Is neurotrophin-3 (NT-3): a potential therapeutic target for depression and anxiety?

Introduction: Neurotrophin-3 (NT-3) is thought to play a role in the neurobiological processes implicated in mood and anxiety disorders. NT-3 is a potential pharmacological target for mood disorders because of its effects on monoamine neurotransmitters, regulation of synaptic plasticity and neurogenesis, brain-derived neurotrophic factor (BDNF) signaling boosting, and modulation of the hypothalamic-pituitary-adrenal (HPA) axis. The mechanisms underlying NT-3 anxiolytic properties are less clear and require further exploration and definition. Areas covered: The evidence that supports NT-3 as a pharmacological target for anxiety and mood disorders is presented and this is followed by a reflection on the quandaries, stumbling blocks, and future perspectives for this novel target. Expert opinion: There is evidence for miRNAs being key post-transcriptional regulators of neurotrophin-3 receptor gene (NTRK3) in anxiety disorders; however, the anxiolytic properties of NT-3 need further examination and delineation. Moreover, NT-3 expression by non-neuronal cells and its role in brain circuits that participate in anxiety and mood disorders require further scrutiny. Further work is vital before progression into clinical trials can be realized.

Histoplasmosis, an underdiagnosed disease affecting people living with HIV/AIDS in Brazil: Results of a multicenter prospective cohort study using both classical mycology tests and histoplasma urine antigen detection

BACKGROUND: Histoplasmosis is highly endemic in the American continent. This condition is associated with a high mortality, particularly in people living with HIV/AIDS (PLWHA). Diagnosis of histoplasmosis is usually late in South America, as Histoplasma antigen detection is rarely available. Here we determined the prevalence, risk factors, and outcome of histoplasmosis in PLWHA in Brazilian hospitals. METHODS: This was a prospective cohort study (2016­2018) involving 14 tertiary medical centers in Brazil. We included hospitalized PLWHA presenting with fever and additional clinical findings. Patients were investigated at each participant center with classical mycology methods. Also, Histoplasma antigen detection was performed in urine samples (IMMY). Probable/proven histoplasmosis was defined according to European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group/National Institute of Allergy and Infectious Diseases Mycoses Study Group criteria. RESULTS: From 616 eligible patients, 570 were included. Histoplasmosis was identified in 21.6% (123/570) of patients. Urine antigen testing increased the diagnostic yield in 53.8%, in comparison with standard mycology methods. Variables independently associated with histoplasmosis were CD4+ count <50 cells/mm3, use of an antiretroviral (protective effect), and sample collection in the Northeast region of Brazil. Dyspnea at presentation was independently associated with death. Histoplasmosis was more frequent than tuberculosis in patients with low CD4+ counts. Overall 30-day mortality was 22.1%, decreasing to 14.3% in patients with antigen-based diagnosis. CONCLUSIONS: Histoplasmosis is a very frequent condition affecting PLWHA in Brazil, particularly when CD4+ counts are lower than 50 cells/mm3. Antigen detection may detect earlier disease, with a probable impact on outcomes. Access to this diagnostic tool is needed to improve clinical management of PLWHA in endemic countries

Evidence for the contribution of adult neurogenesis and hippocampal cell death in experimental cerebral malaria cognitive outcome.

Cognitive dysfunction is a major sign of cerebral malaria (CM). However, the underlying mechanisms of CM cognitive outcome remain poorly understood. A body of evidence suggests that adult neurogenesis may play a role in learning and memory processes. It has also been reported that these phenomena can be regulated by the immune system. We hypothesized that memory dysfunction in CM results from hippocampal neurogenesis impairment mediated by the deregulated immune response during the acute phase of CM. C57Bl/6 mice were infected with Plasmodium berghei ANKA (PbA) strain, using a standardized inoculation of 10(6) parasitized erythrocytes. Long-term working memory was evaluated using the novel object recognition test. The mRNA expression of brain-derived neurotrophic factor (BDNF), tropomyosin-receptor-kinase (TRK-B) and nerve growth factor (NGF) in the frontal cortex and hippocampus was estimated by real-time polymerase chain reaction (PCR). The protein levels of cytokine interleukin-2 (IL-2), IL-4, IL-6, IL-10, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and CCL11 and neurotrophins BDNF and NGF were determined using a cytometric bead array (CBA) kit or enzyme-linked immunosorbent assay. Cell viability in the hippocampus was analyzed by Confocal Microscopy. Neurogenesis in the dentate gyrus was determined through quantification of doublecortin (DCX) positive cells. PbA-infected mice presented working memory impairment on day 5 post-infection. At this same time point, CM mice exhibited a decrease in DCX-positive cells in the dentate gyrus in parallel with increased cell death and elevated inflammatory cytokines (IL-6, TNF-α, IFN-γ and CCL11) in the hippocampus and frontal cortex. A significant reduction of BDNF mRNA expression was also found. IL-6 and TNF-α correlated negatively with BDNF and NGF levels in the hippocampus of CM mice. In summary, we provide further evidence that neuroinflammation following PbA-infection influences neurotrophin expression, impairs adult hippocampal neurogenesis and increases hippocampal cell death in association with memory impairment following CM course. The current study identified potential mediators of memory impairment in CM.

Clinical trial: a nutritional supplement Viusid, in combination with diet and exercise, in patients with nonalcoholic fatty liver disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a significant health problem for which there is no universally accepted pharmacological treatment. The combination of weight loss and antioxidant drugs to ameliorate insulin resistance and improve steatosis, inflammation and fibrosis provides the rational for therapeutic trials. AIM: To evaluate the efficacy and safety of a nutritional supplement Viusid in association with diet and exercise for NAFLD. METHODS: A randomized, controlled and parallel-group trial was conducted at a tertiary care academic centre (National Institute of Gastroenterology, Havana, Cuba). We randomly assigned 60 patients with liver biopsy-proven NAFLD to 6 months of treatment with a hypocaloric diet plus aerobic exercise daily and three Viusid sachets daily or a hypocaloric diet and exercise. Endpoints were improvement in the NAFLD activity score (NAS), fibrosis and normalization of serum aminotransferase levels. RESULTS: A significant improvement in steatosis, necroinflammation and fibrosis was seen in each group of treatment (P < 0.01 for each feature). The Viusid group, as compared with the control group, significantly reduced the mean of NAS [from 4.18 to 0.54 points in the Viusid group vs. 4.45 to 2.2 points in the control group (P < 0.001)]. On between-group comparison, Viusid was found to be associated with a significantly greater improvement in steatosis (P < 0.001), ballooning (P = 0.002) and lobular inflammation (P = 0.025), but not in fibrosis (P = 0.07). Viusid was well tolerated. CONCLUSIONS: Our results indicate that treatment with diet and exercise leads to a notable improvement in the histological features of NAFLD; however, the administration of Viusid intensifies the improvements of histological findings, especially of steatosis and inflammation.

[Influence of hyponutrition on occurrence of complications and mortality among cirrhosis patients]. / Influencia de la desnutrición en la aparición de complicaciones y mortalidad en pacientes cirróticos.

Nutrient Energy Malnutrition (NEM) is a common feature among liver cirrhosis (LC) patients, and might constitute a negative predictor of patient's survival. A prospective descriptive study was carried out in order to assess the influence of LC patient's nutritional status on the occurrence of complications and mortality in a tertiary care health institution in Havana City (Cuba). One-hundred twenty-one patients were recruited for the study (Women: 52.9%; Younger than 60 years: 59.0%; Whites: 90.0%). C virus infection, alcoholism, and B virus infection accounted for 71.0% of LC cases. Ninety-two percents of the patients had less than 5 yearse of diagnosis. Subjective Global Assessment (SGA) of nutritional status returned a 45.0% of malnutrition. Malnutrition was associated with disease progression: twenty-one percent of A Child-Pugh Stage patients was malnourished, but this rate increased to become 90.0% among those in C stage. Fat and skeletal muscle compartments were reduced in 36.0 and 37.0% of the patients, respectively. Complications affected 44.6% of the patients. Sixty percent of them were malnourished (p <0.01). One-year mortality rate was 11.0%. Ninety-two percent of deceased patients were malnourished (p < 0.01). LC malnourished patients have greater risk of complications and death as compared to well-nourished ones.

Influencia de la desnutrición en la aparición de complicaciones y mortalidad en pacientes cirróticos / Influence of hyponutrition on ocurrence of complications and mortality among cirrhosis patients

La Desnutrición Energética Nutrimental (DEN) es una manifestación muy frecuente entre los pacientes con Cirrosis Hepática (CH), y puede constituir un predictor negativo para la supervivencia de los mismos. Se realizó un estudio descriptivo prospectivo para identificar la influencia del estado nutricional de los pacientes con CH en la aparición de complicaciones y mortalidad en una institución terciaria de salud de La Habana (Cuba). Se reclutaron 121 pacientes cirróticos (mujeres: 52,9por ciento; menor de 60 años: 59,0 por ciento; piel blanca: 90,0 por ciento). La infección por virus C, el alcoholismo, y la infección por virus B representarion el 71,0 por ciento de los casos de CH. El 92 por ciento de los enfermos tenían menos de 5 años de diagnosticados. La Evaluación Subjetiva Global (ESG) del estado nutricional arrojó un 45,o por ciento de desnutrición. La desnutrición es proporcional al estadio de progresión de la enfermedad: el 21,0 por ciento de los cirróticos en estadio A (Child-Pugh) estaba desnutrido, pero esta frecuencia llegó a ser del 90,0% entre aquellos en el estadio C. Los compartimentos graso y muscular estaban disminuidos en el 36,0 y 37,0por ciento de los pacientes, respectivamente. El 44,6 por ciento de los pacientes se complicaron durante el periodo de observación. El 60,0por ciento de los enfermos que se complicaron estaba desnutrido (p < 0,01). La mortalidad-al-año fue del 11,0por ciento. El 92,0 por ciento de los fallecidos estaba desnutrido (p < 0,01). Los pacientes con CH desnutridos tienen mayor riesgo de complicaciones y muerte que los no desnutridos(AU)

Nutrient Energy Malnutrition (NEM) is a common feature among liver cirrhosis (LC) patients, and might constitute a negative predictor of patient's survival. A prospective descriptive study was carried out in order to assess the influence of LC patient's nutritional status on the occurrence of complications and mortality in a tertiary care health institution in Havana City (Cuba). One-hundred twenty-one patients were recruited for the study (Women: 52,9 percent; Younger than 60 years: 59,0percent; Whites: 90,0 percent). C virus infection, alcoholism, and B virus infection accounted for 71,0percent of LC cases. Ninety-two percents of the patients had less than 5 yearse of diagnosis. Subjective Global Assessment (SGA) of nutritional status returned a 45,0percent of malnutrition. Malnutrition was associated with disease progression: twenty-one percent of A Child-Pugh Stage patients was malnourished, but this rate increased to become 90,0 percent among those in C stage. Fat and skeletal muscle compartments were reduced in 36,0 and 37,0percent of the patients, respectively. Complications affected 44,6 percent of the patients. Sixty percent of them were malnourished (p < 0,01). One-year mortality rate was 11,0percent. Ninety-two percent of deceased patients were malnourished (p < 0,01). LC malnourished patients have greater risk of complications and death as compared to well-nourished ones(AU)

Influencia de la desnutrición en la aparición de complicaciones y mortalidad en pacientes cirróticos / Influence of hyponutrition on occurrence of complications and mortality among cirrhosis patients

La Desnutrición Energética Nutrimental (DEN) es una manifestación muy frecuente entre los pacientes con Cirrosis Hepática (CH), y puede constituir un predictor negativo para la supervivencia de los mismos. Se realizó un estudio descriptivo prospectivo para identificar la influencia del estado nutricional de los pacientes con CH en la aparición de complicaciones y mortalidad en una institución terciaria de salud de La Habana (Cuba). Se reclutaron 121 pacientes cirróticos (mujeres: 52,9%; menor de 60 años: 59,0%; piel blanca: 90,0%). La infección por virus C, el alcoholismo, y la infección por virus B representaron el 71,0% de los casos de CH. El 92% de los enfermos tenían menos de 5 años de diagnosticados. La Evaluación Subjetiva Global (ESG) del estado nutricional arrojó un 45,o% de desnutrición. La desnutrición es proporcional al estadio de progresión de la enfermedad: el 21,0% de los cirróticos en estadio A (Child-Pugh) estaba desnutrido, pero esta frecuencia llegó a ser del 90,0% entre aquellos en el estadio C. Los compartimentos graso y muscular estaban disminuidos en el 36,0 y 37,0% de los pacientes, respectivamente. El 44,6% de los pacientes se complicaron durante el periodo de observación. El 60,0% de los enfermos que se complicaron estaba desnutrido (p < 0,01). La mortalidad-al-año fue del 11,0%. El 92,0% de los fallecidos estaba desnutrido (p < 0,01). Los pacientes con CH desnutridos tienen mayor riesgo de complicaciones y muerte que los no desnutridos (AU)

Nutrient Energy Malnutrition (NEM) is a common feature among liver cirrhosis (LC) patients, and might constitute a negative predictor of patient's survival. A prospective descriptive study was carried out in order to assess the influence of LC patient's nutritional status on the occurrence of complications and mortality in a tertiary care health institution in Havana City (Cuba). One-hundred twenty-one patients were recruited for the study (Women: 52,9%; Younger than 60 years: 59,0%; Whites: 90,0%). C virus infection, alcoholism, and B virus infection accounted for 71,0% of LC cases. Ninety-two percents of the patients had less than 5 years of diagnosis. Subjective Global Assessment (SGA) of nutritional status returned a 45,0% of malnutrition. Malnutrition was associated with disease progression: twenty-one percent of A Child-Pugh Stage patients was malnourished, but this rate increased to become 90,0% among those in C stage. Fat and skeletal muscle compartments were reduced in 36,0 and 37,0% of the patients, respectively. Complications affected 44,6% of the patients. Sixty percent of them were malnourished (p < 0,01). One-year mortality rate was 11,0%. Ninety-two percent of deceased patients were malnourished (p < 0,01). LC malnourished patients have greater risk of complications and death as compared to well-nourished ones (AU)

Anti-inflammatory and antinociceptive activities of an acid fraction of the seeds of Carpotroche brasiliensis (Raddi) (Flacourtiaceae).

Carpotroche brasiliensis is a native Brazilian tree belonging to the Oncobeae tribe of Flacourtiaceae. The oil extracted from its seeds contains as major constituents the same cyclopentenyl fatty acids hydnocarpic (40.5%), chaulmoogric (14.0%) and gorlic (16.1%) acids found in the better known chaulmoogra oil prepared from the seeds of various species of Hydnocarpus (Flacourtiaceae). These acids are known to be related to the pharmacological activities of these plants and to their use as anti-leprotic agents. Although C. brasiliensis oil has been used in the treatment of leprosy, a disease that elicits inflammatory responses, the anti-inflammatory and analgesic activities of the oil and its constituents have never been characterized. We describe the anti-inflammatory and antinociceptive activities of C. brasiliensis seed oil in acute and chronic models of inflammation and in peripheral and central nociception. The mixture of acids from C. brasiliensis administered orally by gavage showed dose-dependent (10-500 mg/kg) anti-inflammatory activity in carrageenan-induced rat paw edema, inhibiting both the edema by 30-40% and the associated hyperalgesia. The acid fraction (200 mg/kg) also showed significant antinociceptive activity in acetic acid-induced constrictions (57% inhibition) and formalin-induced pain (55% inhibition of the second phase) in Swiss mice. No effects were observed in the hot-plate (100 mg/kg; N = 10), rota-road (200 mg/kg; N = 9) or adjuvant-induced arthritis (50 mg/kg daily for 7 days; N = 5) tests, the latter a chronic model of inflammation. The acid fraction of the seeds of C. brasiliensis which contains cyclopentenyl fatty acids is now shown to have significant oral anti-inflammatory and peripheral antinociceptive effects.

Synthesis and pharmacological evaluation of novel heterotricyclic acylhydrazone derivatives, designed as PAF antagonists.

This paper describes the synthesis and the antiplatelet properties of new heterotricyclic N-acylhydrazone derivatives (7a-e), structurally analogous to known hetrazepinic PAF antagonists, exploring molecular hybridization as a tool for molecular designing. The synthetic route employed to access compounds (7a-e) used, as starting material, the previously described methyl 3-hydroxy-8-methyl-6-phenyl-6H-pyrazolo[3,4-b]thieno[2, 3-d]pyridine-2-carboxylate derivative. The results from inhibitory effects of these novel acylhydrazone derivatives (7a-e) upon PAF-induced platelet aggregation, indicated that all compounds present a significant antithrombotic profile.

Hepatitis B and hepatitis C prevalence among blood donors and HIV-1 infected patients in Florianópolis--Brazil.

Information is scarce on the prevalence of hepatitis B (HBV) and hepatitis C (HCV) among voluntary blood donors and patients infected with the human immunodeficiency virus (HIV) in Florianópolis, Brazil. A total of 2,678 serum samples from 2,583 blood donors and 95 HIV-infected patients, collected between April, 1994, and March, 1995, were examined for markers of HBV and HCV. All the samples were analyzed to detect HBV and HCV markers (HBsAg, anti-HBc, and anti-HCV). Hepatitis B and C prevalence among the studied blood donors reached 9.3% and 1.0%, respectively; 0.7% being seropositive for HBsAg and 9.2% for anti-HBc. It was also verified that 0.1% of blood donors were seropositive for HBsAg alone, 8.6% seropositive for the anti-HBc alone, and 0.6% presented a positive reaction for both of the HBV markers studied. Among HIV-infected patients, prevalence of 69.5% and 54.7% for hepatitis B and hepatitis C, respectively, were observed. Of these patients, 18.9% were seropositive for HBsAg, and 66.3% for the anti-HBc. The prevalence of a reaction for HBsAg alone, and for anti-HBc alone was 3.1% and 50.5%, respectively, for HIV-infected patients, whereas 15.8% were seropositive for both of the studied markers. HBV and HCV coinfection was 0.1% in blood donors, and 40% of those patients tested seropositive for HIV. Results show prevalence of HBV and HCV infection to be significantly greater among HIV-infected patients than among blood donors. These observations confirm the high frequency of HIV-infected patients exposure to these other viruses.

Anti-inflammatory and analgesic activities of the latex containing triterpenes from Himatanthus sucuuba.

Some triterpenes and iridoids were previously isolated from the stem bark of Himatanthus sucuuba. The latex from Himatanthus sucuuba is used in popular amazonian medicine as an anti-inflammatory remedy. Fractions of the latex were pharmacologically evaluated with a view to verify this popular use in the carrageenan-induced rat paw edema and in the acetic acid-induced mouse constriction tests. The hexane fraction inhibited the edema formation by 35.9% at a dose of 200 mg/kg (p.o.) but no activity was observed at 100 mg/kg (p.o.). The triterpenes present in the hexane fraction were identified as lupeol acetate, alpha-amyrin and lupeol cinnamates. The fraction containing only cinnamates inhibited the edema and the abdominal constrictions by 50-40% and 57.9%, respectively, at 100 mg/kg (p.o.). Among all the fractions studied, the fraction containing only cinnamates showed the greatest anti-inflammatory activity which suggests that these compounds were responsible for the previously described activity of the crude extract.

Synthesis and analgesic activity of novel N-acylarylhydrazones and isosters, derived from natural safrole.

Anew series of antinociceptive compounds belonging to the N-acylarylhydrazone (NAH) class were synthesized from natural safrole (7). The most analgesic derivative represented by 10f, [(4'-N,N-dimethylaminobenzylidene-3-(3', 4'-methylenedioxyphenyl)propionylhydrazine], was more potent than dipyrone and indomethacin, used as standards. The NAH compounds described herein were structurally planned by molecular hybridization and classical bioisosterism strategies on previously reported analgesic NAH in order to identify the pharmacophoric contribution of the N-acylarylhydrazone moiety and investigate the structure-activity relationship (SAR) in these series.

Gene expression, amino acid conservation, and hydrophobicity are the main factors shaping codon preferences in Mycobacterium tuberculosis and Mycobacterium leprae.

Mycobacterium tuberculosis and Mycobacterium leprae are the ethiological agents of tuberculosis and leprosy, respectively. After performing extensive comparisons between genes from these two GC-rich bacterial species, we were able to construct a set of 275 homologous genes. Since these two bacterial species also have a very low growth rate, translational selection could not be so determinant in their codon preferences as it is in other fast-growing bacteria. Indeed, principal-components analysis of codon usage from this set of homologous genes revealed that the codon choices in M. tuberculosis and M. leprae are correlated not only with compositional constraints and translational selection, but also with the degree of amino acid conservation and the hydrophobicity of the encoded proteins. Finally, significant correlations were found between GC3 and synonymous distances as well as between synonymous and nonsynonymous distances.

Use of PCR-restriction fragment length polymorphism analysis of the hsp65 gene for rapid identification of mycobacteria in Brazil.

Polymerase chain reaction amplification of part of the gene coding for the heat shock protein hsp65 followed by restriction enzyme analysis (PRA) is a recently described tool for rapid identification of mycobacteria. In this study, the speed and simplicity of PRA for identification of isolates of mycobacteria from patients with clinical symptoms of tuberculosis was evaluated and compared with identification results obtained by commercially available methods. Established PRA patterns were observed for nineteen isolates of Mycobacterium tuberculosis, eleven belonging to the complex M. avium-intracellulare, four of M. kansasii, one of M. fortuitum, one of M. abscessus, three of M. gordonae and one of the recently described species M. lentiflavum, as identified by commercially available methods. Two isolates of M. fortuitum and one of M. gordonae had unique and so far undescribed PRA patterns, suggesting geographically-related intra-species variation within the hsp65 sequence. We propose the inclusion of these new patterns in the PRA identification algorithm and have defined more accurately the molecular weight values of the restriction fragments. This is the first report on the isolation of M. lentiflavum in Brazil suggesting that identification by means of PRA could be useful for detection of mycobacterial species that are usually unnoticed. Where the use of several commercial techniques in combination was necessary for correct identification, PRA demonstrated to be a simple technique with good cost-benefit for characterization of all mycobacterial isolates in this study.

Synthesis and pharmacological evaluation of a new class of bicyclic phospholipids, designed as platelet activating factor antagonists.

(+/-)-3-Alkoxymethyl-(2-oxabicyclo[3.3.0]octane)-5-yl-methyl-phosp horyl- ethyl-pyridinium [alkyl chain = methyl (5a) and (5b), allyl (6a) and (6b), n-propyl (7a) and (7b) and n-hexyl (8a) and (8b)] derivatives, structurally designed as conformationally restricted platelet activating factor (PAF) antagonists were synthesized in 12-26% overall yield, using ethyl (+/-)-3-hydroxymethyl-5-(2-oxabicyclo [3.3.0] octane) carboxylate (13a,b) as key intermediate. The anti-platelet profile of the new derivatives was evaluated in a PAF-induced aggregation model in rabbit platelet-rich plasma; only compound 8a exhibited a modest activity.

TcruziDB, an integrated database, and the WWW information server for the Trypanosoma cruzi genome project.

Data analysis, presentation and distribution is of utmost importance to a genome project. A public domain software, ACeDB, has been chosen as the common basis for parasite genome databases, and a first release of TcruziDB, the Trypanosoma cruzi genome database, is available by ftp from ftp://iris.dbbm.fiocruz.br/pub/genomedb/Tcr uziDB as well as versions of the software for different operating systems (ftp://iris.dbbm.fiocruz.br/pub/unixsoft/). Moreover, data originated from the project are available from the WWW server at http://www.dbbm.fiocruz.br. It contains biological and parasitological data on CL Brener, its karyotype, all available T. cruzi sequences from Genbank, data on the EST-sequencing project and on available libraries, a T. cruzi codon table and a listing of activities and participating groups in the genome project, as well as meeting reports. T. cruzi discussion lists (tcruzil@iris.dbbm.fiocruz.br and tcgenics@iris.dbbm.fiocruz.br) are being maintained for communication and to promote collaboration in the genome project.