantly shorter recurrence free survival, not attenuating over time (p < 0.001). Age-adjusted Cox regression model demonstrated a significantly decreased recurrence-free survival (HR = 2.8 95% CI 1.5, 5.1) in the presence of risk factors. CONCLUSIONS: In patients with stage I endometrial cancer, the presence of histological risk factors is associated with a significantly higher recurrence rate, which does not attenuate over follow up time. This may allow for a selective approach in the follow- up of endometrial cancer patients.

The reproducibility of histological parameters employed in the novel binary grading systems of endometrial cancer.

OBJECTIVE: To compare the interobserver reproducibility and prognostic value of the FIGO grading system with the histological parameters employed in the various recently proposed binary grading systems of endometrial cancer. METHODS: Seventy two consecutive stage I endometrioid endometrial carcinomas from hysterectomy specimens were independently graded by two pathologists. Clinical data and outcome were obtained from the patients' records. The following histological parameters were evaluated: FIGO grade (dichotomized to grades 1 and 2 vs. grade 3), nuclear atypia, presence of more than 50% solid growth, diffusely infiltrative rather than expansive growth pattern, presence of tumor cell necrosis, and mitotic count. Interobserver agreement was measured by the kappa (k) statistics. Kaplan-Meier survival analysis, log-rank tests and Cox proportional hazard regression were used to evaluate the equality of survival distributions and to model the overall effects of the various predictor variables on survival. RESULTS: The interobserver reproducibility was as follows: FIGO grade, k=0.65; nuclear atypia, k=0.63; solid growth, k=0.51; infiltrative growth pattern, k=0.38; tumor necrosis, k=0.52; and mitotic index, k=0.44. In the comparison of the Kaplan-Meier curves, the following parameters were associated with a significantly poorer survival: FIGO grade 3, p=0.02; presence of more than 50% solid growth, p=0.01; and a high mitotic index, p=0.01. The other binary histological parameters were not significantly predictive of survival. CONCLUSIONS: The proposed novel binary grading parameters are not advantageous in terms of interobserver reproducibility and prognostic significance over dichotomization to FIGO grades 1 and 2 vs. grade 3. A simple binary grade based solely on presence of more than 50% solid growth has a comparable reproducibility and prognostic value.

Lower uterine segment involvement is associated with adverse outcome in patients with stage I endometroid endometrial cancer: results of a multicenter study.

OBJECTIVE: To quantify the relative risk associated with lower uterine segment involvement (LUSI) on outcome measures in patients with apparent stage I endometroid endometrial cancer. METHODS: A cohort of 769 consecutive patients with endometroid endometrial carcinoma apparent stage I, who underwent surgery in five gynecological oncology centers in Israel; 138 patients with and 631 without LUSI were followed for a median time of 51 months. Local recurrence, recurrence-free and overall survival were compared between the two groups. RESULTS: LUSI was associated with grade 3 tumor (p=0.002), deep myometrial invasion (p<0.001), and the presence of lymphvascular space involvement (p=0.01). There were 22 cases of local recurrences, 40 cases of distal recurrences and 80 patients died. Univariate survival analysis showed that patients with LUSI had trend toward lower regional recurrence-free survival (p=0.09), and significant lower distant recurrence-free survival (p=0.04) and lower overall survival (p=0.002). The Cox proportional hazards model demonstrated a significantly decreased overall survival (HR=2.3; 95% CI 1.3, 3.9; p=0.003) in cases with LUSI. CONCLUSIONS: In patients with apparent stage I endometroid endometrial cancer, the presence of LUSI is a poor prognostic factor, associated with a significantly higher risk of distal recurrence and death. The presence of LUSI warrants consideration when deciding upon surgical staging or postoperative management.

The outcome of patients with stage I endometrial cancer involving the lower uterine segment.

The objective of this study was to evaluate whether lower uterine segment involvement (LUSI) correlates with recurrence and survival in women with stage I endometrial adenocarcinoma and whether it is associated with poor prognostic histopathologic features. Three hundred seventy-five consecutive patients with endometrial carcinoma stage I compromised the study population. The patients were divided into two groups according to the presence of LUSI with endometrial carcinoma. The two groups were compared with regard to prognostic factors and outcome measures by using the Pearson chi(2) test, log-rank test, and Cox proportional hazards model. LUSI was present in 89 (24%) patients with stage I endometrial carcinoma. LUSI was significantly associated with grade 3 tumor (P = 0.022), deep myometrial invasion (P < 0.0001), and the presence of capillary space-like involvement (CSLI) (P = 0.003). Kaplan-Meier survival curves demonstrated that patients with LUSI had a lower recurrence-free survival (log-rank test; P = 0.009) and a worse overall survival (log-rank test; P = 0.0008). In the Cox proportional hazards model, only a trend toward higher recurrence rate (HR = 2.4, 95% CI 0.7, 8.2; P = 0.16) and a trend toward poorer overall survival (HR = 1.54, 95% CI 0.82, 2.91; P = 0.18) were noted when LUSI was present. In patients with stage I endometrial cancer, the presence of LUSI is associated with grade 3 tumor, deep myometrial invasion, and the presence of CSLI. A larger group of patients is necessary to conclude whether higher recurrence rate and poorer overall survival are associated with the presence of LUSI.

Lymphvascular space involvement compromises the survival of patients with stage I endometrial cancer: results of a multicenter study.

AIMS: To quantify the relative risk associated with lymphvascular space involvement (LVSI) on outcome measures in patients with apparent stage I endometrial cancer. METHODS: Six hundred and ninety nine consecutive patients with endometrial carcinoma apparent stage I, who underwent surgery in one of four gynecological oncology centers in Israel, comprised the study population. Forty cases with and 659 without LVSI were followed for a median time of 39 months. Recurrence free, disease specific and overall survival was compared between the two groups. The effect of LVSI, adjusted for other clinical and histo-pathological prognostic factors, was assessed by multivariate analysis. RESULTS: The univariate Kaplan-Meier procedure for survival analysis showed that patients with LVSI had lower recurrence free survival (p=0.0003), worse disease specific (p=0.0007) and overall survival (p<0.0001). Cox proportional hazards model demonstrated a trend toward shorter recurrence free survival (HR=2.0, 95% CI 0.9, 4.5; p=0.08), a worse disease specific survival (HR=2.8, 95% CI 1.1, 7.4; p=0.04) and decreased overall survival (HR=2.0, 95% CI 1.1, 3.8; p=0.03) in cases with LVSI. CONCLUSIONS: In patients with apparent stage I endometrial cancer the presence of LVSI, an independent poor prognostic factor, is associated with a two fold increased risk of death. The presence of LVSI warrants consideration when deciding upon post operative management.

The significance of the degree of myometrial invasion in patients with stage IB endometrial cancer.

OBJECTIVE: To study the validity of the FIGO staging classification of endometrial cancer Stage IB by correlating degree of myometrial invasion depth with outcome measures. STUDY DESIGN: Fifty patients with endometrial adenocarcinoma FIGO Stage IB who underwent hysterectomy between 1989 and 2001 were divided into two groups according to depth of myometrial invasion. The first group comprised of 31 patients with myometrial invasion of less than or equal to one-third. The second group included 19 patients with invasion greater than one-third but less than one-half. The two groups were compared with regard to prognostic factors and outcome measures. RESULTS: The overall 5-year recurrence-free survival, disease specific survival and overall survival rates were 87%, 94% and 77%, respectively. These outcome measures did not vary significantly between the two groups. There were no statistically significant differences between the two groups with regard to the following parameters: duration of follow-up, age, proportion of patients who underwent complete surgical staging and postoperative adjuvant radiotherapy. Histologic parameters of the two groups, such as histological type, grade and proportion of patients with capillary space-like involvement and lower uterine segment involvement were not significantly different. CONCLUSIONS: In patients with Stage IB endometrial cancer the amount of myometrial invasion defined as less than one third compared with invasion greater than one third does not appear to correlate with their outcome, thus validating the FIGO staging system.

The founder mutations in the BRCA1, BRCA2, and ATM genes in Moroccan Jewish women with breast cancer.

To gain insight into the molecular mechanisms underlying the inherited predisposition to breast cancer in non-Ashkenazi Jews, we genotyped 54 Jewish Moroccan women with breast cancer, unselected for family history of cancer, for the predominant Jewish mutations in BRCA1, BRCA2, and ATM. One patient (2%) was found to have the 185de1AG BRCA1 mutation, none was a carrier of the 6174delT BRCA2 mutation, and 2/54 (4%) were heterozygous for the ATM mutation. These rates were not significantly different from the rates in the general non-Ashkenazi population. These preliminary data may indicate that the predominant Jewish mutations in BRCA1, BRCA2, and ATM genes contribute little, if any, to breast cancer predisposition and risk among Moroccan Jews.

Long-term follow-up of patients with superficial transitional cell carcinoma of the urinary bladder treated by intravesical mitomycin C.

Prophylactic intravesical chemotherapy (IVC) reduces recurrence rates of superficial transitional cell carcinoma (TCC) of the urinary bladder. The patient cohort existed of 86 individuals (stage TaN0M0 or T1N0M0) superficial carcinoma of various grades of malignancy. Following initial transuretheral resection or diagnostic cystoscopy, mitomycin C (MMC), 20 mg dissolved in 50 ml saline, was instilled intravesically by catheter over 1 hr at 2-week intervals, initially and then four more times followed by diagnostic cystoscopy (one course = 12 weeks). Two similar courses were administered thereafter for a total period of 36 weeks. For patients in remission, installations continued in monthly fractionations for 9 more months (cystoscopy every 3 months) and then at 2-month intervals for 12 more months (cystoscopy every 6 months). When cystoscopy revealed recurrence, IVC was repeated from the beginning. No symptoms of MMC-related toxicity were observed. Cystoscopic follow-up evaluations showed a complete response rate of 84% at 3 years and 81% at 5 years after initial therapy. Twenty-seven patients who had not responded to previous treatment with other drugs responded to MMC.

Randomized study comparing chemotherapy with and without estrogen priming in advanced breast-cancer.

A randomized trial was performed to determine if combination chemotherapy (CT) with estrogen (E) priming (E+ study arm) was superior to CT alone (E- study arm) in patients with advanced breast cancer. CT for both arms included adriamycin + vincristine (AV) starting on day 7 alternating with cytoxan + methotrexate + fluorouracil (CMF) starting on day 28, the entire cycle repeated every 6 weeks. Estrogen priming consisting of 2 mg estradiol + 1 mg estriol (E+ arm) was given orally twice daily beginning on day 1 and continuously through CT until disease progression or unacceptable toxicity. Performance status (KPS) for all patients (n=19, E+ arm; n=22, E- arm) ranged between 70-100%. Mean age (53 y, E+ arm; 56 y, E- arm), menopausal and estrogen receptor status and treatment duration (approximately 38 weeks) were similar for both groups. Estrogen priming did not alter or enhance CT toxicity. Objective responses (CR,PR) were noted in 79% on the E+ arm (CR=11%, PR=68%) and in 73% on the E- arm (CR=9%, PR=64%). Thus, estrogen priming in this cohort of patients with advanced breast cancer did not appear to add to the toxicity or palliative benefit of CT.

Efficacy of intravesical mitomycin C in the treatment of superficial transitional cell carcinoma of the urinary bladder.

We treated 47 patients with recurrent transitional cell carcinoma of the bladder with intravesical chemotherapy. Twenty milligrams of mitomycin C per treatment was introduced 7 days after transurethral resection (TUR) or diagnostic cystoscopy, and was repeated at 2-week intervals for five times followed again by cystoscopy. Two more similar courses were administered for a total of 36 weeks. Clinical data revealed no toxicity-related symptoms. Cystoscopic follow-up showed a gradual decline in the presence of tumor to a complete response rate of 87.1% at 36 weeks. Thirteen patients who were previously treatment failures with other drugs responded to mitomycin C.

Nutritional monitoring and counselling for cancer patients during chemotherapy.

The objective of the study was to try to monitor the nutritional status of cancer patients during chemotherapeutic treatment. Concomitantly with chemotherapeutic treatment administered to patients with cancer of the gastrointestinal tract and metastatic carcinoma of unknown origin, levels of carotene, retinol, thiamine, riboflavin, pyridoxine, iron, total protein and hemoglobin were measured in the blood periodically. In addition, anthropometric studies were performed and the nutritional status was established. A total of 19 patients were subject for final evaluation. These patients formed 3 groups according to their nutritional status (good, medium, poor). The effect of chemotherapy was correlated to the nutritional status at 3 different periods of chemotherapy. Most patients with good clinical status maintained the initial nutritional status. Half of the patients with medium nutritional status improved clinically during therapy, and patients initially with poor nutritional status further deteriorated. The levels of most vitamins decreased to a certain degree during therapy and returned to initial values thereafter. Our impression is that cancer patients might benefit from intensive ongoing personal nutritional monitoring and counselling. The results presented have a preliminary meaning because of the small number of patients included in this study.