Sex-Specific Patterns of Cerebral Atrophy and Enlarged Perivascular Spaces in Patients with Cerebral Amyloid Angiopathy and Dementia.

BACKGROUND AND PURPOSE: Cerebral amyloid angiopathy is characterized by amyloid ß deposition in leptomeningeal and superficial cortical vessels. Cognitive impairment is common and may occur independent of concomitant Alzheimer disease neuropathology. It is still unknown which neuroimaging findings are associated with dementia in cerebral amyloid angiopathy and whether they are modulated by sex. This study compared MR imaging markers in patients with cerebral amyloid angiopathy with dementia or mild cognitive impairment or who are cognitively unimpaired and explored sex-specific differences. MATERIALS AND METHODS: We studied 58 patients with cerebral amyloid angiopathy selected from the cerebrovascular and memory outpatient clinics. Clinical characteristics were collected from clinical records. Cerebral amyloid angiopathy was diagnosed on MR imaging on the basis of the Boston criteria. Visual rating scores for atrophy and other imaging features were independently assessed by 2 senior neuroradiologists. RESULTS: Medial temporal lobe atrophy was higher for those with cerebral amyloid angiopathy with dementia versus those cognitively unimpaired (P = .015), but not for those with mild cognitive impairment. This effect was mainly driven by higher atrophy in men with dementia, compared with women with and without dementia (P = .034, P = .012; respectively) and with men without dementia (P = .012). Enlarged perivascular spaces in the centrum semiovale were more frequent in women with dementia versus men with and without dementia (P = .021, P = .011; respectively) and women without dementia (P = .011). CONCLUSIONS: Medial temporal lobe atrophy was more prominent in men with dementia, whereas women showed a higher number of enlarged perivascular spaces in the centrum semiovale. Overall, this finding suggests differential pathophysiologic mechanisms with sex-specific neuroimaging patterns in cerebral amyloid angiopathy.

COVID-19 Induces Neuroinflammation and Suppresses Peroxisomes in the Brain.

OBJECTIVE: Peroxisome injury occurs in the central nervous system (CNS) during multiple virus infections that result in neurological disabilities. We investigated host neuroimmune responses and peroxisome biogenesis factors during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using a multiplatform strategy. METHODS: Brain tissues from coronavirus disease 2019 (COVID-19) (n = 12) and other disease control (ODC) (n = 12) patients, as well as primary human neural cells and Syrian hamsters, infected with a clinical variant of SARS-CoV-2, were investigated by droplet digital polymerase chain reaction (ddPCR), quantitative reverse transcriptase PCR (RT-qPCR), and immunodetection methods. RESULTS: SARS-CoV-2 RNA was detected in the CNS of 4 patients with COVID-19 with viral protein (NSP3 and spike) immunodetection in the brainstem. Olfactory bulb, brainstem, and cerebrum from patients with COVID-19 showed induction of pro-inflammatory transcripts (IL8, IL18, CXCL10, NOD2) and cytokines (GM-CSF and IL-18) compared to CNS tissues from ODC patients (p < 0.05). Peroxisome biogenesis factor transcripts (PEX3, PEX5L, PEX11ß, and PEX14) and proteins (PEX3, PEX14, PMP70) were suppressed in the CNS of COVID-19 compared to ODC patients (p < 0.05). SARS-CoV-2 infection of hamsters revealed viral RNA detection in the olfactory bulb at days 4 and 7 post-infection while inflammatory gene expression was upregulated in the cerebrum of infected animals by day 14 post-infection (p < 0.05). Pex3 transcript levels together with catalase and PMP70 immunoreactivity were suppressed in the cerebrum of SARS-CoV-2 infected animals (p < 0.05). INTERPRETATION: COVID-19 induced sustained neuroinflammatory responses with peroxisome biogenesis factor suppression despite limited brainstem SARS-CoV-2 neurotropism in humans. These observations offer insights into developing biomarkers and therapies, while also implicating persistent peroxisome dysfunction as a contributor to the neurological post-acute sequelae of COVID-19. ANN NEUROL 2023;94:531-546.

Oncofertility case report: live birth 10 years after oocyte in vitro maturation and zygote cryopreservation.

PURPOSE: This study aims to report a case of urgent fertility preservation in an oncological patient with collection of immature oocytes in the absence of ovarian stimulation that, through in vitro maturation (IVM), followed by ICSI and cryopreservation of zygotes resulted, 10 years later, in the live birth of a healthy baby. METHODS: In September 2008, our clinic performed IVM in a 32-year-old woman diagnosed with a ductal invasive carcinoma with positive estradiol receptors, negative progesterone receptors and positive human epidermal growth factor receptor 2. The retrieval of immature oocytes was performed in the absence of ovarian stimulation after a simple mastectomy and prior to any chemotherapy treatment. The compact cumulus-oocyte complexes (COCs) collected were placed in Lag medium for 2 h, followed by incubation in IVM medium, supplemented with heat inactivated patient serum, recombinant FSH, and recombinant LH. After 30 h in culture, cumulus cells were removed, the metaphase II oocytes were microinjected, and the zygotes obtained were cryopreserved. In 2017, the zygotes were thawed and cultured until day 3. One embryo was transferred and the other cryopreserved. RESULTS: Four compact COCs were collected and subjected to IVM. Two oocytes reached metaphase II and were microinjected. Two zygotes were obtained and were cryopreserved at the two pronuclear stage. Approximately 9 years later, the two zygotes were thawed and cultured until day 3. An embryo with 10 cells was transferred and implanted, resulting in the birth of a healthy baby. CONCLUSIONS: In cases where urgency to start adjuvant therapy requires immediate oocyte collection, IVM may be the only option to obtain fully competent mature oocytes allowing for effective preservation of the reproductive potential.

Real-world data from the Portuguese Nivolumab Expanded Access Program (EAP) in previously treated Non Small Cell Lung Cancer (NSCLC).

OBJECTIVE: The main aim of the study was to evaluate the efficacy and safety profile of Nivolumab, an immune-checkpoint-inhibitor antibody, in advanced, previously treated, Non-Small Cell Lung Cancer (NSCLC) patients, in a real world setting. METHODS: We performed a retrospective, multicentre data analysis of patients who were included in the Portuguese Nivolumab Expanded Access Program (EAP). Eligibility criteria included histologically or citologically confirmed NSCLC, stage IIIB and IV, evaluable disease, sufficient organ function and at least one prior line of chemotherapy. The endpoints included Overall Response Rate (ORR), Disease Control Rate (DCR), Progression Free Survival (PFS) and Overall Survival (OS). Safety analysis was performed with the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, and immune-related Adverse Events (irAEs) were treated according to protocol treatment guidelines. Tumour response was assessed using the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Data was analysed using SPSS, version 21.0 (IBM Statistics). RESULTS: From June 2015 to December 2016, a total of 229 patients with advanced NSCLC were enrolled at 30 Portuguese centres. Clinical data were collected up to the end of July 2018. The baseline median age was 64 years (range 37-83) and the majority of patients were males (70.3%) and former/current smokers (69.4%). Patients with non-squamous histology predominated (88.1%), and 67.6% of the patients had received 2 or more prior lines of chemotherapy. Out of 229 patients, data was available for 219 patients (3 patients did not start treatment, while data was unavailable in 7 patients); of the 219 patients, 15.5% were not evaluated for radiological tumour assessment, 1.4% had complete response (CR), 21% partial response (PR), 31% stable disease (SD) and 31.1% progressive disease (PD). Thus, the ORR was 22.4% and DCR was 53.4% in this population. At the time of survival analysis the median PFS was 4.91 months (95% CI, 3.89-6.11) and median OS was 13.21 months (95% CI, 9.89-16.53). The safety profile was in line with clinical trial data. CONCLUSIONS: Efficacy and safety results observed in this retrospective analysis were consistent with observations reported in clinical trials and from other centres.

Using modeling tools for implementing feasible land use and nature conservation governance systems in small islands - The Pico Island (Azores) case-study.

The present study deals with the development of systematic conservation planning as management instrument in small oceanic islands, ensuring open systems of governance, and able to integrate an informed and involved participation of the stakeholders. Marxan software was used to define management areas according a set of alternative land use scenarios considering different conservation and management paradigms. Modeled conservation zones were interpreted and compared with the existing protected areas allowing more fused information for future trade-outs and stakeholder's involvement. The results, allowing the identification of Target Management Units (TMU) based on the consideration of different development scenarios proved to be consistent with a feasible development of evaluation approaches able to support sound governance systems. Moreover, the detailed geographic identification of TMU seems to be able to support participated policies towards a more sustainable management of the entire island.

Wildfire patterns and landscape changes in Mediterranean oak woodlands.

Fire is infrequent in the oak woodlands of southern Portugal (montado) but large and severe fires affected these agro-forestry systems in 2003-2005. We hypothesised transition from forest to shrubland as a fire-driven process and investigated the links between fire incidence and montado change to other land cover types, particularly those related with the presence of pioneer communities (generically designed in this context as "transitions to early-successional communities"). We present a landscape-scale framework for assessing the probability of transition from montado to pioneer communities, considering three sets of explanatory variables: montado patterns in 1990 and prior changes from montado to early-successional communities (occurred between 1960 and 1990), fire patterns, and spatial factors. These three sets of factors captured 78.2% of the observed variability in the transitions from montado to pioneer vegetation. The contributions of fire patterns and spatial factors were high, respectively 60.6% and 43.4%, the influence of montado patterns and former changes in montado being lower (34.4%). The highest amount of explained variation in the occurrence of transitions from montado to early-successional communities was related to the pure effect of fire patterns (19.9%). Low spatial connectedness in montado landscape can increase vulnerability to changes, namely to pioneer vegetation, but the observed changes were mostly explained by fire characteristics and spatial factors. Among all metrics used to characterize fire patterns and extent, effective mesh size provided the best modelling results. Transitions from montado to pioneer communities are more likely in the presence of high values of the effective mesh size of total burned area. This cross-boundary metric is an indicator of the influence of large fires in the distribution of the identified transitions and, therefore, we conclude that the occurrence of large fires in montado increases its probability of transition to shrubland.

Primary spinal glioblastoma: A case report and review of the literature.

Primary spinal glioblastoma (GBM) is a rare disease, with an aggressive course and a poor prognosis. We report a case of a 19-year-old male with a 4-week history of progressive weakness in both lower limbs, which progressed to paraparesis with a left predominance and difficulty in initiating urination over a week. Spine magnetic resonance imaging (MRI) showed an intramedullary expansile mass localised between T6 and T11. We performed a laminotomy and laminoplasty between T6 and T11 and the tumour was partially removed. Histopathological study was compatible with GBM. The patient was administered focal spine radiotherapy with chemotherapy with temozolamide. Serial MRI performed after the initial surgery demonstrated enlargement of the enhancing mass from T3 to T12 and subarachnoid metastatic deposits in C2 and C4, the pituitary stalk, inter-peduncular cistern, left superior cerebellar peduncle and hydrocephalus. We review the literature with regard to the disease and treatment options, and report the unique features of this case. Primary spinal GBM is an extremely rare entity with a poor prognosis and a short survival time. An aggressive management of the different complications as they arise and improvement of current modes of treatment and new treatment options are required to improve survival and ensure better quality of life.

Avaliação do efeito da partição de comprimidos de furosemida sobre a uniformidade da dose / Influence of tablet splitting on dose uniformity

Buscando avaliar a uniformidade da dose unitária de comprimidos submetidos ao procedimento de partição, este trabalho avaliou a dureza, friabilidade, variação de peso e uniformidade de conteúdo em quatro amostras de comprimidos de furosemida de 40 mg, obtidas de diferentes fornecedores. Todas as amostras estudadas atendiam às especificações oficiais antes de serem submetidas ao procedimento de partição; porém, após serem partidas, o teor de fármaco nas metades apresentou excessiva variação, mostrando que esse procedimento pode ser terapeuticamente desaconselhável.

In order to assess the uniformity of the dose of active ingredient in the halves of tablets subjected to splitting, the hardness, friability, weight variability and uniformity of content were studied in four samples of 40 mg tablets of furosemide obtained on the Brazilian market, both whole and split into two parts. All the tablets complied with the official specifications before splitting, but, after this procedure, the drug content in the halves showed excessive variation, indicating that this procedure is inadvisable.

Evaluation of blockbuster drugs under the rule-of-five.

The current drug research techniques, combinatorial synthesis and high throughput screening, enabled the obtaining and pre-evaluation of thousands of compounds in short time. In order to chose the best hits to become leads, observation of drug-likeness tries to optimize this selection. Probably, the most widely used filter is Lipinski's Rule-of-five, which proposes that molecules with poor permeation and oral absorption have molecular weight > 500, Clog P > 5, hydrogen-bond donor > 5 and hydrogen-bond acceptor > 10. In order to evaluate the Rule-of-five, the top pharmaceutical products in 2007 were analyzed. Among 60 drugs, 7 (atorvastatin, montelukast, docetaxel, telmisartan, tacrolimus, leuprolide and olmesartan) did not fit the rule, and 5 failed only one of the threshold values. It was possible to conclude that the rule is very useful to select better compounds in chemolibraries, but it must be used carefully and with criteria, to avoid a possible exclusion of promising compounds.

Possíveis interações medicamentosas com psicotrópicos encontradas em pacientes da Zona Leste de São Paulo / Possible drug interactions with psychotropics found in patients in East São Paulo

Interação medicamentosa é o resultado de uma interferência no efeito de um medicamento por outros agentes. Dentre os fatores que resultam nas interações medicamentosas destacam-se a automedicação e a prática da polifarmácia. O objetivo deste trabalho foi realizar um levantamento de interações medicamentosas que ocorrem com fármacos que atuam no sistema nervoso central, suas possíveis consequências, bem como os motivos que propiciam tal situação. Foi realizado um estudo observacional transversal de 60 indivíduos da zona leste de São Paulo que utilizam medicamentos psicotrópicos, maiores de 21 anos e de ambos os sexos, por meio de um questionário entre junho e agosto de 2008. Os principais psicotrópicos utilizados pelos indivíduos foram benzodiazepínicos e antidepressivos (54 indivíduos), sendo que estes fármacos apresentam alto índice de interações medicamentosas. Cerca de 77% utilizam outros medicamentos em paralelo ao tratamento com psicotrópicos, sendo que destes apenas 35% o fazem com supervisão médica e 27% dos indivíduos utilizaram bebidas alcoólicas concomitantemente. As principais interações encontradas envolveram antidepressivos com benzodiazepínicos, antiulcerogênicos, anticonvulsivantes e álcool. Conclui-se que a automedicação e o uso inadequado de medicamentos são fatores que podem propiciar a ocorrência das interações medicamentosas encontradas, algumas com consequências graves.

A drug interaction is the interference in the effect of a drug by another substance. Outstanding among the factors that result in drug interactions are selfmedication and the practice of polypharmacy. The aim of this work was to conduct a survey of drug interactions that occur with drugs that act on the central nervous system, their possible consequences and the reasons for their occurrence. An observational cross-sectional study was performed on 60 subjects from East Sao Paulo who take psychotropic drugs (over 21 years old and of both genders), by means of a questionnaire applied from June to August 2008. The main drugs taken by those interviewed were benzodiazepines and antidepressants (54 subjects), which are drugs that have high rates of drug interactions. About 77% took other drugs, in parallel with the psychotropic drug treatment, of which only 35% were under medical supervision, and 27% of subjects drank alcohol while taking psychotropic drugs. The main interactions found involved antidepressants with benzodiazepines, antiulcerogenics, anticonvulsants and alcohol. We concluded that self-medication and inadequate drug usage are factors that favor the occurrence of the drug interactions found, some of them with dangerous consequences.

Diffusion-weighted MR imaging findings in an isolated abscess of the clivus.

We report the finding of restricted diffusion in an isolated abscess of the clivus and discuss the imaging differential diagnosis, with an emphasis on the usefulness of diffusion-weighted imaging.

Simultaneous supratentorial and brainstem abscesses due to Listeria monocytogenes.

Multiple supratentorial abscesses caused by Listeria monocytogenes are rare. We report the simultaneous occurrence of multiple supratentorial and brainstem abscesses due to Listeria, in a patient under corticotherapy for an exacerbation of ulcerative colitis. MR imaging features before and after successful conservative treatments are depicted. In immunocompromised patients with supratentorial listerial abscesses, the coexistence of brainstem abscedation is exceptional. Despite high mortality associated with listerial abscesses, this case illustrates the possibility of a good clinical outcome, if the appropriate antibiotic regimen is instituted and the immunosuppressant agent is discontinued.

Theoretical evaluation of the susceptometric measurement of iron in human liver by four different susceptometers.

This paper is an evaluation of liver iron quantification using a simulated magnetic susceptibility measurement in the hepatic region. Susceptometers having homogeneous and non-homogeneous magnetizing fields coupled with axial second-order and planar first-order gradiometric magnetic detectors were considered. The intensity of magnetic flux threading the detector coils was evaluated considering samples with volume and susceptibility equivalent to liver iron, tissue and lung air individually. These volumes were represented by cylindrical and spherical geometries. The main sources of error in quantifying iron overload in susceptometric measurement of hepatic tissue were evaluated for four configurations of the susceptometer.

Comparative evaluation of European methods for sampling and sample preparation of soils--the Portuguese contribution.

The main purpose of this work was to prepare a Portuguese sampling strategy, according to the existing Portuguese recommendations, for the soil sampling exercise at Dornach in the framework of the CEEM soil project of the SMT Programme of the EU. Within this project, the results obtained from the Dornach study were compared with the results obtained by other European participants and also with the reference sampling. The objective of this comparison was to validate the method used and to evaluate possible factors of uncertainty that may arise from the application of our national guideline as well as possible advantages. Another objective, also important, was to provide information regarding the need for a harmonised procedure within the European Union related to soil sampling and sample preparation of soils. The results obtained were consistent with the results obtained by other participants, however, in the Portuguese recommendations there is a general lack of specific information that may complicate its application to polluted scenarios. In fact, those guidelines are valuable to detect the average contamination of the soil, but they are not useful to identify hot spots or the edge influence in a contaminated land. As a conclusion, the results obtained by the CEEM soil project helped to evaluate the Portuguese sampling plan. This may provide a basis for further standardisation of soil sampling for specific purposes, e.g. contaminated land, and to establish a technical support for criteria used in the accreditation of laboratories for soil sampling.

Short-term intensive consolidation therapy after all-trans retinoic acid in acute promyelocytic leukemia.

Complete remission induced by all-trans retinoic acid (ATRA) in acute promyelocytic leukemia is short lived, and several consolidation chemotherapy courses usually are given to reduce the relapse rate. To assess the value of short-term intensive consolidation, 38 patients with newly diagnosed acute promyelocytic leukemia entered a prospective study in which induction therapy with ATRA immediately was followed by a single course of mitoxantrone plus high-dose cytarabine (3 g/m2 every 12 hours, days 1-4), with no further treatment. Complete remission was achieved in 31 patients (81.6%) after a median time of 49 days of ATRA (to which chemotherapy was added at entry in 10 patients with leukocytosis). Thirty patients received the planned consolidation course. After a median follow-up of 36 months, four of these patients have relapsed and 24 are still in first complete remission, for an estimated disease-free survival of 75% at 60 months. The authors conclude that this single course consolidation of ATRA-induced remission provides excellent long-term control of acute promyelocytic leukemia.

Granulocyte-macrophage colony-stimulating factor in post-remission therapy of acute myeloid leukemia.

The impact on occult leukemia of GM-CSF as a sensitizing agent has not been studied. We treated 41 adult patients with de novo acute myeloid leukemia, 25 of whom achieved complete remission and were given 1 to 3 post-remission courses, each course including GM-CSF begun 4 days prior to chemotherapy and given until day 3. After a median follow-up of 32 months, the probability of remaining in continuous complete remission was 17% at 46 months. GM-CSF in this setting was not associated with an improved outcome, arguing against a priming effect.