Development of [18F]DASA-10 for enhanced imaging of pyruvate kinase M2.

PURPOSE: The aim of this study was to develop a positron emission tomography (PET) radiotracer for measuring pyruvate kinase M2 (PKM2) with improved physicochemical and pharmacokinetic properties compared to [18F]DASA-23. EXPERIMENTAL DESIGN: First, we synthesized [18F]DASA-10 and tested its uptake and retention compared to [18F]DASA-23 in human and mouse glioma cell lines. We then confirmed the specificity of [18F]DASA-10 by transiently modulating the expression of PKM2 in DU145 and HeLa cells. Next, we determined [18F]DASA-10 pharmacokinetics in healthy nude mice using PET imaging and subsequently assessed the ability of [18F]DASA-10 versus [18F]DASA-23 to enable in vivo detection of intracranial gliomas in syngeneic C6 rat models of glioma. RESULTS: [18F]DASA-10 demonstrated excellent cellular uptake and retention with values significantly higher than [18F]DASA-23 in all cell lines and timepoints investigated. [18F]DASA-10 showed a 73 % and 65 % reduced uptake respectively in DU145 and HeLa cells treated with PKM2 siRNA as compared to control siRNA treated cells. [18F]DASA-10 showed favorable biodistribution and pharmacokinetic properties and a significantly improved tumor-to-brain ratio in rat C6 glioma models relative to [18F]DASA-23 (3.2 ± 0.8 versus 1.6 ± 0.3, p = 0.01). CONCLUSION: [18F]DASA-10 is a new PET radiotracer for molecular imaging of PKM2 with potential to overcome the prior limitations observed with [18F]DASA-23. [18F]DASA-10 shows promise for clinical translation to enable imaging of brain malignancies owing to its low background signal in the healthy brain.

PET imaging of TREM1 identifies CNS-infiltrating myeloid cells in a mouse model of multiple sclerosis.

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS) that causes substantial morbidity and diminished quality of life. Evidence highlights the central role of myeloid lineage cells in the initiation and progression of MS. However, existing imaging strategies for detecting myeloid cells in the CNS cannot distinguish between beneficial and harmful immune responses. Thus, imaging strategies that specifically identify myeloid cells and their activation states are critical for MS disease staging and monitoring of therapeutic responses. We hypothesized that positron emission tomography (PET) imaging of triggering receptor expressed on myeloid cells 1 (TREM1) could be used to monitor deleterious innate immune responses and disease progression in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. We first validated TREM1 as a specific marker of proinflammatory, CNS-infiltrating, peripheral myeloid cells in mice with EAE. We show that the 64Cu-radiolabeled TREM1 antibody-based PET tracer monitored active disease with 14- to 17-fold higher sensitivity than translocator protein 18 kDa (TSPO)-PET imaging, the established approach for detecting neuroinflammation in vivo. We illustrate the therapeutic potential of attenuating TREM1 signaling both genetically and pharmacologically in the EAE mice and show that TREM1-PET imaging detected responses to an FDA-approved MS therapy with siponimod (BAF312) in these animals. Last, we observed TREM1+ cells in clinical brain biopsy samples from two treatment-naïve patients with MS but not in healthy control brain tissue. Thus, TREM1-PET imaging has potential for aiding in the diagnosis of MS and monitoring of therapeutic responses to drug treatment.

Visions by Women in Molecular Imaging Network: Antiracism and Allyship in Action.

Recent events in America in 2020 have stimulated a worldwide movement to dismantle anti-Black racism in all facets of our lives. Anti-Black racism is, as defined by the Movement for Black Lives, a "term used to specifically describe the unique discrimination, violence, and harm imposed on and impacting Black people specifically." In science, technology, engineering, and mathematics (STEM), we have yet to achieve the goal and responsibility to ensure that the field reflects the diversity of our lived experiences. Members of the Women in Molecular Imaging Network (WIMIN) have come together to take a stand on diversity, equity, and inclusion in the field of molecular imaging. We strongly condemn oppression in all its forms and strive to identify and dismantle barriers that lead to inequities in the molecular imaging community and STEM as a whole. In this series coined "Visions" (Antiracism and Allyship in Action), we identify and discuss specific actionable items for improving diversity and representation in molecular imaging and ensuring inclusion of all members of the community, inclusive of race, disability, ethnicity, religion, or LGBTQ+ identity. Although the issues highlighted here extend to other under-recruited and equity-seeking groups, for this first article, we are focusing on one egregious and persistent form of discrimination: anti-Black racism. In this special article, Black women residing in America present their lived experiences in the molecular imaging field and give candid insights into the challenges, frustrations, and hopes of our Black friends and colleagues. While this special article focuses on the experiences of Black women, we would like the readers to reflect on their anti-Blackness toward men, transgender, nonbinary, and gender non-conforming people. From the vulnerability we have asked of all our participants, these stories are meant to inspire and invoke active antiracist work among the readership. We present strategies for dismantling systemic racism that research centers and universities can implement in the recruitment, retention, mentorship, and development of Black trainees and professionals. We would like to specifically acknowledge the Black women who took the time to be interviewed, write perspectives, and share their lived experiences in hopes that it will inspire genuine and lasting change.

Tau PET imaging with 18F-PI-2620 in aging and neurodegenerative diseases.

PURPOSE: In vivo measurement of the spatial distribution of neurofibrillary tangle pathology is critical for early diagnosis and disease monitoring of Alzheimer's disease (AD). METHODS: Forty-nine participants were scanned with 18F-PI-2620 PET to examine the distribution of this novel PET ligand throughout the course of AD: 36 older healthy controls (HC) (age range 61 to 86), 11 beta-amyloid+ (Aß+) participants with cognitive impairment (CI; clinical diagnosis of either mild cognitive impairment or AD dementia, age range 57 to 86), and 2 participants with semantic variant primary progressive aphasia (svPPA, age 66 and 78). Group differences in brain regions relevant in AD (medial temporal lobe, posterior cingulate cortex, and lateral parietal cortex) were examined using standardized uptake value ratios (SUVRs) normalized to the inferior gray matter of the cerebellum. RESULTS: SUVRs in target regions were relatively stable 60 to 90 min post-injection, with the exception of very high binders who continued to show increases over time. Robust elevations in 18F-PI-2620 were observed between HC and Aß+ CI across all AD regions. Within the HC group, older age was associated with subtle elevations in target regions. Mildly elevated focal uptake was observed in the anterior temporal pole in one svPPA patient. CONCLUSION: Preliminary results suggest strong differences in the medial temporal lobe and cortical regions known to be impacted in AD using 18F-PI-2620 in patients along the AD trajectory. This work confirms that 18F-PI-2620 holds promise as a tool to visualize tau aggregations in AD.

Two Patient Studies of a Companion Diagnostic Immuno-Positron Emission Tomography (PET) Tracer for Measuring Human CA6 Expression in Cancer for Antibody Drug Conjugate (ADC) Therapy.

An antigen binding fragment (BFab) derived from a tumor-associated mucin 1-sialoglycotope antigen (CA6) targeting antibody (huDS6) was engineered. We synthesized a companion diagnostic positron emission tomography (PET) tracer by radiolabeling BFab with [64Cu] to measure CA6 expression on cancer tissues prior to anti-human CA6 (huDS6-DM4 antibody-drug conjugate) therapy for ovarian and breast cancer patients. After chemotherapy, the ovarian patient received PET scan with 18F-2-fluoro-2-deoxyglucose ([18F]FDG: 10 mCi), followed by [64Cu]-DOTA-BFab ([64Cu]BFab; 5.5 mCi) 1 week later for PET scanning of CA6 expression and subsequent surgery. The breast cancer patient was treated with chemotherapy before primary tumor resection and subsequent [18F]FDG-PET scan. 4 weeks later the patient received of [64Cu]BFab (11.7 mCi) for CA6 PET scan. Whole body [18F]FDG-PET of the breast cancer patient indicated FDG-avid tumor metastases to the liver, bilateral hila and thoracic spine, but no uptake was observed for the ovarian patient. Each patient was also imaged by PET/CT with [64Cu]BFab at 1 and 24 hours after tracer administration. The [64Cu]BFab tracer was well tolerated by both patients without adverse effects, and no significant tracer uptake was observed in both patients. Immunohistochemistry (IHC) data indicated CA6 expressions were weak to intermediate and matched with the [64Cu]BFab-PET signals.

Acquisition and transmission of group B Streptococcus during pregnancy.

Group B Streptococcus (GBS) is a major cause of neonatal sepsis and meningitis. We followed up 78 pregnant couples for < or =2 months to estimate the risk of GBS transmission. Among couples with discordant GBS status, we observed 1 male-to-female transmission event (1 of 3 couples in which the woman was GBS negative at enrollment), but no female-to-male transmission events (0 of 8 couples in which the man was GBS negative at enrollment).

Serum levels of brain-derived neurotrophic factor in schizophrenia on a hypocaloric diet.

Dietary factors influence BDNF in animal studies, but there is no comparable data in clinical populations. We examined the effect of a dietary intervention on BDNF serum levels in 67 DSM-IV schizophrenic outpatients (51 males and 16 females). Two groups were assessed in a cross-sectional study: one on a hypocaloric diet (HD) and the other not on a hypocaloric diet. Weight, height and BMI data were collected concurrently with 5-ml blood sampling of each subject. BDNF levels were measured with a sandwich-ELISA. The blood sample was obtained a minimum of one month after the exposure to dietary intervention. Serum BDNF levels were significantly higher in patients on the HD (p=0.023). Additional research examining the interaction among patterns of nutritional food behavior and underlying physiopathology may result in insights upon which evidence-based decisions regarding dietary interventions can be made in people identified with major psychiatric disorders, such as schizophrenia.

O impacto dos agentes antipsicóticos na densidade mineral óssea de pacientes esquizofrênicos / Impact of antipsychotic agents in bone mineral density of schizophrenic patients

Estudos têm evidenciado o alto risco de osteoporose em pacientes esquizofrênicos. Alguns estudos têm demonstrado que os neurolépticos típicos e a risperidona podem induzir a osteoporose ou reduzir a densidade mineral óssea. Isso pode ser atribuído ao fato de estas drogas, em uso prolongado, induzirem a hiperprolactinemia a níveis acima do normal, em ambos os sexos, e a baixa dos níveis de estrogênio e de testosterona, aumentando o risco para osteopenia/osteoporose. Neste relato, será apresentado um caso de osteopenia em uma paciente mulher de 53 anos, em uso de antipsicóticos há 30 anos, sendo comentados os procedimentos recomendados para detecção dessa ocorrência e as diretrizes existentes para seu manejo.

Studies have shown a high risk of osteoporosis in schizophrenic patients. Some studies have demonstrated that typical neuroleptics and risperidone may induce osteoporosis or reduce bone mineral density. This can be due to the fact that prolonged use of those drugs induces hyperprolactinemia to levels above normal in both genders, and reduces the levels of estrogen and testosterone, thus increasing the risk of osteopenia/osteoporosis. We report on a case of osteopenia in a 53-year-old female patient using antipsychotics for 30 years. We comment on the recommended procedures to detect osteopenia and on the existing guidelines for its management.

Increased dyslipidemia in schizophrenic outpatients using new generation antipsychotics

OBJECTIVE: First and second generation antipsychotics are associated with metabolic disturbances. A cross-sectional study was designed to follow outpatients at the Schizophrenia and Dementia Program at a major teaching hospital in Porto Alegre, Brazil (Hospital de Clínicas de Porto Alegre) in order to verify whether second generation antipsychotics were associated with higher glucose and lipid levels regardless of age and gender. METHOD: Four metabolic parameters (cholesterol and fractions, glucose and triglycerides) and anthropometric measures were obtained from 124 consecutive adult outpatients diagnosed with schizophrenia by DSM-IV and ICD-10 with the Operational Criteria Checklist for Psychotic Disorders system using the same antipsychotic drug for at least 9 weeks. RESULTS: Most patients had elevated BMI (76.6 percent) and dyslipidemia (84.7 percent). Clozapine users had lower HDL levels compared to first generation antipsychotics users. Both groups had elevated body mass index (p = 0.033; OR = 3.3; 95 percentCI = 1.1-9.8) and second generation antipsychotics (p = 0.021; OR = 3.5; 95 percentCI = 1.1-11.2) showed significant effect, adjusted for age and gender in the logistic regression for dyslipidemia, and significant age effect for hyperglycemia (p = 0.030; OR = 1.1; 95 percentCI = 1.0-1.1). DISCUSSION: There was statistically significant association between the use of second generation antipsychotics and dyslipidemia. It raises the issue of increased vulnerability of second generation antipsychotics-treated patients, regardless of age, as well as the need for assertive treatment for overweight and dyslipidemia in schizophrenia in order to reduce the risk of diabetes and cardiovascular disease.

OBJETIVO: Antipsicóticos de primeira e de segunda geração estão implicados em alterações metabólicas. Foi elaborado este estudo transversal para verificar se os antipsicóticos de segunda geração estavam associados a maiores níveis de glicose e lipídeos, independente de idade e sexo, em pacientes atendidos no Programa de Esquizofrenia e Demência do Hospital de Clínicas de Porto Alegre. MÉTODO: Foram obtidos colesterol e frações, glicose e triglicerídeos séricos, e medidas antropométricas em 124 pacientes esquizofrênicos, encaminhados consecutivamente, diagnosticados pelo DSM-IV e CID-10 pelo sistema Operational Criteria Checklist for Psychotic Disorders, e em uso do mesmo antipsicótico por, no mínimo, nove semanas. RESULTADOS: A maioria dos pacientes apresentou IMC elevado (76,6 por cento) e dislipidemia (84,7 por cento). Os usuários de clozapina apresentaram níveis de colesterol-HDL mais baixos que os de antipsicóticos de primeira geração. O índice de massa corporal elevado (p = 0,033; OR = 3,3; IC95 por cento = 1,1-9,8) e antipsicóticos de segunda geração (p = 0,021; OR = 3,5; IC95 por cento = 1,1-11,2) mostraram efeito significante, ajustado para idade e sexo, na regressão logística para dislipidemia, e efeito significativo de idade para hiperglicemia (p = 0,030; OR = 1,1; IC95 por cento = 1,0-1,1). DISCUSSÃO: Houve associação estatisticamente significante entre o uso de antipsicóticos de segunda geração e dislipidemia. Isto levanta a questão da vulnerabilidade aumentada dos usuários de antipsicóticos de segunda geração, independente de idade, e a necessidade do tratamento adequado de sobrepeso e dislipidemia em esquizofrenia para reduzir o risco de diabete e doenças cardiovasculares.

Sobrepeso e obesidade em pacientes esquizofrênicos em uso de clozapina comparado com o uso de outros antipsicóticos / Overweight and obesity in schizophrenic patients taking clozapine compared to the use of other antipsychotics

INTRODUÇÃO: O uso de antipsicóticos tem sido fundamental no tratamento de portadores de esquizofrenia. Entretanto, tanto a clozapina quanto a maior parte dos antipsicóticos atípicos podem induzir um maior ganho de peso corporal e alterações metabólicas. OBJETIVO: Comparar a freqüência de sobrepeso e obesidade em pacientes esquizofrênicos expostos à clozapina com a dos expostos a demais antipsicóticos. MÉTODO: Foram estudados 121 pacientes esquizofrênicos, com idade de 18 anos ou mais, de ambos os sexos, atendidos no Ambulatório de Esquizofrenia e Demências do Hospital de Clínicas de Porto Alegre, encaminhados de forma consecutiva. Foram avaliadas medidas antropométricas de 53 pacientes em uso de clozapina e de 68 usando outros antipsicóticos, e todos preencheram os critérios diagnósticos de esquizofrenia do DSM-IV e CID-10. RESULTADOS: Não houve diferença significativa na freqüência do IMC entre os esquizofrênicos em uso de clozapina, quando comparado com o dos que usam os demais antipsicóticos. As análises mostraram uma elevada prevalência de pacientes (72,7 por cento) com excesso de peso (sobrepeso + obesidade). DISCUSSÃO: Devido à maior freqüência de excesso de peso na população esquizofrênica, pode-se evidenciar na amostra um indicativo de maior risco para transtornos vasculares e metabólicos. A ausência de diferença significativa em relação ao uso de clozapina, comparada com os demais antipsicóticos, demonstra a necessidade da montagem de estudos prospectivos determinando a magnitude de ganho de peso e o aumento de risco relativo à exposição específica de cada antipsicótico.

BACKGROUND: The use of antipsychotics has been crucial in the treatment of schizophrenic patients. However, clozapine, as well as most atypical antipsychotics, may lead to higher weight gain and metabolic changes. OBJECTIVE: To compare the frequency of overweight and obesity between schizophrenic patients exposed to clozapine to the prevalence of patients exposed to other antipsychotics. METHOD: This study assessed 121 schizophrenic outpatients aged 18 years or older, both genders, consecutively referred to an outpatient clinic for schizophrenia and dementia at Hospital de Clínicas de Porto Alegre, a public hospital in Porto Alegre, Brazil. Anthropometric measures of 53 patients taking clozapine and of 68 taking other antipsychotics were assessed. All patients met DSM-IV and ICD-10 diagnostic criteria for schizophrenia. RESULTS: There was no significant difference in body mass index between schizophrenic patients taking clozapine and patients taking other antipsychotics. Analyses showed high frequency of overweight and obesity (72.7 percent). DISCUSSION: Due to higher frequency of overweight in the schizophrenic population, it was possible to confirm a higher risk of vascular and metabolic disorders in the sample. Absence of a significant difference with regard to the use of clozapine, compared to other antipsychotics, provides evidence for the need of prospective studies in order to determine the magnitude of weight gain and risk increase related to specific exposure to each antipsychotic drug.

Increased dyslipidemia in schizophrenic outpatients using new generation antipsychotics.

OBJECTIVE: First and second generation antipsychotics are associated with metabolic disturbances. A cross-sectional study was designed to follow outpatients at the Schizophrenia and Dementia Program at a major teaching hospital in Porto Alegre, Brazil (Hospital de Clínicas de Porto Alegre) in order to verify whether second generation antipsychotics were associated with higher glucose and lipid levels regardless of age and gender. METHOD: Four metabolic parameters (cholesterol and fractions, glucose and triglycerides) and anthropometric measures were obtained from 124 consecutive adult outpatients diagnosed with schizophrenia by DSM-IV and ICD-10 with the Operational Criteria Checklist for Psychotic Disorders system using the same antipsychotic drug for at least 9 weeks. RESULTS: Most patients had elevated BMI (76.6%) and dyslipidemia (84.7%). Clozapine users had lower HDL levels compared to first generation antipsychotics users. Both groups had elevated body mass index (p = 0.033; OR = 3.3; 95%CI = 1.1-9.8) and second generation antipsychotics (p = 0.021; OR = 3.5; 95%CI = 1.1-11.2) showed significant effect, adjusted for age and gender in the logistic regression for dyslipidemia, and significant age effect for hyperglycemia (p = 0.030; OR = 1.1; 95%CI = 1.0-1.1). DISCUSSION: There was statistically significant association between the use of second generation antipsychotics and dyslipidemia. It raises the issue of increased vulnerability of second generation antipsychotics-treated patients, regardless of age, as well as the need for assertive treatment for overweight and dyslipidemia in schizophrenia in order to reduce the risk of diabetes and cardiovascular disease.

Promoçäo de saúde: uma experiência baseada na antroposofia: o caso da favela Monte Azul / Health promotion: an experience based on Anthroposofy: the case of Monte Azul slum

Objetivo: Analisa a Associaçäo Comunitária Monte Azul (ACOMA), uma organizaçäo näo governamental (ONG), quanto ao referencial teórico verificando se suas estratégias de promoçäo humana, promovem saúde. Métodos: Análise institucional, metodologia de pesquisa qualitativa, de base empírica, que é pesquisa e intervençäo. Fontes de dados: a) estudo do referencial teórico da ACOMA; b) acompanhamento e observaçäo do cotidiano do berçário e das creches da ACOMA; c) realizaçäo de entrevistas semi-estruturadas e grupos focais com os pais das crianças atendidas pela ACOMA; "mäes de creche"; dirigentes e colaboradores envolvidos na coordenaçäo pedagógica e na assistência médica. Resultados: A análise do cotidiano do berçário e das creches da ACOMA revela a reproduçäo na prática, das idéias pedagógicas baseadas na antroposofia e que esta é promotora de saúde. As atividades desenvolvidas com as crianças säo promotoras de saúde. Falha apontada: ausência de um trabalho com os pais das crianças. Os pais näo revelam consciência acerca da filosofia que orienta os serviços prestados pela ACOMA, sendo saúde "ausência de doença". Conclusöes: As idéias antroposóficas foram compreendidas e adotadas, sendo as açöes coerentes com a mesma

Falso positivo de aumento uterino na urografia excretora: correlaçäo com a ultra-sonografia

Os autores realizaram exame ultra-sonográfico em 43 pacientes submetidos previamente a urografia excretora. As medidas do útero obtidas com a ultra-sonografia foram correlacionadas ao aspecto de sua impressäo na face superior da bexiga, observada na urografia excretora. Chegaram a conclusäo de que é dificil na prática diagnosticar aumento do volume uterino pela urografia excretora