Changes in behavioural parameters, oxidative stress and neurotrophins in the brain of adult offspring induced to an animal model of schizophrenia: The effects of FA deficient or FA supplemented diet during the neurodevelopmental phase.

A deficiency of maternal folic acid (FA) can compromise the function and development of the brain, and may produce a susceptibility to diseases such as schizophrenia (SZ) in the later life of offspring. The aim of this study was to evaluate the effects of both FA deficient and FA supplemented diets during gestation and lactation on behavioural parameters, the markers of oxidative stress and neurotrophic factors in adult offspring which had been subjected to an animal model of SZ. Female mother rats (Dam's) were separated into experimental maternal groups, which began receiving a special diet (food) consisting of the AIN-93 diet, a control diet, or an FA deficient diet during the periods of pregnancy and lactation. Dam's receiving the control diet were further subdivided into four groups: one group received only control diet, while three groups to receive supplementation with FA at different doses (5, 10 and 50 mg/kg). Adult offspring bred from the Dam's were divided into ten groups for induction of the animal model of SZ through the administration of ketamine (Ket) (25 mg/kg). After the last administration of the drug, the animals were subjected to the behavioural tests and were then euthanized. The frontal cortex (FC) and hippocampus (Hip) were then dissected for later biochemical analysis. Our data demonstrates that Ket induced the model of SZ by altering the behavioural parameters (e.g. hyperlocomotion, social impairment, deficits in the sensory-motor profile and memory damage in the adult animals); and also caused changes in the parameters of oxidative stress (lipid hydroperoxide - LPO; 8-isoprostane - 8-ISO; 4-hydroxynonenal - 4-HNE; protein carbonyl content; superoxide dismutase - SOD and catalase - CAT) as well as in the levels of neurotrophic factors (brain-derived neurotrophic factor - BDNF and nerve growth factor - NGF) particularly within the FC of adult offspring. A deficiency in maternal FA, alone or in combination with ket, was able to induce hyperlocomotion and social impairment in the offspring with increased levels of lipid and protein damage (LPO, 8-ISO, 4-HNE, carbonylation of protein) within the FC, increased activity of antioxidant enzymes (SOD and CAT) in both of the brain structures studied, and also reduced the levels of neurotrophins (BDNF and NGF), particularly within the Hip of the adult offspring. Supplementation of FA (5, 10 and 50 mg/kg) to the Dam's was mostly able to prevent the cognitive damage which was induced by Ket in the adult animals. FA (10 and 50 mg/kg) attenuated the action of Ket in the animals in relation to the biochemical parameters, proving the possible neuroprotective effect of FA in the adulthood of offspring that were subjected to the animal model of SZ. Our study indicates that the intake of maternal FA during pregnancy and lactation plays an important role, particularly in the regulation of markers of oxidative stress and neurotrophins.

The Evaluation of Folic Acid-Deficient or Folic Acid-Supplemented Diet in the Gestational Phase of Female Rats and in Their Adult Offspring Subjected to an Animal Model of Schizophrenia.

Although folic acid (FA) supplementation is known to influence numerous physiological functions, especially during pregnancy, little is known about its direct effects on the mothers' health. However, this vitamin is essential for the health of the mother and for the normal growth and development of the fetus. Thus, the aim of this study was (1) to evaluate the cognitive effects and biochemical markers produced by the AIN-93 diet (control), the AIN-93 diet supplemented with different doses of FA (5, 10, and 50 mg/kg), and a FA-deficient diet during pregnancy and lactation in female mother rats (dams) and (2) to evaluate the effect of maternal diets on inflammatory parameters in the adult offspring which were subjected to an animal model of schizophrenia (SZ) induced by ketamine (Ket). Our study demonstrated through the Y-maze test that rats subjected to the FA-deficient diet showed significant deficits in spatial memory, while animals supplemented with FA (5 and 10 mg/kg) showed no deficit in spatial memory. Our results also suggest that the rats subjected to the FA-deficient diet had increased levels of carbonylated proteins in the frontal cortex and hippocampus and also increased plasma levels of homocysteine (Hcy). Folate was able to prevent cognitive impairments in the rats supplemented with FA (5 and 10 mg/kg), data which may be attributed to the antioxidant effect of the vitamin. Moreover, FA prevented protein damage and elevations in Hcy levels in the rats subjected to different doses of this vitamin (5, 10, and 50 mg/kg). We verified a significant increase of the anti-inflammatory cytokine (interleukin-4 (IL-4)) and a reduction in the plasma levels of proinflammatory cytokines (interleukin-6 (IL-6)) and TNF-α) in the dams that were subjected to the diets supplemented with FA (5, 10, and 50 mg/kg), showing the possible anti-inflammatory effects of FA during pregnancy and lactation. In general, we also found that in the adult offspring that were subjected to an animal model of SZ, FA had a protective effect in relation to the levels of IL-4, IL-6, and TNF-α, which indicates that the action of FA persisted in the adult offspring, since FA showed a lasting effect on the inflammatory response, which was similar in both the dams and their offspring. In conclusion, the importance of supplementation with FA during pregnancy and lactation should be emphasized, not only for the benefit of the offspring but also for the health of the mother. All this is due to the considerable protective effect of this vitamin against oxidative damage, cognitive impairment, hyperhomocysteinemia, immune function, and also its ability in preventing common processes in post-pregnancy stages, as well as in reducing the risks of neurodevelopmental disorders and enhancing fetal immune development.

Predictors of Locoregional Failure and Impact on Overall Survival in Patients With Resected Exocrine Pancreatic Cancer.

PURPOSE: Resection of exocrine pancreatic cancer is necessary for cure, but locoregional and distant relapse is common. We evaluated our institutional experience to better understand risk factors for locoregional failure (LRF) and its impact on overall survival (OS). METHODS AND MATERIALS: We reviewed 1051 consecutive patients with nonmetastatic exocrine pancreatic cancer who underwent resection at our institution between March 1987 and January 2011. Among them, 458 had adequate follow-up and evaluation for study inclusion. All patients received adjuvant chemotherapy (n=80 [17.5%]) or chemoradiation therapy (n=378 [82.5%]). Chemotherapy and chemoradiation therapy most frequently consisted of 6 cycles of gemcitabine and 50.4 Gy in 28 fractions with concurrent 5-fluorouracil, respectively. Locoregional control (LRC) and OS were estimated with the Kaplan-Meier method. Univariate and multivariate analyses were performed with Cox proportional hazards regression models incorporating propensity score. RESULTS: Median patient age was 64.5 years (range: 29-88 years). Median follow-up for living patients was 84 months (range: 6-300 months). Extent of resection was R0 (83.8%) or R1 (16.2%). Overall crude incidence of LRF was 17% (n=79). The 5-year LRC for patients with and without radiation therapy was 80% and 68%, respectively (P=.003; hazard ratio [HR]: 0.45; 95% confidence interval [CI]: 0.28-0.76). Multivariate analysis, incorporating propensity score, indicated radiation therapy (P<.0001; HR: 0.23; 95% CI: 0.12-0.42) and positive lymph node ratio of ≥0.2 (P=.02; HR: 1.78; 95% CI: 1.10-2.9) were associated with LRC. In addition, LRF was associated with worse OS (P<.0001; HR: 5.0; 95% CI: 3.9-6.3). CONCLUSIONS: In our analysis of 458 patients with resected pancreatic cancer, positive lymph node ratio of ≥0.2 and no adjuvant chemoradiation therapy were associated with increased LRF risk. LRF was associated with poor OS. Radiation therapy should be considered as adjuvant locoregional treatment following pancreatic cancer resection.

Long-term Treatment Outcomes for Locally Advanced Esophageal Cancer: A Single-Institution Experience.

OBJECTIVES: To determine long-term outcomes in patients with locally advanced esophageal carcinoma treated with trimodality therapy (chemoradiotherapy [CRT] and surgery, TMT) or definitive CRT. METHODS: We retrospectively identified patients with advanced esophageal carcinoma treated with curative intent at our institution between 1998 and 2004. Identified patients were separated into 3 groups: patients who received TMT, patients who received CRT, and patients who began treatment with trimodality intent but did not undergo surgery (PTMT). Local control, overall survival (OS), and distant metastasis-free survival were compared using Kaplan-Meier statistics. RESULTS: Among the 265 patients included, median follow-up was 6.4 years for surviving patients and 1.7 years for all patients. Type of esophageal cancer was adenocarcinoma in 213 patients (80%) and squamous cell carcinoma in 46 patients (17%). Treatment groups comprised 169 patients (64%) completing TMT, 46 patients medically unable to undergo surgery after neoadjuvant therapy (PTMT), and 50 (19%) who underwent CRT. Median OS was 20.5 months; actuarial 5- and 10-year OS were 27% and 12%, respectively. The TMT group had the highest 5- and 10-year OS (32% and 19%, respectively). Local control rates at 2, 5, and 10 years for all patients were 80%, 70%, and 69%, respectively. By treatment modality, 5-year local control was best (82%) for TMT, compared with 60% for CRT and 40% for PTMT groups (P<0.001). CONCLUSIONS: Patients who completed TMT had the best local control and long-term OS. In the context of TMT, surgery seemed more beneficial in patients with esophageal adenocarcinoma versus squamous cell carcinoma.

Omega-3 prevents behavior response and brain oxidative damage in the ketamine model of schizophrenia.

Supplementation with omega-3 has been identified as an adjunctive alternative for the treatment of psychiatric disorders, in order to minimize symptoms. Considering the lack of understanding concerning the pathophysiology of schizophrenia, the present study hypothesized that omega 3 prevents the onset of symptoms similar to schizophrenia in young Wistar rats submitted to ketamine treatment. Moreover, the role of oxidative stress in this model was assessed. Omega-3 (0.8g/kg) or vehicle was given by orogastric gavage once daily. Both treatments were performed during 21days, starting at the 30th day of life in young rats. After 14days of treatment with omega-3 or vehicle, a concomitant treatment with saline or ketamine (25mg/kg ip daily) was started and maintained until the last day of the experiment. We evaluated the pre-pulse inhibition of the startle reflex, activity of antioxidant systems and damage to proteins and lipids. Our results demonstrate that supplementation of omega-3 prevented: decreased inhibition of startle reflex, damage to lipids in the hippocampus and striatum and damage to proteins in the prefrontal cortex. Furthermore, these changes are associated with decreased GPx in brain tissues evaluated. Together, our results suggest the prophylactic role of omega-3 against the outcome of symptoms associated with schizophrenia.

Intraperitoneal treatment for peritoneal mucinous carcinomatosis of appendiceal origin after operative management: long-term follow-up of the Mayo Clinic experience.

OBJECTIVE: To determine prognostic factors and the impact of intraperitoneal (IP) treatment after surgical resection of peritoneal mucinous carcinomatosis (PMC) of appendiceal origin. SUMMARY OF BACKGROUND DATA: PMC is a rare, malignant, intra-abdominal neoplasm that produces large amounts of mucin. Patients typically present with diffuse peritoneal disease. After surgical treatment, multiple locoregional recurrences are common; recurrences outside the abdomen are infrequent. Treatment regimens include debulking, radiotherapy with IP radioisotopes, and chemotherapies (IP, systemic, or both). Because reported data are variable and heterogeneous, treatment evaluations are challenging. METHODS: We retrospectively reviewed 115 consecutive patients with PMC who underwent maximal surgical resection with or without postoperative therapy between 1985 and 2000 at Mayo Clinic Rochester. After maximal resection, 37 patients received IP 5-fluorouracil, 35 of whom also received IP chromic phosphate P 32. The Kaplan-Meier method was used to estimate overall survival (OS) and disease-free survival. RESULTS: All gross disease was removed in 61% of patients. With a median follow-up of 6.1 years, the median OS was 8.1 years. Median OS for patients receiving versus not receiving IP therapy was 23.5 years versus 7.5 years, respectively. The 5-, 10-, and 15-year OS for those receiving and not receiving IP therapy was 82%, 65%, and 52% versus 60%, 27%, and 15%, respectively. Adverse prognostic factors for OS identified by univariate analysis included partial mucin debulking, adenocarcinoma histology, systemic chemotherapy, diffuse IP disease at presentation, and no IP therapy. On multivariate analysis, diffuse IP disease at presentation and no IP therapy remained significant. A separate analysis was performed for the 70 patients who underwent gross total resection, 51% of whom received IP therapy. Adverse prognostic factors for OS included adenocarcinoma histology, systemic chemotherapy, and no IP therapy. CONCLUSIONS: This large, single-institution, retrospective series with long-term follow-up suggests that IP chromic phosphate P 32 and 5-fluorouracil after maximal surgical resection of PMC of appendiceal origin is associated with improved OS and disease-free survival.

Effect of heat and high-pressure treatments on microbiological quality and immunoglobulin G stability of caprine colostrum.

Caprine colostrums (6 batches) were subjected to heat (56 degrees C for 60 min and 63 degrees C for 30 min) and high-pressure (400 and 500 MPa for 10 min at 20 degrees C) treatments at laboratory scale, and analyses of the main microbial groups and the extent of IgG denaturation (determined by immunodiffusion) were performed. Overall mean microbial values in raw colostrums were: total count, 5.55 log cfu/mL; Enterobacteriaceae, 2.64 log cfu/mL; lactococci, 5.41 log cfu/mL; lactobacilli, 2.34 log cfu/mL; and enterococci, 4.06 log cfu/mL. Neither Salmonella spp. nor Listeria monocytogenes were detected, whereas coagulase-positive staphylococci were found in various colostrum samples with an overall mean of 1.02 log cfu/mL. Heat and high-pressure treatments significantly reduced total count (1.47 log), lactococci (1.45 log), enterococci (2.47 log), and Enterobacteriaceae, whereas lactobacilli and coagulase-positive staphylococci counts were reduced to undetectable levels, but differences between technological treatments were not statistically significant. High-pressure treatments were as efficient in reducing the bacterial population as were heat pasteurization treatments: 95.50 and 96.93% for pressure treatments of 400 and 500 MPa, and 91.61 and 97.59% for heat treatments of 56 degrees C for 60 min and 63 degrees C for 30 min, respectively. All treatments assayed produced a reduction in colostrum IgG concentration (27.53, 23.58, 23.33, 22.09, and 17.06 mg/mL for raw, heat-treated at 56 degrees C for 60 min or 63 degrees C for 30 min, and pressure-treated at 400 and 500 MPa, respectively), but differences were only observed between raw colostrums and those pressure-treated at 500 MPa. This laboratory-scale study indicated that 20- to 30-mL volumes of goat colostrum could be heated and pressure-treated (400 MPa) to produce hygienic colostrum without affecting IgG concentration.

Neonatal iron exposure induces oxidative stress in adult Wistar rat.

Oxidative stress and excess of iron in the brain has been implicated in a variety of acute and chronic neurological conditions. The neonatal period is critical for the establishment of normal iron content in the adult brain. In the present study, the long-term oxidative effects of iron exposure during this period were assessed by treating Wistar rats orally with 0, 7.5 or 15 mg Fe(+2)/kg of body weight on postnatal days 10-12. Thiobarbituric acid reactive species, protein carbonyl, superoxide dismutase activity were measured at the age of 3 months. It was found that there was an increase in thiobarbituric acid reactive species and protein carbonyl in the substantia nigra of iron treated rats. In contrast, oxidative stress in the striatum was decreased. Superoxide dismutase activity was decreased in the substantia nigra iron treated rats. There were no differences in cerebellum measures among the groups. Our results demonstrated that iron supplementation in a critical neonatal period induced oxidative stress and modulated SOD activity in the adult life in selective brain regions.

Comparative pharmacological study of hydroethanol extracts of Passiflora alata and Passiflora edulis leaves.

Several species of the genus Passiflora, known in Brazil as "maracujá", have widespread use in folk medicine as sedatives and tranquillizers. The anxiolytic activity of hydroethanol extracts of P. alata and P. edulis leaves was evaluated using the elevated plus-maze test. The extracts presented anxiolytic activity in dosages around 50, 100 and 150 mg/kg.

Psychopharmacological screening of Pfaffia glomerata Spreng. (Amarathanceae) in rodents.

The alcoholic extract of Pfaffia glomerata roots (100, 500, 1000 mg/kg, intraperitoneally (i.p.), and 500, 1000, 1500 mg/kg, per os) was studied in several behavioral animal models for the evaluation of central activity: open field, barbiturate sleeping time, pentilenotetrazole (PTZ)-induced convulsions, elevated plus-maze, step-down inhibitory avoidance and forced swimming test. The acute treatment (500 mg/kg, i.p.) interfered with the open-field habituation, decreased sleep latency and increased barbiturate-induced sleeping time, protected partially the animals of PTZ-induced convulsions, decreased the memory retention in step-down inhibitory avoidance, and did not have an important effect in the elevated plus-maze test and forced swimming test. The same extract at 1000 mg/kg per os did not cause any effect in barbiturate sleeping time and pentilenotetrazole-induced convulsions models. Thus, the effect on the memory was deeper evaluated in the step-down inhibitory avoidance task. When administered by intraperitoneal route, the extract showed a dose-dependent effect causing full amnesia at 1000 mg/kg. On the other hand, when it was given by oral route at 500, 1000 and 1500 mg/kg, no influence on the memory retention was observed. These results suggest that the alcoholic extract of P. glomerata roots presents different effects depending on the route of administration: by i.p route, it seems to be a central nervous system depressant agent; by oral route, it seems to be ineffective, at least in the tested doses.

[Group psychotherapy. Working team in community psychiatry]. / Psicoterapia en grupos. El grupo operativo en la psiquiatría comunitaria.

A Community Psychiatry program was begun, based on the needs and requests of a clinic (this approach is restricted because there are institutional factors that only the institution can change). The work was aimed at sensitizing the beneficiaries and change clinic factors modifiable through operative group technique. When a great deal of every day stereotypes appeared, role playing was used: as a result, people in the clinic realized how they acted and how they asked from others behaviors that they themselves found difficult to show. As results, it was found that when workers were confronted with reality, desertion from operative groups appeared, with projection of problems (them, not me), great fear of change (fantasized in different ways), group passivity and the image of the institution, that the group saw as a persecutor.