Propranolol Decreases Fear Expression by Modulating Fear Memory Traces.

BACKGROUND: Posttraumatic stress disorder can develop after a traumatic event and results in heightened, inappropriate fear and anxiety. Although approximately 8% of the U.S. population is affected by posttraumatic stress disorder, only two drugs have been approved by the Food and Drug Administration to treat it, both with limited efficacy. Propranolol, a nonselective ß-adrenergic antagonist, has shown efficacy in decreasing exaggerated fear, and there has been renewed interest in using it to treat fear disorders. METHODS: Here, we sought to determine the mechanisms by which propranolol attenuates fear by utilizing an activity-dependent tagging system, ArcCreERT2 x eYFP mice. 129S6/SvEv mice were administered a 4-shock contextual fear conditioning paradigm followed by immediate or delayed context reexposures. Saline or propranolol was administered either before or after the first context reexposure. To quantify hippocampal, prefrontal, and amygdalar memory traces, ArcCreERT2 x eYFP mice were administered a delayed context reexposure with either a saline or propranolol injection before context reexposure. RESULTS: Propranolol decreased fear expression only when administered before a delayed context reexposure. Fear memory traces were affected in the dorsal dentate gyrus and basolateral amygdala after propranolol administration in the ArcCreERT2 x eYFP mice. Propranolol acutely altered functional connectivity between the hippocampal, cortical, and amygdalar regions. CONCLUSIONS: These data indicate that propranolol may decrease fear expression by altering network-correlated activity and by weakening the reactivation of the initial traumatic memory trace. This work contributes to the understanding of noradrenergic drugs as therapeutic aids for patients with posttraumatic stress disorder.

Semiquantitative mercury determination in fish: a tool for poisoning prevention.

Human exposure to mercury intoxication through contaminated fish ingestion has been well studied, mainly among Japanese population. The Brazilian population, particularly in the Amazon region, is now in focus due to findings of fish contamination. Major health impacts caused by mercury affect mostly people who have a regular fish diet. A continuous checking for mercury content in the most consumed fish could prevent human intoxication. A simple, non-instrumental method to allow a continuous checking of the mercury content in fish was developed. Based on this method, we are proposing a prevention action where community agents can be trained to perform fish analysis. Technical Schools and Universities located nearby the affected areas would be in charge of quality control programs for the fish analysis as well as for the selection, training and update for operators.

Semiquantitative mercury determination in fish: a tool for poisoning prevention

Human exposure to mercury intoxication through contaminated fish ingestion has been well studied, mainly among Japanese population. The Brazilian population, particulaly in the Amazon region, is now in focus due to findings of fish contamination. Major health impacts caused by mercury affect mostly people who have a regular fish diet. A continuous checking for mercury content in the most consumed fish could prevent human intoxication. A simple, non-instrumental method to allow a continuous checking of the mercury content in fish was developed. Based on this method, we are proposing a prevention action where community agents can be trained to perform fish analysis. Technical Schools and Universities located nearby the affected areas would be in charge of quality control programs for the fish analysis as well as for the selection, training and update for operators

Lipid and apolipoprotein patterns during erythropoietin therapy: roles of erythropoietin, route of administration, and diet.

BACKGROUND: Long-term effects of rHuEpo on the blood lipid profile have not been well documented. The aim of this paper is to prospectively evaluate whether rHuEpo therapy affects lipid metabolism, and whether these effects are influenced by changes in dietary habits and by route of rHuEpo administration. METHODS: The study was performed in 33 maintenance haemodialysis patients (MHP) treated for one year with rHuEpo either intravenously (n = 15) or subcutaneously (n = 18), three times per week at the end of each dialysis session. The doses were 50 IU/kg intravenously or 35 IU/kg subcutaneously during the first 6 months and 20 IU/kg during the following months. The control group consisted of 17 MHP not treated with rHuEpo. Total cholesterol, LDL-cholesterol and HDL-cholesterol, triglycerides, apolipoproteins Al and B, haemoglobin, serum albumin, blood urea nitrogen, serum creatinine, Kt/V, protein catabolic rate, and plasma erythropoietin were assessed at months 0, 2, 4, 6, 9, 12 and 2 weeks after rHuEpo discontinuation. Changes in food intake were evaluated on the basis of weekly dietary diaries before, and 3 and 9 months after treatment. Patients were divided into two groups: group A consisted of 19 patients who showed an increase in their energy intake (10% or more of basal value), and group B was formed by 14 patients without or with slight changes in their food intake. After the 6th month, dialysis schedules were adapted to new protein catabolic rate values in patients who increased their food intake. RESULTS: During follow-up, there were no significant changes in any of the parameters in the control group. In group A, blood urea nitrogen, serum creatinine, protein catabolic rate, cholesterol, LDL cholesterol, triglycerides and apolipoprotein B increased significantly since the first months of rHuEpo treatment, and changes in cholesterol and apolipoprotein B correlated significantly with changes in protein catabolic rate. In group B, cholesterol, LDL cholesterol, and apolipoprotein B decreased significantly after the 6th month of treatment, without changes in blood urea nitrogen, serum creatinine and protein catabolic rate values. In both groups A and B, HDL cholesterol decreased significantly until the 6th month and returned to basal values in the following months and apolipoprotein Al decreased until the 4th month and rose to levels higher than basal values in the following months. First rHuEpo administration and rHuEpo suspension at end of follow-up did not show any acute effect on lipid profile, despite significant changes in plasma erythropoietin values. Changes in lipid profile were similar with intravenous and subcutaneous administration of rHuEpo. CONCLUSIONS: We infer that long-term rHuEpo treatment positively affects the lipid profile, but in some patients who show exaggerated increase in their food intake these effects may be balanced and overcome by increment in some atherogenic blood lipid fractions. The changes in lipid and apolipoprotein patterns during rHuEpo therapy are not influenced by route of rHuEpo administration.

Early and late effects of erythropoietin on glucose metabolism in maintenance hemodialysis patients.

The effects of recombinant human erythropoietin (rHuEPO) on the glucose metabolism were evaluated by intravenous glucose tolerance test in 20 maintenance hemodialysis patients. In 8 cases the glucose tolerance tests were performed before and after a single intravenous injection of 50 IU/kg of rHuEPO and in 12 cases before and after 3 months of rHuEPO therapy at doses of 50 IU/kg three times/week and 2 weeks after rHuEPO withdrawal. For each test glucose, immunoreactive insulin (IRI) and C peptide (C-p) plasma values were measured, and glucose constant decay, whole IRI (area IRI) and C-p area C-p) production, insulinogenic index, and insulin resistance index were calculated. After 3 months of rHuEPO therapy, the glucose constant decay increased significantly, area IRI, area C-p, and insulin resistance index decreased significantly, and the insulinogenic index did not change. No correlations were found between changes in hemoglobin values and changes in glucose metabolism parameters. Acute rHuEPO administration and rHuEPO withdrawal had no effect on glucose metabolism, despite significant changes in plasma erythropoietin levels. Long-term rHuEPO therapy improves glucose metabolism in maintenance hemodialysis patients significantly, mainly by reduction of insulin resistance. Neither anemia correction nor a direct effect of rHuEPO on some metabolic steps seem to be responsible of these effects.

Erythropoietin and cardiovascular risk.

We studied the changes in some cardiovascular risk (CVR) factors in 24 maintenance hemodialysis patients treated for 1 year with recombinant human erythropoietin (rHuEPO) either intravenously (12 cases) or subcutaneously (12 cases). In order to clarify whether changes in some parameters were due to direct action of rHuEPO or to changes in food intake, we divided the patients into two groups: group A was formed by 14 patients who showed an increase in their food intake during rHuEPO therapy and group B by 10 patients without or with slight changes in their food intake. rHuEPO induced an improvement in well-being in 20 of 24 patients and in physical working capacity in 14 of 24, an increase in mean blood pressure in all patients, and hypertension in 4 of 24 patients. The incidence of hypertension was slightly higher after intravenous (3/12) than after subcutaneous (1/12) treatment. The rate of dialysis treatment with symptomatic hypertension significantly decreased from 44.0 +/- 8.0 to 12.1 +/- 2.2% after intravenous and from 41.3 +/- 6.8 to 10.0 +/- 3.8% after subcutaneous treatment. Evaluation of glucose metabolism (intravenous glucose tolerance test) before and after 3 months of rHuEPO therapy showed an improvement in glucose utilization (insulin resistance reduction). Cholesterol (CH), low-density lipoprotein CH, triglycerides, and apolipoprotein B significantly increased in group A, but not in group B. Both in groups A and B, high-density lipoprotein CH significantly decreased during the first 6 months and returned to basal values during the following months, and the apolipoprotein A1 level significantly decreased during the first 4 months and increased to levels higher than basal values during the following months. Changes in CH and apolipoprotein B were also positively correlated with changes in the protein catabolic rate. We infer that rHuEPO has opposite effects on CVR, but subcutaneous administration, dietary control, and antihypertensive treatment may produce a net decrease in CVR of maintenance hemodialysis patients on rHuEPO therapy.

Glucose-induced insulin secretion in uremia: role of 1 alpha,25(HO)2-vitamin D3.

To evaluate the role and mechanism of action of calcitriol on glucose-induced insulin secretion in uremia, 17 patients with severe chronic renal failure were studied. Glucose metabolism was investigated by the intravenous glucose tolerance test (IVGTT) before and after treatment for 21 days with 0.5 microgram/day of calcitriol and 500 mg/day of calcium (C+Ca) (6 cases) or 0.5 microgram/day of calcitriol alone (C) (11 cases). After these evaluations the patients on C+Ca were shifted to C and 6 patients on C were shifted to C+Ca, and IVGTT was repeated 21 days after the shift. For each test plasma glucose (G), immunoreactive insulin (IRI) and C-peptide (C-p) were measured at -30, 0, 2, 5, 15, 30, 45, 60 min, and baseline plasma values of 1 alpha,25(HO)2-vitamin D3, C-terminal parathyroid hormone (PTH-C), intact parathyroid hormone (PTH-I), calcitonin, and serum values of total and ionized calcium were dosed. Also, glucose constant decay (K-G), insulin response (IRI area), C-p production (C-p area), insulinogenic index (IGI) and insulin resistance index (RI) were calculated. A historical group of 21 healthy volunteers formed the normal controls. 1 alpha,25(HO)2-vitamin D3 plasma levels in uremic patients before treatment were significantly lower than normal range. As compared to controls, uremic patients showed significantly lower K-G, IRI area and IGI values and significantly higher RI values. After treatment with C or C+Ca, the insulin response improved significantly at 2 and 5 min and G decrement was more marked at 30, 45 and 60 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Glucose-induced insulin secretion in uremia: relation with acid-base balance and effects of bicarbonate administration.

In order to evaluate effects of metabolic acidosis on glucose metabolism in uremia, we studied, by an intravenous glucose tolerance test (IVGTT), 46 patients with severe chronic renal failure divided into three groups according to their blood bicarbonate (BB) values: group A formed by 15 patients without or with light metabolic acidosis (BB > or = 20 mEq/1); group B formed by 18 patients with moderate metabolic acidosis (16 < or = BB < 20 mEq/1); group C formed by 13 patients with severe metabolic acidosis (BB < 16 mEq/1). In 8 patients of group B (subgroup B1) and in 8 of group C (subgroup C1), IVGTT was also repeated after adjustment of acid-base balance by intravenous or oral bicarbonate administration. Twenty-nine healthy volunteers formed the normal controls. For each test, glucose constant decay (K), immunoreactive insulin (IRI) area and C-peptide (C-p) area response, insulinogenic index (IGI) and insulin resistance index (RI) were calculated. Compared to controls, all uremic groups showed significantly lower values of K and IGI and significantly higher values of C-p area and RI. In group C, RI was significantly higher than in groups A and B. No differences were found in the other glucose metabolism parameters among the uremic groups. After bicarbonate administration, subgroup C1 showed a significant decrease in RI and a rise in K values, while subgroup B1 showed no changes in glucose metabolism parameters. From these data, we infer that abnormalities of acid-base balance do not affect insulin response but severe metabolic acidosis may play an additional role in the insulin resistance of uremic patients.

Immune response after vaccination with recombinant hepatitis surface antigen in maintenance hemodialysis patients and healthy controls.

We evaluated anti-HBs titers 2 months after vaccination with recombinant hepatitis surface antigen (rDNA-HBsAg) in 43 maintenance hemodialysis patients (MHP). Of these, 34 had not undergone hepatitis B virus vaccination previously (NV-MHP) and 9 had shown negative response to vaccination with plasma-derived HBsAg (HEVAC Pasteur; V-MHP). 120 healthy workers from the same hospital undergoing rDNA-HBsAg immunization were used as controls. All low responders (LR) (anti-HBs less than 100 mIU/ml) and nonresponders (NR; anti-HBs less than 10 mIU/ml) were given a booster dose 3 months after the last dose of vaccine. Seroconversion rates were lower in NV-MHP (52.9%) than in controls (98.4%). V-MHP showed higher seroconversion rates (88.9%) than NV-MHP. In each group, the number of responders (R; anti-HBs greater than or equal to 100 mIU/ml), LR and NR was as follows: controls 101, 17, 2; NV-MHP 6, 12, 16; V-MHP 8, 0, 1. After booster dose, 17/17 controls LR and no NV-MHP LR showed a rise in anti-HBs titers over 100 mIU/ml. Six months after the last dose of vaccine or the booster dose, anti-HBs titer fell under 10 mIU/ml in 4/12 MHP LR and under 100 mIU/ml in 6/14 MHP R. To achieve high seroconversion rates and to avoid the decline of anti-HBs to nonprotective titers in MHP, a booster injection should be made at different dates after the first vaccination.

Prospective and retrospective assessment of clinical and laboratory parameters in maintenance hemodialysis patients with and without HCV antibodies.

In order to clear some aspects of HCV infection, we evaluated quarterly HCV markers by a RIBA 1 test (antigens c100-3 and 5.1.1) and monthly transaminases (ALT and AST) for 14 months in 89 HBsAg-free maintenance hemodialysis patients (MHP), and we retrospectively examined clinical records until the start of hemodialysis treatment. At the start of the study, 16 patients showed HCV antibodies (HCV+) and 73 were antibody-free (HCV-). 39 subjects of the staff were also examined. No HCV+ patient showed seroconversion, 10 showed irregular or persistent elevation of AST and ALT. In the retrospective evaluation 14 patients suffered from acute hepatitis (AH). Only 3 cases showed temporal relation with blood transfusions. In 1 case a 36-month temporary normalization of transaminases was noticed. 3 HCV-patients showed seroconversion (1 during AH), 13 showed severe or moderate elevations of transaminases. In the retrospective evaluation, 6 patients suffered from AH. All subjects of the staff were HCV- and showed no seroconversion or changes of transaminases. At the end of the study, we performed a RIBA 2 test containing the HCV antigens c100-3, 5.1.1, c22-3 and c33c. The 6 patients who suffered from AH showed at least 1 positivity for new proteins. Most of AH in MHP are likely due to HCV infection; besides transfusions, cross-infection during the dialytic procedure may be responsible for many cases of HCV infection; long-term normalization of transaminases may not secure against infectivity.

Iron deficiency in maintenance hemodialysis patients: assessment of diagnosis criteria and of three different iron treatments.

The study was carried out in order to evaluate in maintenance hemodialysis (MH) patients: (1) the reliability of serum ferritin (SF) measurement in iron deficiency diagnosis and therapy; (2) the possibility to improve iron stores assessment through laboratory indexes routinely used in clinical practice; (3) the most effective iron deficiency treatment. After a preliminary assessment of SF reference values in 250 healthy volunteers, we studied 72 MH patients divided into three groups according to their SF baseline values: high (group A), normal (group B), low (group C) (normal range 19-191 ng/ml). Each group was further divided into three subgroups receiving three different iron treatments for 6 months: (1) oral administration of 67.5 mg/day of Fe3+ as Fe-ferritin (subgroups A1, B1, C1); (2) oral administration of 60 mg/day of Fe3+ as Fe-chondroitin sulfate (subgroups A2, B2, C2); (3) i.v. administration at the end of each dialytic session of 31 mg of Fe3+ as Fe-gluconate-Na (subgroups A3, B3, C3). The response to the iron therapy was considered positive when the hemoglobin (Hb) and the hematocrit (Ht) increased to greater than or equal to 15% of the baseline values. The rate of positive responses in each subgroup was as follows: A1 0/5, A2 0/5, A3 0/7, B1 2/10, B2 1/6, B3 5/11, C1 1/7, C2 3/7, C3 10/16. We concluded that SF values above 191 ng/ml allow to exclude iron deficiency whereas SF values less than or equal to the normal range are inadequate. In an attempt to improve diagnostic sensitivity we divided patients of subgroup B3 and C3 into responders (R) and nonresponders (NR).(ABSTRACT TRUNCATED AT 250 WORDS)

Glucose-induced insulin secretion in uremia: effects of aminophylline infusion and glucose loads.

To explain mechanisms responsible for derangement of insulin release in uremia, we investigated glucose metabolism through three different tests in 14 patients with end-stage chronic renal failure. These tests were: intravenous glucose tolerance test with 0.33 g/kg of glucose solution (IVGTT); IVGTT with 0.5 g/kg of glucose solution (IVGTT2); IVGTT during aminophylline infusion (IVGTT + A). Twelve of the patients had IVGTT repeated after two to four months of thrice-weekly regular hemodialysis (IVGTT3). In each test we measured plasma glucose (G), immunoreactive insulin (IRI) and C-peptide. We also calculated glucose constant decay (K), insulin production (IRI area), insulinogenic index (IGI), and insulin resistance index (RI). Twenty-nine healthy volunteers formed the normal controls for IVGTT. As compared to controls, during IVGTT uremic patients showed significantly lower values in K, IRI area and IGI, and showed a significant RI value increase. During IVGTT2, IRI are values were higher than during IVGTT but IGI and K values were unchanged. During IVGTT + A both IRI area and IGI values were higher than during IVGTT. After hemodialysis treatment (IVGTT3) K, IRI areas and IGI increased significantly as compared to the predialysis period. K increase after hemodialysis correlated directly to IGI increase and inversely to RI changes. IGI increase during IVGTT3 was directly correlated to IGI rise during IVGTT + A. From these data we infer that defective insulin release in uremia is due to a decrease of beta-cell glucose sensitivity rather than to their functional exhaustion. An impaired adenyl cyclase-cAMP system may have an important role in the pathogenesis of this abnormality.

Glucose metabolism, lipidic pattern, apolipoprotein A and B during hemodialysis with cuprophan and hemodialysis-hemoperfusion.

We studied differences in the glucose metabolism, lipid pattern and apolipoprotein A and B after one month of combined hemodialysis-hemoperfusion (HD-HP) in eight regular maintenance hemodialysis (HD) patients. After one month of HD-HP predialytic serum creatinine and phosphate were lower than during the preceding HD period; the lipidic pattern and apolipoproteins were unchanged. A single HD-HP session significantly reduced triglycerides; this does not occur during HD. Postdialytic changes of all other lipoprotein metabolism parameters are identical in the two techniques. As regards glucose metabolism, after one month of regular HD-HP treatment glycemic curves during the intravenous glucose tolerance test (IVGTT) were perfectly matched with those in HD. However, insulin production was lower, with a reduction of the insulin resistance index. Differences did not reach statistical significance. The Authors infer that activated charcoal, even though it achieves better blood purification in uremia, may be unable to remove specific substances which hamper some key enzyme activities of the carbohydrate and lipid metabolism.

Metabolic and hormonal assessment of patients on maintenance hemodialysis for 10 years or more and their importance in long-term survival.

We studied metabolic and hormonal patterns in 11 patients on hemodialysis for over 10 years (group A) to determine whether some metabolic abnormalities worsen with long-term dialysis or whether a particular endocrine-metabolic pattern discriminates long-term hemodialysis survivors. Data were compared to those of 14 subjects of similar age and sex on dialysis for 1-3 years (group B) and to those measured in the same patients during the 1st year of dialytic treatment. As to glucose metabolism, group A showed elevation of fasting plasma glucose and a decrease of glucose constant decay (K) and insulin production (IIG) values as compared to the 1st year of dialysis. No difference was found between group A now and group B. However in the 1st year of dialysis group A showed significantly higher K values than group B. As regards lipid metabolism, group A presented higher alpha-lipoprotein values and high-density lipoprotein-cholesterol/cholesterol, high-density lipoprotein-cholesterol/apoprotein A, and apoprotein A/apoprotein B ratios, while low-density lipoprotein-cholesterol and apoprotein B values and beta/alpha-lipoprotein ratio were lower. These data demonstrate less vascular risk in group A. We explain these results as depending on natural selection. Multivariate analysis of survival confirmed that survival in hemodialysis patients is influenced negatively by glucose and lipid metabolism abnormalities. As to Ca-P metabolism, group A showed higher carboxy-terminal parathyroid hormone and alkaline phosphatase values than group B. However, these data may be superimposed to those determined in the same patients in 1981, when we began the regular use of 1 alpha,25-(OH)2-vitamin D3.(ABSTRACT TRUNCATED AT 250 WORDS)