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Administration of interferon-g to pregnant rats reverses the depressed adjuvant-induced arthritis of their chronically Trypanosoma cruzi-infected offspring  [cached]
Didoli G.,Revelli S.,Davila H.,Ferro M.E.
Brazilian Journal of Medical and Biological Research , 1999,
Abstract: We demonstrated that administration of interferon gamma (IFN-g) to the inbred "l" strain of pregnant rats conferred partial resistance on their offspring to challenge with Trypanosoma cruzi. We now examine if this intervention also modifies the reportedly immunodepressed cellular responses which occur during chronic infection. Offspring were born to mothers undergoing one of the following procedures during gestation: subcutaneous injections of recombinant rat IFN-g, 50,000 IU/rat, five times/week for 3 weeks, which was started on the day of mating (IFN-Mo); infection with 106 trypomastigotes of T. cruzi at 7, 14, and 21 days after mating plus IFN-g treatment as given to the former group (TcIFN-Mo); the same protocol except that physiological saline was injected instead of IFN-g (Tc-Mo); injection of physiological saline only (control-Mo). All offspring groups (N = 8-10/group) were infected at weaning and were assessed 90 days later for their adjuvant-induced arthritic response or levels of major T cell subsets in spleen and lymph nodes. TcIFN-Mo and IFN-Mo offspring showed a reestablished arthritic response, which remained within the range seen in controls. Immunolabeling studies on parallel groups of 90-day-infected offspring showed that the inverse CD4/CD8 cell ratio that is usually seen in lymphoid organs from these chronically infected rats (median 0.61) appeared to have recovered in the TcIFN-Mo and IFN-Mo groups (median 1.66 and 1.78, respectively) and was not different from uninfected controls (1.96). These studies indicate that early stimulation with IFN-g is able to reverse the immunosuppressive state that is usually present during the chronic period of the experimental infection.
The way early-onset chronically depressed patients are treated today makes me sad  [PDF]
James P. McCullough
Open Journal of Psychiatry (OJPsych) , 2012, DOI: 10.4236/ojpsych.2012.21002
Abstract: The author has treated almost 400 chronically depressed outpatients during his career. He has also participated as a Field Trial Coordinator in the Unipolar Field Trials of DSM-IV and consulted with the DSM-V Mood Disorders Workgroup concerning his research for the new diagnostic nomenclature for the chronic depressions, Chronic Depression Disorder. In addition, he has served as Principal Investigator in several large clinical trials involving 2200 chronically depressed outpatients. The current paper is a Brief Report describing his negative reactions to the way 40 of his chronically depressed patients have been treated today by both Psychologists and Psychiatrists. All the patients are his patients and have been seen by him in psychotherapy over the past decade. Several reasons are proposed for the inadequate treatment and specific proposals are made for the improvement of treatment for the early-onset chronically depressed patient.
Neuronal counting and parasympathetic dysfunction in the hearts of chronically Trypanosoma cruzi - infected rats
Chapadeiro, E.;Florêncio, R.F.C.;Afonso, P.C.;Beraldo, P.S.S.;Jesus, P.C. de;Junqueira Jr., L.F.;
Revista do Instituto de Medicina Tropical de S?o Paulo , 1991, DOI: 10.1590/S0036-46651991000500001
Abstract: ten male wistar rats, chronically infected with colombian, s?o felipe (12sf) and y strains of trypanosoma cruzi and ten non-infected control animals were submitted to the bradycardia responsiveness test, an assessment of heart parasympathetic function, after phenylephrine injection. six chagasic animals showed heart parasympathetic dysfuntion characterized by reduction in the index of bradycardia baroreflex responsiveness, as compared with the control group. microscopic examination of the atrial heart ganglia of chagasic rats showed ganglionitis, but no statiscally significant reduction in the number of neurons.
Treatment with benznidazole in association with immunosuppressive drugs in mice chronically infected with Trypanosoma cruzi: investigation into the possible development of neoplasias
Andrade, Sonia G.;Mesquita, Igor Marcelo Oliveira;Jambeiro, Jamile F.;Santos, Isis F. Magalh?es;Portella, Renata Siqueira;
Revista da Sociedade Brasileira de Medicina Tropical , 2003, DOI: 10.1590/S0037-86822003000400002
Abstract: benznidazole is recommended in brazil for the treatment of trypanosoma cruzi infection in acute and early chronic phases of chagas' disease. observations by others have indicated a higher incidence of neoplasias in immunosuppressed patients, presenting chagas' disease reactivation, submitted to treatment with benznidazole. in the present study, we investigated whether there is a potentiation in the generation of lymphomas in chronically infected mice, treated with immunosuppressive drugs and benznidazole. for this, 142 swiss mice chronically infected with the 21 sf strain of t. cruzi and 72 normal swiss mice were used. both infected and normal mice were divided into experimental groups and submitted to one of the following treatment regimens: benznidazole alone; immunosuppressive drugs (azathioprine, betamethasone and cyclosporin); a combination of immunosuppressive drugs and benznidazole; and untreated controls. in the infected group treated with benznidazole, one mouse developed a non-hodgkin's lymphoma. this finding has been interpreted as a spontaneous tumor of mice. the study of the chronically infected mice treated with the combination of immunosuppressive drugs and benznidazole demonstrated an absence of lymphomas or other neoplasias. these findings support the indication of benznidazole, as the drug of choice, for immunosuppressed patients that develop a reactivation of chagas' disease.
Treatment with benznidazole in association with immunosuppressive drugs in mice chronically infected with Trypanosoma cruzi: investigation into the possible development of neoplasias
Andrade Sonia G.,Mesquita Igor Marcelo Oliveira,Jambeiro Jamile F.,Santos Isis F. Magalh?es
Revista da Sociedade Brasileira de Medicina Tropical , 2003,
Abstract: Benznidazole is recommended in Brazil for the treatment of Trypanosoma cruzi infection in acute and early chronic phases of Chagas' disease. Observations by others have indicated a higher incidence of neoplasias in immunosuppressed patients, presenting Chagas' disease reactivation, submitted to treatment with benznidazole. In the present study, we investigated whether there is a potentiation in the generation of lymphomas in chronically infected mice, treated with immunosuppressive drugs and benznidazole. For this, 142 Swiss mice chronically infected with the 21 SF strain of T. cruzi and 72 normal Swiss mice were used. Both infected and normal mice were divided into experimental groups and submitted to one of the following treatment regimens: benznidazole alone; immunosuppressive drugs (azathioprine, betamethasone and cyclosporin); a combination of immunosuppressive drugs and benznidazole; and untreated controls. In the infected group treated with benznidazole, one mouse developed a non-Hodgkin's lymphoma. This finding has been interpreted as a spontaneous tumor of mice. The study of the chronically infected mice treated with the combination of immunosuppressive drugs and benznidazole demonstrated an absence of lymphomas or other neoplasias. These findings support the indication of benznidazole, as the drug of choice, for immunosuppressed patients that develop a reactivation of Chagas' disease.
Evolution of subpatent parasitaemia in Trypanosoma cruzi chronically infected mice with the help of a cyclophosphamide amplification transfer assay
Alvarez, José M.;Oshima, Ayumi;Mozer, Veronica;Guimar?es, Liliane;Menezes, Hércules;
Revista do Instituto de Medicina Tropical de S?o Paulo , 1991, DOI: 10.1590/S0036-46651991000600013
Abstract: we have evaluated the sensitivity of the classical blood subinoculation method, modified through cyclophosphamide treatment of transferred mice, for the detection of occult parasitaemias in trypanosoma cruzi chronically infected mice. besides its simplicity, the method was shown to be highly sensitive for both the "chronic" phase parasites (99% of chronic cases were shown to harbour occult parasitaemias) and for the acute phase parasites (t. cruzi could be detected in 53.8% of animals transferred with one y strain parasite and in 20% of animals transferred with one cl strain parasite). using acute phase bloodforms, the assay proved to be more sensitive than conventional subinoculation when dealing with the cl, but not the y strain of the parasite. with the help of this parasite detection tool, we have studied during a one year period, the evolution of subpatent parasitaemias in a group of mice which survived through chemotherapy from lethal acute phase of t. cruzi infection. cyclophosphamide transfer assay revealed occult parasitaemias in 100% of the chronic animals, nevertheless, continuous and discontinuous patterns of positivity were observed.
Preventing mood and anxiety disorders in youth: a multi-centre RCT in the high risk offspring of depressed and anxious patients
Maaike H Nauta, Helma Festen, Catrien G Reichart, Willem A Nolen, A Stant, Claudi LH Bockting, Nic JA van der Wee, Aartjan Beekman, Theo AH Doreleijers, Catharina A Hartman, Peter J de Jong, Sybolt O de Vries
BMC Psychiatry , 2012, DOI: 10.1186/1471-244x-12-31
Abstract: The current STERK-study (Screening and Training: Enhancing Resilience in Kids) is a randomized controlled clinical trial combining selected and indicated prevention: it is targeted at both high risk individuals without symptoms and at those with subsyndromal symptoms. Individuals without symptoms meet two of three criteria of the High Risk Index (HRI; female gender, both parents affected, history of a parental suicide (attempt). This index was developed in an earlier study and corresponds with elevated risk in offspring of depressed patients. Children aged 8–17 years (n?=?204) with subthreshold symptoms or meeting the criteria on the HRI are randomised to one of two treatment conditions, namely (a) 10 weekly individual child CBT sessions and 2 parent sessions or (b) minimal information. Assessments are held at pre-test, post-test and at 12 and 24 months follow-up. Primary outcome is the time to onset of a mood or anxiety disorder in the offspring. Secondary outcome measures include number of days with depression or anxiety, child and parent symptom levels, quality of life, and cost-effectiveness. Based on models of aetiology of mood and anxiety disorders as well as mechanisms of change during interventions, we selected potential mediators and moderators of treatment outcome, namely coping, parent–child interaction, self-associations, optimism/pessimism, temperament, and emotion processing.The current intervention trial aims to significantly reduce the risk of intergenerational transmission of mood and anxiety disorders with a short and well targeted intervention that is directed at strengthening the resilience in potentially vulnerable children. We plan to evaluate the effectiveness and cost-effectiveness of such an intervention and to identify mechanisms of change.NTR2888Anxiety disorders are highly prevalent among children and adolescents with estimates of 11.6% year prevalence in adolescents alone [1], and depression is highly prevalent among adolescents, with es
Reversibility of cardiac fibrosis in mice chronically infected with Trypanosoma cruzi, under specific chemotherapy
Andrade, Sonia G.;Stocker-Guerret, Sylviane;Pimentel, Ariane S.;Grimaud, Jean Alexis;
Memórias do Instituto Oswaldo Cruz , 1991, DOI: 10.1590/S0074-02761991000200008
Abstract: this investigation was performed to verify the effect of specific chemotherapy (benznidazole or mk-346) on the inflammatory and fibrotic cardiac alterations in mice chronically infected with the strains 21 sf (type ii) and colombian (type iii) of trypanosoma cruzi. to obtain chronically infected mice, two groups of 100 swiss mice each, were infected with either the 21 sf or the colombian strain (2x 10 [raised to the power of] 4 and 5x 10 [raised to the power of] 4 blood forms respectively). the rate of morality in the acute phase was of 80% for both groups. twenty surviving mice chronically infected with the 21 sf strain and 20 with the colombian strain were then divided in treated and untreated groups. excluding those that died during the course of treatment, 14 mice chronically infected with the 21 sf strain and 15 with the colombian strain were evaluated in the present study. chemotherapy was performed with benznidazole (n-benzil-2-nitro-1-imidazolacetamide) in the dose of 100mg/k.b.w/day, for 60 days, or with the mk-436(3(1-methyl-5 nitroimidazol-2-yl) in two daily doses of 250 mg/k.b.w, for 20 days. parasitological cure tests were performed (xenodiagnosis, haemoculture, subinovulation of the blood into newborn mice), and serological indirect immunofluorescence test. the treated and untreated mice as well as intact controls were killed at different periods after treatment and the heart were submitted to histopathological study with hematoxilineosin and picrosirius staining; ultrastructural study; collagen immunotyping, fibronectin and laminin identification by immunofluorescence tests. results: the untreated controls either infected with 21 sf or colombian strain, showed inflammatory and fibrotic alterations that were mild to moderate with the 21 sf strain and intense with the colombian strain. redpicrosirius staining showed bundles of collagen in the interstitial space and around cardiac fibers. increased deposits of mitritial components and collagen fibers, ma
Pre-Weaning Growth Hormone Treatment Reverses Hypertension and Endothelial Dysfunction in Adult Male Offspring of Mothers Undernourished during Pregnancy  [PDF]
Clint Gray, Minglan Li, Clare M. Reynolds, Mark H. Vickers
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0053505
Abstract: Maternal undernutrition results in elevated blood pressure (BP) and endothelial dysfunction in adult offspring. However, few studies have investigated interventions during early life to ameliorate the programming of hypertension and vascular disorders. We have utilised a model of maternal undernutrition to examine the effects of pre-weaning growth hormone (GH) treatment on BP and vascular function in adulthood. Female Sprague-Dawley rats were fed either a standard control diet (CON) or 50% of CON intake throughout pregnancy (UN). From neonatal day 3 until weaning (day 21), CON and UN pups received either saline (CON-S, UN-S) or GH (2.5 ug/g/day)(CON-GH, UN-GH). All dams were fed ad libitum throughout lactation. Male offspring were fed a standard diet until the end of the study. Systolic blood pressure (SBP) was measured at day 150 by tail cuff plethysmography. At day 160, intact mesenteric vessels mounted on a pressure myograph. Responses to pressure, agonist-induced constriction and endothelium-dependent vasodilators were investigated to determine vascular function. SBP was increased in UN-S groups and normalised in UN-GH groups (CON-S 121±2 mmHg, CON-GH 115±3, UN-S 146±3, UN-GH 127±2). Pressure mediated dilation was reduced in UN-S offspring and normalised in UN-GH groups. Vessels from UN-S offspring demonstrated a reduced constrictor response to phenylephrine and reduced vasodilator response to acetylcholine (ACh). Furthermore, UN-S offspring vessels displayed a reduced vasodilator response in the presence of L-NG-Nitroarginine Methyl Ester (L-NAME), carbenoxolone (CBX), L-NAME and CBX, Tram-34 and Apamin. UN-GH vessels showed little difference in responses when compared to CON and significantly increased vasodilator responses when compared to UN-S offspring. Pre-weaning GH treatment reverses the negative effects of maternal UN on SBP and vasomotor function in adult offspring. These data suggest that developmental cardiovascular programming is potentially reversible by early life GH treatment and that GH can reverse the vascular adaptations resulting from maternal undernutrition.
The conduction system of the heart in mice chronically infected with Trypanosoma cruzi: histopathological lesions and electrocardiographic correlations
Andrade, Sonia G.;Sadigursky, Moysés;
Memórias do Instituto Oswaldo Cruz , 1987, DOI: 10.1590/S0074-02761987000100010
Abstract: chronic focal and diffuse myiocarditis with interstitial fibrosis developed in swiss outbred mice and in the inbred akr and a/j strains of mice which were chronically infected with several trypanosoma cruzi strains belonging to three biological types (type i, ii and iii). high incidence of electrocardiographic changes with predominance of intraventricular conduction disturbances, 1st. and 2nd. degree av block, arrhythmias, comparable with those found in human chagas' disease, were also present. morphological study of the conduction tissue of the heart revealed inflammatory and fibrotic changes. the presence of inflammation in the inter-atrial septum almost always coincided with the inflammatory involvement of the ventricular conduction system. focal inflammation was associated with vacuolization and focal necrosis of the specific fibers. most of the lesions were seen affecting the his bundel (76.3% of the cases), the right bundle branch (73.3%), av node (43.9%) and left bundle branch (37.5%). correlation between morphological changes in the conduction tissue and electrocardiographic alteration occured in 53.0 to 62.5% of the cases, according to the experimental groups.
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