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Background: Adherence to anti-tuberculosis treatment (ATT) in Brazil remains a challenge in achieving the goals set by the World Health Organization (WHO). Patients who are lost to follow-up during treatment pose a significant public health problem. This study aimed to investigate the factors associated with unfavorable ATT outcomes among those undergoing retreatment in Brazil. Methods: We conducted an observational study of patients aged ≥18 years with tuberculosis (TB) reported to the Brazilian National Notifiable Disease Information System between 2015 and 2022. Clinical and epidemiologic variables were compared between the study groups (new cases and retreatment). Regression models identified variables associated with unfavorable outcomes. Results: Among 743 823 reported TB cases in the study period, 555 632 cases were eligible, consisting of 462 061 new cases and 93 571 undergoing retreatments (44 642 recurrent and 48 929 retreatments after loss to follow-up [RLTFU]). RLTFU (odds ratio [OR], 3.96 [95% confidence interval {CI}, 3.83-4.1]) was a significant risk factor for any type of unfavorable ATT. Furthermore, RLTFU (OR, 4.93 [95% CI, 4.76-5.11]) was the main risk factor for subsequent LTFU. For death, aside from advanced age, living with HIV (OR, 6.28 [95% CI, 6.03-6.54]) was the top risk factor. Conclusions: Retreatment is a substantial risk factor for unfavorable ATT outcomes, especially after LTFU. The rates of treatment success in RLTFU are distant from the WHO End TB Strategy targets throughout Brazil. These findings underscore the need for targeted interventions to improve treatment adherence and outcomes in persons who experience RLTFU.
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Background: The increased risk of tuberculosis (TB) among people deprived of liberty (PDL) is due to individual and institution-level factors. We followed a cohort of PDL from 5 prisons in Paraguay to describe the risk of TB during incarceration and after they were released. Methods: We linked a 2013 national census of prisons with TB records from the TB Program from 2010 to 2021 to identify TB notifications among incarcerated and formerly incarcerated individuals. We used multivariable Cox regression models to quantify the risk of TB during and following incarceration and to identify risk factors associated with TB. Findings: Among 2996 individuals incarcerated, 451 (15.1%) were diagnosed with TB. Of these, 262 (58.1%) cases occurred during incarceration and 189 (41.9%) occurred in the community after release. In prison, the hazard ratio of developing TB was 1.97 (95% CI: 1.52-2.61) after six months of incarceration and increased to 2.78 (95% CI: 1.82-4.24) after 36 months compared with the first six months. The overall TB notification rate was 2940 per 100,000 person-years. This rate increased with the duration of incarceration from 1335 per 100,000 person-years in the first year to 8455 per 100,000 person-years after 8 years. Among former prisoners, the rate of TB decreased from 1717 in the first year after release to 593 per 100 000 person-years after 8 years of follow up. Interpretation: Our study shows the alarming risk of TB associated with prison environments in Paraguay, and how this risk persists for years following incarceration. Effective TB control measures to protect the health of people during and following incarceration are urgently needed. Funding: Paraguay National Commission of Science and Technology grant CONACYT PIN 15-705 (GS, GES, SA).
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BACKGROUND: An active search for tuberculosis cases through mass screening is widely described as a tool to improve case detection in hyperendemic settings. However, its effectiveness in high-risk populations, such as incarcerated people, is debated. METHODS: Between 2017 and 2021, 3 rounds of mass screening were carried out in 3 Brazilian prisons. Social and health questionnaires, chest X-rays, and Xpert MTB/RIF were performed. RESULTS: More than 80% of the prison population was screened. Overall, 684 cases of pulmonary tuberculosis were diagnosed. Prevalence across screening rounds was not statistically different. Among incarcerated persons with symptoms, the overall prevalence of tuberculosis per 100 000 persons was 8497 (95% confidence interval [CI], 7346-9811), 11 115 (95% CI, 9471-13 082), and 7957 (95% CI, 6380-9882) in screening rounds 1, 2, and 3, respectively. Similar to our overall results, there were no statistical differences between screening rounds and within individual prisons. We found no statistical differences in Computer-Aided Detection for TB version 5 scores across screening rounds among people with tuberculosis-the median scores in rounds 1, 2, and 3 were 82 (interquartile range [IQR], 63-97), 77 (IQR, 60-94), and 81 (IQR, 67-92), respectively. CONCLUSIONS: In this environment with hyperendemic rates of tuberculosis, 3 rounds of mass screening did not reduce the overall tuberculosis burden. In prisons, where a substantial number of tuberculosis cases is undiagnosed annually, a range of complementary interventions and more frequent tuberculosis cases screening may be required.
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Programas de Rastreamento , Prisioneiros , Prisões , Tuberculose Pulmonar , Humanos , Brasil/epidemiologia , Prisioneiros/estatística & dados numéricos , Programas de Rastreamento/métodos , Masculino , Adulto , Feminino , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/epidemiologia , Prevalência , Pessoa de Meia-Idade , Prisões/estatística & dados numéricos , Adulto Jovem , Mycobacterium tuberculosis/isolamento & purificação , Tuberculose/diagnóstico , Tuberculose/epidemiologiaRESUMO
Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder without a cure, despite the enormous number of investigations and therapeutic approaches. AD is a consequence of microglial responses to "damage signals", such as aggregated tau oligomers, which trigger a neuro-inflammatory reaction, promoting the misfolding of cytoskeleton structure. Since AD is the most prevalent cause of dementia in the elderly (>60 years old), new treatments are essential to improve the well-being of affected subjects. The pharmaceutical industry has not developed new drugs with efficacy for controlling AD. In this context, major attention has been given to nutraceuticals and novel bioactive compounds, such as molecules from the Andean Shilajit (AnSh), obtained from the Andes of Chile. Primary cultures of rat hippocampal neurons and mouse neuroblastoma cells were evaluated to examine the functional and neuroprotective role of different AnSh fractions. Our findings show that AnSh fractions increase the number and length of neuronal processes at a differential dose. All fractions were viable in neurons. The AnSh fractions inhibit tau self-aggregation after 10 days of treatment. Finally, we identified two candidate molecules in M3 fractions assayed by UPLC/MS. Our research points to a novel AnSh-derived fraction that is helpful in AD. Intensive work toward elucidation of the molecular mechanisms is being carried out. AnSh is an alternative for AD treatment or as a coadjuvant for an effective treatment.
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The research interest of the scientific community in biofilm-forming microorganisms is growing due to the problems caused by their infections affecting humans and animals, mainly because of the difficulty of the host immune system in eradicating these microbial complex communities and the increasing antimicrobial resistance rates worldwide. This review describes the virulence factors and their interaction with the microbial communities of four well-known and highly biofilm-forming pathogens, more exactly, Pseudomonas aeruginosa, Escherichia coli, Staphylococcus spp., and Candida spp. The innate and adaptive immune responses caused by the infection with these microorganisms and their evasion to the host immune system by biofilm formation are discussed in the present work. The relevance of the differences in the expression of certain virulence factors and the immune response in biofilm-associated infections when compared to planktonic infections is usually described as the biofilm architecture protects the pathogen and alters the host immune responses, here we extensively discussed these mechanisms.
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The high prevalence of nosocomial infections is related to the use of medical insertion devices such as central venous catheters (CVCs). Most of the microorganisms causing nosocomial infections are biofilm producers, this characteristic allows them to adhere to abiotic surfaces and cause initial catheter infections that can lead to bloodstream infections. Our main goal in this systematic review was to evaluate the prevalence of biofilm among CVC-related infections, particularly among Intensive Care Unit (ICU) patients, in the studies applying different in vitro and in vivo methodologies. All studies reporting clinical isolates from patients with catheter-related nosocomial infections and biofilm evaluation published up to 24 June 2022 in the PubMed and Scopus databases were included. Twenty-five studies met the eligibility criteria and were included in this systematic review for analysis. Different methodologies were applied in the assessment of biofilm-forming microorganisms including in vitro assays, catheter-infected in vitro, and in vivo mouse models. The present study showed that between 59 and 100% of clinical isolates were able to form biofilms, and the prevalence rate of biofilm formation varied significantly between studies from different countries and regions. Among the clinical isolates collected in our study set, a wide variety of microorganisms including Gram-positive strains, Gram-negative strains, and Candida albicans were found. Many authors studied resistance mechanisms and genes related to biofilm development and surface adherence properties. In some cases, the studies also evaluated biofilm inhibition assays using various kinds of catheter coatings.
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BACKGROUND: Although systematic tuberculosis screening in high-risk groups is recommended by the World Health Organization (WHO), implementation in prisons has been limited due to resource constraints. Whether Xpert Ultra sputum pooling could be a sensitive and efficient approach to mass screening in prisons is unknown. METHODS: In total, 1280 sputum samples were collected from incarcerated individuals in Brazil during mass screening and tested using Xpert G4. We selected samples for mixing in pools of 4, 8, 12, and 16, which were then tested using Ultra. In each pool, a single positive sample of differing Xpert mycobacterial loads was used. Additionally, 10 pools of 16 negative samples each were analyzed as controls. We then simulated tuberculosis screening at prevalences of 0.5-5% and calculated the cost per tuberculosis case detected at different sputum pooling sizes. RESULTS: The sensitivity and specificity of sputum pooling were high (sensitivity: 94%; 95% confidence interval [CI]: 88-98; specificity: 100%, 95% CI: 84-100). Sensitivity was greater in pools in which the positive sample had a high mycobacterial load compared to those that were very low (100% vs 88%). In settings with a higher tuberculosis prevalence, pools of 4 and 8 were more efficient than larger pool sizes. Larger pools decreased the costs by 87% at low prevalences, whereas smaller pools led to greater cost savings at higher prevalence at higher prevalences (57%). CONCLUSIONS: Sputum pooling using Ultra was a sensitive strategy for tuberculosis screening. This approach was more efficient than individual testing across a broad range of simulated tuberculosis prevalence settings and could enable active case finding to be scaled while containing costs.
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Mycobacterium tuberculosis , Tuberculose , Humanos , Programas de Rastreamento , Mycobacterium tuberculosis/genética , Prisões , Sensibilidade e Especificidade , Escarro/microbiologia , Tuberculose/diagnóstico , Tuberculose/epidemiologiaRESUMO
A cimentação de pinos de fibra de vidro à dentina intrarradicular, principalmente no terço apical, continua sendo um desafio na odontologia. O objetivo desse estudo foi avaliar a influência do controle de umidade com etanol na resistência de união de pinos de fibra de vidro em diferentes terços de dentina intrarradicular, 24 horas e 6 meses após o processo de cimentação adesiva. Sessenta e quatro incisivos bovinos extraídos foram submetidos ao tratamento endodôntico e divididos em dois grupos, de acordo com o tipo de controle de umidade (técnica convencional e alcoólica). Cada grupo foi dividido em 4 subgrupos (n=8) de acordo com a cimentação: RXU: Single bond Universal + RelyX Ultimate; PNV: primer de dentes Panavia V5 + Panavia V5; U200: RelyX U200; SET: Set PP. A resistência de união do pushout foi medida em diferentes áreas da interface entre o pino e a superfície radicular, 24 horas e 6 meses após o procedimento de união. Os dados foram submetidos ao teste de Bonferroni (α = 0,05). Os menores valores de resistência de união foram encontrados para o grupo SET, com diferença estatisticamente significante entre os demais grupos para os terços cervical e médio. Os maiores valores de resistência de união foram encontrados para o grupo PNV com diferença estatisticamente significante para os demais grupos nos terços médio e apical em 24 horas. Avaliando os diferentes terços, em geral, os maiores valores de resistência de união foram encontrados para o terço cervical. O grupo PNV apresentou maiores valores de resistência de união para os terços cervical e médio, sem diferença estatisticamente significante entre eles. Quanto ao tipo de controle de umidade, pode-se observar que não há diferença estatisticamente significativa para o grupo PNV às 24 horas, U200 e SET aos 6 meses. Na comparação entre os tempos (24 horas e 6 meses), em geral, os valores de resistência de união diminuíram após o armazenamento. Diferenças significativas com menores valores foram observadas após o tempo de seis meses nos valores de envelhecimento para a resistência de união. Por meio de um microscópio óptico e um aparelho de microscopia eletrônica de varredura o padrão de fratura na interface adesiva foi caracterizado.
Cementation of fiberglass posts to intraradical dentin, especially in the apical third, remains a challenge in dentistry. The study was to evaluate the influence of moisture control with ethanol on the bond strength of fiberglass posts in different thirds of intraradicular dentin, 24 hours and 6 months after the adhesive cementation process. Sixty-four extracted bovine incisors were endodontically protected and divided into two groups, according to the type of moisture control (conventional and alcoholic technique). Each group was divided into 4 subgroups (n=8) according to cementation: RXU: Single bond Universal + RelyX Ultimate; PNV: Panavia V5 tooth primer + Panavia V5; U200: RelyX U200; SET: Set PP. The pushout bond strength was measured in different areas of the interface between the post and the root surface, 24 hours and 6 months after the bonding procedure. The data were confirmed by the Bonferroni test (α = 0.05). The lowest bond strength values were found for the SET group, with a statistically significant difference between the other groups for the cervical and middle thirds. The highest bond strength values were found for the PNV group, with a statistically significant difference for the other groups in the middle and apical thirds at 24 hours. Evaluating the different thirds, in general, the highest bond strength values were found for the cervical third. The PNV group showed higher bond strength values for the cervical and middle thirds, with no statistically significant difference between them. As for the type of humidity control, it can be observed that there is no statistically significant difference for the PNV group at 24 hours, U200 and SET at 6 months. In the comparison between times (24 hours and 6 months), in general, the bond strength values decreased after storage. Minor elevation differences with values were observed after the six-month time in the ageing values for bond strength. Using an optical microscope and a scanning electron microscopy device, the fracture pattern at the adhesive interface was characterized.
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Adesivos Dentinários , Cimentos Dentários , Pinos Dentários , DentinaRESUMO
BACKGROUND: Clinically-evaluated nutraceuticals are candidates for Alzheimer's disease (AD) prevention and treatment. Phase I studies showed biological safety of the nutraceutical BrainUp-10®, while a pilot trial demonstrated efficacy for treatment. Cell studies demonstrated neuroprotection. BrainUp-10® blocks tau self-assembly. Apathy is the most common of behavioral alterations. OBJECTIVE: The aim was to explore efficacy of BrainUp-10® in mitigating cognitive and behavioral symptoms and in providing life quality, in a cohort of Chilean patients with mild to moderate AD. METHODS: The was a multicenter, randomized, double blind, placebo-controlled phase II clinical study in mild to moderate AD patients treated with BrainUp-10® daily, while controls received a placebo. Primary endpoint was Apathy (AES scale), while secondary endpoints included Mini-Mental State Examination (MMSE), Trail Making Test (TMT A and TMT B), and Neuropsychiatry Index (NPI). AD blood biomarkers were analyzed. Laboratory tests were applied to all subjects. RESULTS: 82 patients were enrolled. The MMSE score improved significantly at week 24 compared to baseline with tendency to increase, which met the pre-defined superiority criteria. NPI scores improved, the same for caregiver distress at 12th week (pâ=â0.0557), and the alimentary response (pâ=â0.0333). Apathy tests showed a statistically significant decrease in group treated with BrainUp-10®, with pâ=â0.0321 at week 4 and pâ=â0.0480 at week 12 treatment. A marked decrease in homocysteine was shown with BrainUp-10® (pâ=â0.0222). CONCLUSION: Data show that BrainUp-10® produces a statistically significant improvement in apathy, ameliorating neuropsychiatric distress of patients. There were no compound-related adverse events. BrainUp-10® technology may enable patients to receive the benefits for their cognitive and behavioral problems.
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Doença de Alzheimer/tratamento farmacológico , Suplementos Nutricionais/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/psicologia , Inibidores da Colinesterase/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
In the past decade, tuberculosis incidence has declined in much of the world, but has risen in central and South America. It is not yet clear what is driving this reversal of progress in tuberculosis control. Since 2000, the incarcerated population in central and South America has grown by 206%, the greatest increase in the world. Over the same period, notified tuberculosis cases among the incarcerated population (hereinafter termed persons deprived of their liberty [PDL], following the Inter-American Commission on Human Rights) have risen by 269%. In both central and South America, the rise of disease among PDL more than offsets tuberculosis control gains in the general population. Tuberculosis is increasingly concentrated among PDL; currently, 11% of all notified tuberculosis cases in central and South America occur among PDL who comprise less than 1% of the population. The extraordinarily high risk of acquiring tuberculosis within prisons creates a health and human rights crisis for PDL that also undermines wider tuberculosis control efforts. Controlling tuberculosis in this region will require countries to take urgent measures to prioritise the health of PDL.
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Prisioneiros/estatística & dados numéricos , Tuberculose/epidemiologia , América Central/epidemiologia , Acessibilidade aos Serviços de Saúde , Humanos , Incidência , Fatores de Risco , América do Sul/epidemiologiaRESUMO
One of the major puzzles in medical research and public health systems worldwide is Alzheimer's disease (AD), reaching nowadays a prevalence near 50 million people. This is a multifactorial brain disorder characterized by progressive cognitive impairment, apathy, and mood and neuropsychiatric disorders. The main risk of AD is aging; a normal biological process associated with a continuum dynamic involving a gradual loss of people's physical capacities, but with a sound experienced view of life. Studies suggest that AD is a break from normal aging with changes in the powerful functional capacities of neurons as well as in the mechanisms of neuronal protection. In this context, an important path has been opened toward AD prevention considering that there are elements of nutrition, daily exercise, avoidance of toxic substances and drugs, an active social life, meditation, and control of stress, to achieve healthy aging. Here, we analyze the involvement of such factors and how to control environmental risk factors for a better quality of life. Prevention as well as innovative screening programs for early detection of the disease using reliable biomarkers are becoming critical to control the disease. In addition, the failure of traditional pharmacological treatments and search for new drugs has stimulated the emergence of nutraceutical compounds in the context of a "multitarget" therapy, as well as mindfulness approaches shown to be effective in the aging, and applied to the control of AD. An integrated approach involving all these preventive factors combined with novel pharmacological approaches should pave the way for the future control of the disease.
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Envelhecimento/psicologia , Doença de Alzheimer/psicologia , Doença de Alzheimer/terapia , Qualidade de Vida/psicologia , Terapia por Acupuntura/métodos , Terapia por Acupuntura/psicologia , Envelhecimento/metabolismo , Envelhecimento/patologia , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/metabolismo , Biomarcadores/metabolismo , Suplementos Nutricionais , Diagnóstico Precoce , Humanos , Medicina Tradicional Chinesa/métodos , Medicina Tradicional Chinesa/psicologia , Meditação/métodos , Meditação/psicologia , Resultado do TratamentoRESUMO
BACKGROUND: Tuberculosis (TB) is a major cause of morbidity and mortality among incarcerated populations globally. We performed mass TB screening in 3 prisons and assessed yield, efficiency, and costs associated with various screening algorithms. METHODS: Between 2017 and 2018, inmates from 3 prisons in Brazil were screened for TB by symptom assessment, chest radiography, sputum testing by Xpert MTB/RIF fourth-generation assay, and culture. Chest radiographs were scored by an automated interpretation algorithm (Computer-Aided Detection for Tuberculosis [CAD4TB]) that was locally calibrated to establish a positivity threshold. Four diagnostic algorithms were evaluated. We assessed the yield (percentage of total cases found) and efficiency (prevalence among those screened) for each algorithm. We performed unit costing to estimate the costs of each screening or diagnostic test and calculated the cost per case detected for each algorithm. RESULTS: We screened 5387 prisoners, of whom 214 (3.9%) were diagnosed with TB. Compared to other screening strategies initiated with chest radiography or symptoms, the trial of all participants with a single Xpert MTB/RIF sputum test detected 74% of all TB cases at a cost of US$249 per case diagnosed. Performing Xpert MTB/RIF screening tests only on those with symptoms had a similar cost per case diagnosed (US$255) but missed 35% more cases (73 vs 54) as screening all inmates. CONCLUSIONS: In this prospective study in 3 prisons in a high TB burden country, we found that testing all inmates with sputum Xpert MTB/RIF was a sensitive approach, while remaining cost-efficient. These results support use of Xpert MTB/RIF for mass screening in TB-endemic prisons.
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Infecções por HIV , Mycobacterium tuberculosis , Tuberculose , Algoritmos , Brasil/epidemiologia , Humanos , Programas de Rastreamento , Prisões , Estudos Prospectivos , Sensibilidade e Especificidade , Escarro , Tuberculose/diagnóstico , Tuberculose/epidemiologiaRESUMO
Incarcerated populations are at high-risk to develop tuberculosis (TB), however their impact on the population-level tuberculosis epidemic has been scarcely studied. We aimed to describe the burden and trends of TB among incarcerated populations over time in Paraguay, its clinical and epidemiological differences and the population attributable fraction. This is an observational, descriptive study including all TB cases notified to the National TB control Program in Paraguay during the period 2009-2018. We also used case registries of prisoners diagnosed with tuberculosis from the Minister of Justice. The population attributable fraction of TB in the community due to incarcerated cases was estimated through Levin's formula. The characteristics of TB cases in and outside of prison were compared as well as the characteristics of TB in prisons were modified over time. During 2009-2018, 2764 (9.7%) of the 28,534 TB reported cases in Paraguay occurred in prisons. The number of prisoners in Paraguay increased from 6258 in 2009 to 14,627 in 2018 (incarceration rate, 101 to 207 per 100,000 persons) while the number of TB cases among prisoners increased by 250% (n = 192 in 2009 versus n = 480 in 2018). The annual TB notification rate among male prisoners was 3218 and 3459 per 100,000 inmates in 2009 and 2018, respectively. The percentage of all TB cases occurring among prisoners increased from 7.1% in 2009 to 14.5% in 2018. The relative risk of TB in prisons compared to community was 70.3 (95% CI, 67.7-73.1); the overall population attributable risk was 9.5%. Among the 16 penitentiary centers in the country, two of them-Tacumbú (39.0%) and Ciudad del Este (23.3%)-represent two thirds of all TB cases in prisons. TB among inmates is predominantly concentrated in those 20-34 years old (77.3% of all), twice the percentage of cases for the same age group outside of prison. Our findings show that the TB epidemic in prisons represents one of the most important challenges for TB control in Paraguay, especially in the country's largest cities. Appropriate TB control measures among incarcerated populations are needed and may have substantial impact on the overall TB burden in the country.
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Tuberculose/economia , Doenças Transmissíveis/microbiologia , Feminino , Humanos , Masculino , Paraguai , Prisioneiros/estatística & dados numéricos , Prisões/estatística & dados numéricos , Doenças Respiratórias/microbiologiaRESUMO
In many low- and middle-income countries, tuberculosis (TB) incidence in prisons is high, exposing incarcerated populations to an elevated risk of TB infection. We conducted a randomized, double-blind, placebo-controlled trial among HIV-negative male inmates of a high TB burden prison to determine whether isoniazid given twice weekly (900 mg) for 12 months prevents TB infection. The primary outcome was QuantiFERON-TB Gold in Plus (QFT) conversion to ≥ 0.35 international units per milliliter (IU/mL) at 6 months; secondary outcomes included alternative QFT thresholds (≥ 0.7, ≥ 2.0, and ≥ 4.0 IU/mL). In total, 467 participants were randomly assigned to intervention (N = 258) or control (N = 209). In an interim analysis of participants who had completed 6 months of follow-up (N = 170), QFT conversion occurred in 20.8% (19/91) and 21.5% (17/79) of participants in intervention and control arms (efficacy: 2.9%, P = 0.91), respectively. The trial was then stopped according to the trial protocol, and the remaining participants prematurely discontinued. In an analysis of secondary outcomes, the intervention arm had significantly lower rates of conversion at a cutoff of ≥ 2.0 IU/mL (efficacy: 82.6%, P < 0.01). In conclusion, 900 mg of isoniazid, administered twice a week, did not effectively prevent QFT conversion at a cutoff point ≥ 0.35 IU/mL in a trial of QFT-negative inmates. Higher QFT cutoffs are associated with sustained conversion and greater protection. Future clinical trials that evaluate protection for latent infection should use the highest cutoff than that recommended by the manufacturer.
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Isoniazida , Tuberculose Latente/tratamento farmacológico , Prevenção Primária , Prisioneiros , Tuberculose/prevenção & controle , Adulto , Método Duplo-Cego , Humanos , Incidência , Testes de Liberação de Interferon-gama/métodos , Isoniazida/administração & dosagem , Isoniazida/uso terapêutico , Tuberculose Latente/epidemiologia , Mycobacterium tuberculosis/isolamento & purificação , Prisões/estatística & dados numéricos , Teste Tuberculínico/métodos , Adulto JovemRESUMO
BACKGROUND: A major drawback in Alzheimer's disease (AD) is the lack of validated biomarkers for routine clinical diagnostic. We have reported earlier a novel blood biomarker, named Alz-tau®, based on variants of platelet tau. This marker evaluates the ratio of high molecular weight tau (HMWtau) and the low molecular weight (LMWtau) tau. OBJECTIVE: To analyze a potential novel source of antigen for Alz-tau®, plasma tau, detected by immunoreactivity with the novel monoclonal antibody, tau51. METHODS: We evaluated tau variants in plasma precipitated with ammonium sulfate from 36 AD patients and 15 control subjects by western blot with this novel monoclonal antibody. RESULTS: The HMW/LMWtau ratio was statistically different between AD patients and controls. CONCLUSIONS: Plasma tau variants are suitable to be considered as a novel antigen source for the Alz-tau® biomarker for AD.
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Doença de Alzheimer/sangue , Doença de Alzheimer/diagnóstico , Anticorpos Monoclonais/sangue , Variação Genética/fisiologia , Proteínas tau/sangue , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Anticorpos Monoclonais/genética , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas tau/genéticaRESUMO
Several hypotheses have been postulated to explain how Alzheimer's disease is triggered, but none of them provide a unified view of its pathogenesis. The dominant hypothesis based on build-ups of the amyloid-ß peptide has been around for longer than three decades; however, up to today, numerous clinical trials based on the amyloid postulates have been attempted, but all of them have failed. Clearly, the revisited tau hypothesis provides a better explanation of the clinical observations of patients, but it needs to integrate the cumulative observations on the onset of this disease. In this context, the neuroimmuno modulation theory, based on the involvement of inflammatory events in the central nervous system, accounts for all these observations. In this review we intend to emphasize the idea that neuroinflammation is a main target for the search of new therapeutic strategies to control Alzheimer's disease. Beyond mono-targeting approaches using synthetic drugs that control only specific pathophysiological events, emerging therapeutics views based on multi targeting compounds appear to provide a new pathway for Alzheimer's disease treatment.
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Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Inflamação/metabolismo , Doença de Alzheimer/patologia , Astrócitos/metabolismo , Encéfalo/patologia , Humanos , Inflamação/patologia , Microglia/metabolismo , Neurônios/metabolismo , Proteínas tau/metabolismoRESUMO
Neurodegenerative diseases share the fact that they derive from altered proteins that undergo an unfolding process followed by formation of ß-structures and a pathological tendency to self-aggregate in neuronal cells. This is a characteristic of tau protein in Alzheimer's disease and several tauopathies associated with tau unfolding, α-synuclein in Parkinson's disease, and huntingtin in Huntington disease. Usually, the self-aggregation products are toxic to these cells, and toxicity spreads all over different brain areas. We have postulated that these protein unfolding events are the molecular alterations that trigger several neurodegenerative disorders. Most interestingly, these events occur as a result of neuroinflammatory cascades involving alterations in the cross-talks between glial cells and neurons as a consequence of the activation of microglia and astrocytes. The model we have hypothesized for Alzheimer's disease involves damage signals that promote glial activation, followed by nuclear factor NF-kß activation, synthesis, and release of proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, and IL-12 that affect neuronal receptors with an overactivation of protein kinases. These patterns of pathological events can be applied to several neurodegenerative disorders. In this context, the involvement of innate immunity seems to be a major paradigm in the pathogenesis of these diseases. This is an important element for the search for potential therapeutic approaches for all these brain disorders.
RESUMO
Introducción: Los pacientes críticamente enfermos presentan cambios fisiopatológicos que alteran las concentraciones de antibióticos betalactámicos. El objetivo fue determinar si las dosis de uso habitual en pacientes críticos alcanzan las concentraciones asociadas con mayor actividad y establecer las variables de PK/PD que se asocian con concentraciones subóptimas de antibiótico.Métodos: Estudio prospectivo realizado en una terapia intensiva de adultos en un periodo de 13 meses. Se incluyeron pacientes que recibieron cefazolina, ceftriaxona, ceftazidima o meropenem. Se realizó dosaje de concentración de antibiótico en plasma en el 50% del intervalo de dosis. Se calculó la concentración de antibiótico libre y se comparó con el objetivo 50% fT>CIM y el objetivo 50% fT>CIM x 4 para los microorganismos susceptibles definidos, según criterios del CLSI. Se comparó el grupo de pacientes que cumplió el objetivo 50% fT>CIM x 4 con el que no, en términos de variables de PK/PD.Resultados: Se incluyeron 29 determinaciones y 55 comparaciones. En el 92,7% de los casos se alcanzó el objetivo 50% fT>CIM y en el 61,8% el objetivo 50% fT>CIM x 4. En el peor escenario, es decir considerando el germen susceptible con CIM más alta, solo el 48,3% de los pacientes cumplieron el objetivo 50% fT>CIM x 4. Los pacientes que no llegaron al objetivo 50% fT>CIM x 4 tuvieron mayor RESUMENARTÍCULO ORIGINALaclaramiento renal que los que sí lo hicieron (160 vs 108,5 ml/min/1,73m2, p= 0,01). Conclusiones: un gran porcentaje de pacientes críticos que recibe betalactámicos no alcanza las metas de PK/PD recomendadas en la actualidad
Introduction: critically ill patients have physiopathological changes that upset the concentrations of beta-lactam antibiotics. The aim was to determine if the doses of usual use in critically ill patients reach the concentrations associated with maximal activity and to establish the variables of PK/PD that are associated with suboptimal concentrations of antibiotic. Methods: prospective study conducted in an intensive therapy of adults in a period of 13 months. Patients who received cefazolin, ceftriaxone, ceftazidime or meropenem were included. Dosage of antibiotic concentration in plasma was performed at 50% of the dose interval. The concentration of free antibiotic was calculated and compared with the objective 50% fT>MIC and the objective 50% fT>MIC x 4 for susceptible microorganisms, according to CLSI criteria. The group of patients who met the 50% objective fT>MIC x 4 was compared with the one who did not, in terms of PK/PD variables. Results: 29 determinations and 55 comparisons were included. The objective 50% fT>MIC was reached in 92.7% of the cases and the target 50% fT>MIC x 4 was achieved in 61.8%. In the worst scenario, that is, considering the germ susceptible with MIC higher, only 48.3% of patients met the objective 50% fT>MIC x 4. Patients who did not reach the goal 50% fT>MIC x 4 had greater renal clearance than those who reached the goal (160 vs 108.5 ml/min/1.73m2, p=0.01). Conclusions: a large percentage of critically ill patients receiving beta-lactams do not reach the PK/PD goals recommended nowadays
Assuntos
Humanos , Idoso , Idoso de 80 Anos ou mais , Farmacocinética , Coleta de Dados , Estudos Prospectivos , Estado Terminal , Ações Farmacológicas , Cuidados Críticos , beta-Lactamas/administração & dosagem , beta-Lactamas/efeitos adversos , Gestão de AntimicrobianosRESUMO
Alzheimer´s disease (AD) and related forms of dementia are increasingly affecting the aging population throughout the world, at an alarming rate. The World Alzheimer´s Report indicates a prevalence of 46.8 million people affected by AD worldwide. As population ages, this number is projected to triple by 2050 unless effective interventions are developed and implemented. Urgent efforts are required for an early detection of this disease. The ultimate goal is the identification of viable targets for the development of molecular markers and validation of their use for early diagnosis of AD that may improve treatment and the disease outcome in patients. The diagnosis of AD has been difficult to resolve since approaches for early and accurate detection and follow-up of AD patients at the clinical level have been reported only recently. Some proposed AD biomarkers include the detection of pathophysiological processes in the brain in vivo with new imaging techniques and novel PET ligands, and the determination of pathogenic proteins in cerebrospinal fluid showing anomalous levels of hyperphosphorylated tau and low Aß peptide. These biomarkers have been increasingly accepted by AD diagnostic criteria and are important tools for the design of clinical trials, but difficulties in accessibility to costly and invasive procedures have not been completely addressed in clinical settings. New biomarkers are currently being developed to allow determinations of multiple pathological processes including neuroinflammation, synaptic dysfunction, metabolic impairment, protein aggregation and neurodegeneration. Highly specific and sensitive blood biomarkers, using less-invasive procedures to detect AD, are derived from the discoveries of peripheric tau oligomers and amyloid variants in human plasma and platelets. We have also developed a blood tau biomarker that correlates with a cognitive decline and also with neuroimaging determinations of brain atrophy.
Assuntos
Doença de Alzheimer/diagnóstico , Biomarcadores/análise , HumanosRESUMO
The cyclin-dependent kinase 5 (CDK5) is known as an exceptional component of the CDK family, due to its characteristic regulatory pathways and its atypical roles in comparison to the classical cyclins. Despite its functional uniqueness, CDK5 shares a great part of its structural similarity with other members of the cyclin-dependent kinase family. After its discovery 26 years ago, a progressive set of cellular functions has been associated with this protein kinase, ranging from neuronal migration, axonal guidance, and synaptic plasticity in diverse stages of brain development, including specific and complex cognitive functions. More than 30 substrates for CDK5 have been found in different cellular pathways. Together with its essential physiological roles, a major discovery was the finding twenty years ago that CDK5 participates in neurodegenerative diseases responsible for tau hyperphosphorylations, and, as a consequence, it becomes a neurotoxic factor. This review focuses on the wide roles of CDK5 in the central nervous system, its implications in neurodegeneration, and provides an integrative insight of its involvement in pain modulation, Alzheimer's disease, and other contexts.