A novel experimental immunomodulatory therapy against Nocardia brasiliensis in a BALB/c murine model.

BACKGROUND: Mycetoma is recognized as a neglected tropical disease and there are still therapeutic challenges, especially in cases recalcitrant to standard therapy or with high risk of dissemination. Subcultures have been used previously to decrease the virulence of human pathogens. Previous reports have demonstrated that after carrying out 200 subcultures of Nocardia brasiliensis, a decrease in virulence was observed. AIM: To evaluate the effect of attenuated N. brasiliensis strains on the development of lesions in an established mycetoma infection. METHODS: Female 8-12-week-old BALB/c mice were injected with N. brasiliensis suspension to establish a mycetoma. Sixty mice were selected and divided into three groups: two of these groups were inoculated in the dorsum with N. brasiliensis subcultured 200 and 400 times, respectively, while the third group served as control. The thickness of each lesion was measured with calipers every week for 12 weeks. RESULTS: After 12 weeks, we observed that inoculation of 1 × 105 colony-forming units of attenuated N. brasiliensis strains was able to modify the natural history of the infection, with a decrease in the size of the lesions, particularly with P400, compared with the control group (P < 0.01). CONCLUSION: In this experimental evaluation of an immunomodulatory therapy with attenuated N. brasiliensis strains in a murine model, there was a greater stability in the size of the lesion over time in BALB/c mice inoculated with the P400 strain. This treatment could open the possibility of using the attenuated strain as immunomodulatory therapy in patients recalcitrant to standard therapy, with high risk of dissemination or who develop drug-related adverse effects.

Taking or not taking medications: psychiatric treatment perceptions in patients diagnosed with bipolar disorder.

WHAT IS KNOWN AND OBJECTIVE: Bipolar disorder is a common and disabling condition. Although its negative impact may be limited in some way by the use of different treatment options, lack of adherence to psychiatric treatment is still an obstacle to overcome. Because there are many factors involved in non-adherence to treatment, in this study, we sought to examine the subjective aspect of this phenomenon. We analysed perceptions of both the disease and the treatment in a group of patients with bipolar disorder. METHODS: We incorporated a qualitative design that included 50 outpatients diagnosed with bipolar disorder type 1. Through semi-structured interviews, we explored patients' perceptions of bipolarity and psychiatric medication management. RESULTS AND DISCUSSION: The participants reported the use of medications as one of the most troubling aspects of having bipolar disorder. The fear of becoming addicted to psychiatric drugs was repeatedly mentioned among the patients as an argument for abandoning treatment. The main expectation of treatment was to achieve stable mood, but the patients considered that drugs were not the only way to be euthymic. WHAT IS NEW AND CONCLUSIONS: The patients expressed ambivalence between the need to take medication to remain stable and the fear of negative consequences of using psychiatric drugs. Personal beliefs and environmental influences seem to determine each individual's final choice of whether to maintain or discontinue treatment; so, in everyday clinical practice, it would be necessary to discuss perceptions of the disease with patients and their families.

Microtubule organization and L-type voltage-activated calcium current in olfactory neuronal cells obtained from patients with schizophrenia and bipolar disorder.

Olfactory neuroepithelial cells in culture have been proposed as a model to study the physiopathology of psychiatric disorders and biomarker characterization for diagnosis. In patients with schizophrenia (SZ) and bipolar disorder (BD) diminished microtubule-associated proteins expression occurs, which might lead to aberrant microtubular organization and which in turn may affect Ca(2+) voltage-activated currents. The aim of this work was to characterize of microtubule organization as well as of the L-type Ca(2+) current in neuronal precursors obtained from nasal exfoliates of patients with SZ and BD. Microtubule organization was studied by immunofluorescence with a specific anti-III ß-tubulin antibody and by quantification of globular and assembled tubulin by Western blot. L-type current recording was performed by whole-cell patch-clamp technique and nifedipine superfusion. The results showed differential altered microtubular organization in neuronal precursors of SZ and BD. Short microtubules were observed in BD neurons, while extensive, unstained subcellular areas and disorganized microtubules were evident in SZ neuronal precursors. Patients with BD showed a decrease in amounts of tubulin in total homogenates and 40% decrease in the globular fraction. However, L-type current in BD was similar to that in healthy subjects (HS). In contrast, this current in SZ was 50% lower. These reduction in L-type current in SZ together with differential microtubule alterations are potential biomarkers that may differentiates SZ and BD.

A non-invasive method to isolate the neuronal linage from the nasal epithelium from schizophrenic and bipolar diseases.

Brain imaging and histopathological studies suggest that neurodevelopmental anomalies play a key role in the etiology of schizophrenia (SZ) and bipolar disorder (BD). New neuron formation and maturation occur in human olfactory epithelium throughout life. Therefore, the olfactory epithelium has been proposed as a model to study alterations in neurodevelopment, particularly in some psychiatric diseases. However, former studies were done with olfactory epithelium biopsies taken post mortem or under anesthesia from patients with SZ and BD. In this work we have developed a new method to obtain viable neural precursors by exfoliation of the anterior region of the medial lateral turbinate of the nasal cavity from healthy controls, and ambulatory patients. Cells were propagated to establish neural precursor banks. Thawed cells showed cytoskeletal phenotypes typical of developing neurons. They also conserved the ability to differentiate in presence of 2mM dibutyril-cyclic adenosine monophosphate, and maintained voltage-operated Ca(2+) currents in culture. Moreover, proportions of neuronal maturation stages were maintained in cultured exfoliates obtained from SZ and BD patients. Data support that neural precursors obtained from a nasal exfoliate are an excellent experimental model to later approach studies on biomarkers, neural development and cellular alterations in the pathophysiology of SZ and BD.

Reduction in the latency of action of antidepressants by 17 beta-estradiol in the forced swimming test.

RATIONALE: Antidepressants (ADs) are slow to produce their therapeutic effect. This long latency promotes the development of new strategies to short their onset of action. Previous reports indicated that 17beta-estradiol (E(2)) promotes the antidepressant-like activity of fluoxetine (FLX) and desipramine (DMI) in the forced swimming test (FST). OBJECTIVE: The aim of the present work was to analyze if E(2) reduces the antidepressant-like onset of action of venlafaxine (VLX), FLX, and DMI. MATERIALS AND METHODS: Independent groups of ovariectomized female Wistar rats were tested in the FST and in the open field after chronic (1 to 14 days) treatment with VLX (20 mg/kg/day), FLX (1.25 mg/kg/day), or DMI (1.25 mg/kg/day) alone or in combination with a single injection of E(2) (2.5 microg/rat sc, 8 h before FST). RESULTS: VLX, FLX, or DMI by themselves at these doses did not induce changes in the FST at short intervals after their injection (from 1 to 7 days). The addition of E(2) promoted the antidepressant-like effect of VLX and DMI as early as day 1. Such action was also evident after 3, for FLX, and 14 days for both FLX and DMI, but not for VLX. The behavioral actions of these ADs combined with E(2) were not accompanied by increases in general activity in the open-field test. CONCLUSION: E(2) clearly reduced the latency to the onset of action for these ADs in the FST. These results represent an interesting therapeutic strategy for the treatment of depression in perimenopausal women.

[Early and intermediate responses as factors predicting efficiency of antidepressive agents]. / Respuestas temprana e intermedia como factores de predicción de la eficacia de los antidepresivos.

An important limitation in the treatment of depression is the lack of reliable factors for predicting treatment response. Most of these factors have been related to biological and clinical aspects. A clinical aspect that has proved to reasonably predict long-term efficacy is early response. An adequate early response predicts a good outcome at the long term. The purpose of this study was to quantify the proportion of patients who show no response to a fixed dose of antidepressants after 2,4, and 6 weeks of treatment, and then respond by week 8. Additionally, a subgroup of patients was followed using the same methodology until 12 weeks of treatment. A lack of response by weeks 4 and 6 predicted a final lack of response both at weeks 8 and 12 of treatment. Alternatively, a robust response as early as week 2 predicted a good response by the end of the two treatment periods. These findings should help clinicians revalorate treatment when finding no response after 4 or 6 weeks of treatment.

Personality and clinical predictors of recurrence of depression.

OBJECTIVE: To help clinicians more accurately predict outcomes of treatment for depression, variables associated with recurrence of depression in the year after treatment were examined in a group of patients who completed treatment for an index episode of depression. METHODS: Forty-two depressed patients who participated in a double-blind pharmacological treatment study were followed for one year after treatment was discontinued. Length of treatment for the index episode was determined by clinicians and ranged from eight to 76 consecutive weeks. Eighteen patients who had a recurrent episode (43 percent) and 24 patients who did not (57 percent) were compared on sociodemographic and clinical variables, including scores on the Eysenck Personality Questionnaire (EPQ). RESULTS: A combination of three variables predicted recurrence of depression in 90 percent of cases. They were an elevated EPQ score on the neuroticism subscale, a short duration of treatment of the index episode, and a slow onset of response to treatment of the index episode. CONCLUSIONS: The findings suggest that personality traits, treatment duration, and variations in response to treatment might have an impact on long-term treatment outcome. Clinicians should consider these factors when making treatment decisions for depressed patients.

A 3-year follow-up of a group of treatment-resistant depressed patients with a MAOI/tricyclic combination.

Treatment-resistant depression is a clinical complication that not infrequently affects a certain number of patients. Within the treatment strategies proposed for this condition, the association of a MAO inhibitor (MAOI) with a tricyclic antidepressant has gained reputation both for its unusual efficacy, as for its potential toxicity. However, when cautions are taken, it may be safely administered. Most reports on this combination have been carried in nonresistant patients and, when resistant patients are included, only the acute phase of the treatment is reported. In this study, a group of well-defined resistant patients received an open trial with the association of isocarboxazide and amitryptiline (n = 25). Those who responded were followed during the next 3 years (n = 12) and every 6 months an attempt was made to discontinue the MAOI and continue only with amitryptiline. At the end of the study, 4 patients maintained response with single medication, 6 still required both drugs and 2 relapsed. No clinical differences were apparent between the outcome groups, except that those who maintained their response only with the 2 combined drugs had more previous depressive episodes than the others. The isocarboxazide/amitryptiline combination may be a good treatment option for at least some forms of resistant depression. The safety of this treatment modality is confirmed, even when given for long periods of time. The study also suggest that there are no clinical characteristics in resistant depression that may predict the treatment outcome but, perhaps in some patients, a combined treatment is required to obtain a broader biochemical effect that could convert them from nonresponders to responders.

Efficacy of S-adenosyl-L-methionine in speeding the onset of action of imipramine.

A double-blind clinical trial was carried out to evaluate the efficacy of S-adenosyl-L-methionine (SAMe) in speeding the onset of action of imipramine (IMI). SAMe is a naturally occurring substance that has been shown to possess antidepressant activity with a rapid mode of onset and minimal side effects. Sixty-three outpatients with moderate to severe depression were included in the study. After an initial 1-week placebo period, only 40 patients entered the active treatment phase. During the first 2 weeks of the trial, half of these patients received 200 mg/day of SAMe intramuscularly, while the other half received placebo. Simultaneously, oral IMI was administered to all patients at a fixed dose of 150 mg/day. The onset of clinical response was determined by evaluating patients every second day. By the end of week 2, the parenteral treatment was suppressed and IMI was adjusted according to individual needs. Depressive symptoms decreased earlier in the patients who were receiving the SAMe-IMI combination than in those who were receiving the placebo-IMI combination.

Mania induced by tricyclic-MAOI combination therapy in bipolar treatment-resistant disorder: case reports.

Three patients with bipolar disorder developed manic symptoms while receiving a combination of isocarboxazid and amitriptyline during an episode of major depression refractory to previous treatments. It is suggested that mania be considered a possible complication of combined treatment with an MAO inhibitor and a tricyclic antidepressant.

[In search of biological markers of affective disorders]. / En busca de marcadores biológicos de trastornos afectivos.

The field of biological markers of affective disorders is defined on its conceptual and methodological basis, and the results of some studies in this area conducted at the Mexican Institute of Psychiatry are reported. Urinary MHPG levels greater than 2800 micrograms/24 hs, suggest a poor response to conventional drug treatment. Allnight EEG recordings, showed that sleep architecture of depressed patients is substantially different from that of normal subjects; particularly REM sleep latency, which can reliably discriminate between patients and controls. The dexamethasone suppression test showed a diagnostic confidence of 77% which is similar to that reported from other centers. The author suggests caution on interpreting these results, as further prospective longitudinal studies are needed before firm conclusions can be drawn.

En busca de marcadores biológicos de trastornos afectivos. / [In search of biological markers of affective disorders]

The field of biological markers of affective disorders is defined on its conceptual and methodological basis, and the results of some studies in this area conducted at the Mexican Institute of Psychiatry are reported. Urinary MHPG levels greater than 2800 micrograms/24 hs, suggest a poor response to conventional drug treatment. Allnight EEG recordings, showed that sleep architecture of depressed patients is substantially different from that of normal subjects; particularly REM sleep latency, which can reliably discriminate between patients and controls. The dexamethasone suppression test showed a diagnostic confidence of 77

which is similar to that reported from other centers. The author suggests caution on interpreting these results, as further prospective longitudinal studies are needed before firm conclusions can be drawn.