Practical management of disease-related manifestations and drug toxicities in patients with multiple myeloma.

Multiple myeloma (MM) is a very heterogeneous disease with multiple symptoms and clinical manifestations. MM affects mainly elderly patients and is difficult to manage in the presence of comorbidities, polypharmacy, frailty and adverse events of disease-targeted drugs. The rapid changes in MM treatment resulting from constant innovations in this area, together with the introduction of numerous new drugs with distinct mechanisms of action and toxicity profiles, have led to an increased complexity in the therapeutic decision-making and patient management processes. The prolonged exposure to novel agents, sometimes in combination with conventional therapies, makes this management even more challenging. A careful balance between treatment efficacy and its tolerability should be considered for every patient. During treatment, a close monitoring of comorbidities, disease-related manifestations and treatment side effects is recommended, as well as a proactive approach, with reinforcement of information and patient awareness for the early recognition of adverse events, allowing prompt therapeutic adjustments. In this review, we discuss various issues that must be considered in the treatment of MM patients, while giving practical guidance for monitoring, prevention and management of myeloma-related manifestations and treatment-related toxicities.

Bringing up to date the toolkit for the catabolism of aromatic compounds in fungi: The unexpected 1,2,3,5-tetrahydroxybenzene central pathway.

Saprophytic fungi are able to catabolize many plant-derived aromatics, including, for example, gallate. The catabolism of gallate in fungi is assumed to depend on the five main central pathways, i.e., of the central intermediates' catechol, protocatechuate, hydroxyquinol, homogentisate and gentisate, but a definitive demonstration is lacking. To shed light on this process, we analysed the transcriptional reprogramming of the growth of Aspergillus terreus on gallate compared with acetate as the control condition. Surprisingly, the results revealed that the five main central pathways did not exhibit significant positive regulation. Instead, an in-depth analysis identified four highly expressed and upregulated genes that are part of a conserved gene cluster found in numerous species of fungi, though not in Aspergilli. The cluster comprises a monooxygenase gene and a fumarylacetoacetate hydrolase-like gene, which are recognized as key components of catabolic pathways responsible for aromatic compound degradation. The other two genes encode proteins with no reported enzymatic activities. Through functional analyses of gene deletion mutants in Aspergillus nidulans, the conserved short protein with no known domains could be linked to the conversion of the novel metabolite 5-hydroxydienelatone, whereas the DUF3500 gene likely encodes a ring-cleavage enzyme for 1,2,3,5-tetrahydroxybenzene. These significant findings establish the existence of a new 1,2,3,5-tetrahydroxybenzene central pathway for the catabolism of gallate and related compounds (e.g. 2,4,6-trihydroxybenzoate) in numerous fungi where this catabolic gene cluster was observed.

Interstitial Ectopic Pregnancy: A Rare Diagnosis.

An ectopic pregnancy is located outside the uterus, mostly found in the fallopian tubes. The main predisposing factors are usually related to anatomical and/or functional disturbances of the fallopian tubes. Typically, an ectopic pregnancy presents with vaginal bleeding or abdominal pain in the first trimester of pregnancy, although it may be asymptomatic. The diagnosis of ectopic pregnancy, which is based on transvaginal ultrasound associated with the serum beta fraction of human chorionic gonadotropin values, is of the highest relevance due to the mortality risk involved. We report the case of a 26-year-old woman who presented with a four-week history of amenorrhea and abdominal pain. Initially, the diagnostic hypothesis was a pelvic inflammatory disease, as the patient complained of pain during deep palpation of the lower quadrants of the abdomen, and gynecological observation detected malodorous discharge and cervical tenderness. Antibiotic treatment was initiated. The patient was later diagnosed with ectopic pregnancy, which was discovered during a routine pregnancy ultrasound. She was submitted to urgent laparotomy with intraoperative confirmation of the interstitial location of the gestational sac.

Purification of archetypal soybean root suberin mostly comprising alka(e)noic acids using an ionic liquid catalyst.

Soybean (Glycine max) is an increasingly relevant crop due to its economic importance and also a model plant for the study of root symbiotic associations with nodule forming rhizobia. Plant polyesters mediate plant-microbe interactions with both pathogenic and beneficial microbes; suberin has been hypothesized to play a key role during the early steps of rhizobia attachment to the root. The downside is that suberin chemistry in soybean root is still scarcely studied. This study addresses this outstanding question by reporting a straightforward workflow for a speedy purification of suberin from soybean root and for its subsequent detailed chemical analysis. To purify suberin, cholinium hexanoate (an ionic liquid) was used as the catalyst. The ensuing suberin is highly esterified as observed by a precise Nuclear Magnetic Resonance quantification of each ester type, discriminating between primary and acylglycerol esters. Moreover, the composing hydrolysable monomers detected through GC-MS revealed that hexadecanoic acid is the most abundant monomer, similar to that reported before by others. Overall, this study highlights the adequacy of the ionic liquid catalyst for the isolation of suberin from soybean roots, where the polymer natural abundance is low, and builds new knowledge on the specificities of its chemistry; essential to better understand the biological roles of suberin in roots.

[Multiple Myeloma Treatment Guidelines by the Portuguese Group of Multiple Myeloma]. / Recomendações do Grupo Português do Mieloma Múltiplo para Tratamento do Mieloma Múltiplo.

The treatment of multiple myeloma has profoundly changed with the introduction of several innovative therapies. The optimization of therapeutic sequencing through the combined use of the various drugs developed in recent years and the attention given to the characteristics of patients have allowed the reduction of toxicities and increased survival and quality of life of patients with multiple myeloma. These treatment recommendations from the Portuguese Multiple Myeloma Group offer guidance for first-line treatment and progression/relapse situations. These recommendations are given highlighting the data that justify each choice and referring to the respective levels of evidence that support these options. Whenever possible, the respective national regulatory framework is presented. These recommendations constitute an advance towards the best treatment of multiple myeloma in Portugal.

O tratamento do mieloma múltiplo tem sido amplamente alterado com introdução de várias terapêuticas inovadoras. A otimização da sequenciação terapêutica através do uso combinado dos vários fármacos desenvolvidos nos últimos anos e a atenção dada às características dos doentes têm permitido diminuir toxicidades e aumentar a sobrevivência dos doentes, bem como aumentar a sua qualidade de vida. As presentes recomendações terapêuticas do Grupo Português do Mieloma Múltiplo oferecem orientações para o tratamento de primeira linha e progressão/recaída. As recomendações são fundamentadas evidenciando os dados que justificam cada escolha e referindo os respetivos níveis de evidência que suportam essas opções. Sempre que possível é apresentado o respetivo enquadramento regulamentar nacional. Estas recomendações constituem um avanço para o melhor tratamento do mieloma múltiplo em Portugal.

A Metastatic Invasive Mole in a Perimenopausal Woman: A Rare Case.

Gestational trophoblastic neoplasia (GTN) represents a heterogeneous group of pregnancy-related tumors that usually develop from the malignant transformation of trophoblastic tissue after molar evacuation. The first presentation as an invasive mole is particularly rare. GTN is considered the most curable gynecological malignancy as most cases are treated successfully with chemotherapy agents. Although extremes of reproductive age are an established risk factor for complete moles, GTN is extremely rare in perimenopausal women. GTN should be considered in the differential diagnosis of patients with abnormal uterine bleeding. Delays in the diagnosis and treatment can worsen the prognosis of patients with GTN. Here, we describe the case of a 54-year-old woman who presented to the emergency department with abdominal pain and heavy vaginal bleeding. She reported pregnancy-related symptoms that had developed over two months but was apprehensive to search for medical care. The final diagnosis was an invasive mole that had a catastrophic clinical course. Arterial embolization should be considered in patients with uncontrollable vaginal bleeding and hemodynamic instability.

Breast Phyllodes Tumor: A Tumor With Unpredictable Clinical Behavior.

Phyllodes tumors are uncommon biphasic breast tumors with a wide range of clinical behaviors. The distinction between a phyllodes tumor and a fibroadenoma can be difficult. The diagnosis of phyllodes tumor should be suspected in all women who present with a rapidly growing breast lump. Based on the histological characteristics, the World Health Organization (WHO) classifies phyllodes tumors as benign, borderline, or malignant. The risk of recurrence and metastatic potential varies based on histological features. Wide excision or mastectomy is the standard of care ensuring histologically clear margins. Despite the grading criteria defined by the WHO, the management of phyllodes tumors continues to be a challenge. We report the case of a 48-year-old woman who presented to the emergency department with a large and ulcerated phyllodes tumor of the left breast. The tumor size did not allow conservative surgery. The final diagnosis of a borderline phyllodes tumor was made, and, in this case, the patient did not undergo adjuvant treatment.

Impact of an Electronic Alert in Combination with a Care Bundle on the Outcomes of Acute Kidney Injury.

Early diagnosis is essential for the appropriate management of acute kidney injury (AKI). We evaluated the impact of an electronic AKI alert together with a care bundle on the progression and mortality of AKI. This was a single-center prospective study that included AKI patients aged ≥ 18 years, whereas those in palliative care, nephrology, and transplantation departments were excluded. An AKI alert was issued in electronic medical records and a care bundle was suggested. A series of classes were administered to the multidisciplinary teams by nephrologists, and a clinical pharmacist audited prescriptions. Patients were categorized into pre-alert and post-alert groups. The baseline characteristics were comparable between the pre-alert (n = 1613) and post-alert (n = 1561) groups. The 30-day mortality rate was 33.6% in the entire cohort and was lower in the post-alert group (30.5% vs. 36.7%; p < 0.001). Age, pulmonary disease, malignancy, and ICU admission were associated with an increase in 30-day mortality. The electronic AKI alert together with a care bundle and a multidisciplinary education program was associated with a reduction in 30-day mortality in patients with AKI.

Porphyrin nanoemulsion for antimicrobial photodynamic therapy: effective delivery to inactivate biofilm-related infections.

The management of biofilm-related infections is a challenge in healthcare, and antimicrobial photodynamic therapy (aPDT) is a powerful tool that has demonstrated a broad-spectrum activity. Nanotechnology has been used to increase the aPDT effectiveness by improving the photosensitizer's delivery properties. NewPS is a simple, versatile, and safe surfactant-free nanoemulsion with a porphyrin salt shell encapsulating a food-grade oil core with promising photodynamic action. This study evaluated the use of NewPS for aPDT against microorganisms in planktonic, biofilm, and in vivo models of infected wounds. First, the potential of NewPS-mediated aPDT to inactivate Streptococcus pneumoniae and Staphylococcus aureus suspensions was evaluated. Then, a series of protocols were assessed against S. aureus biofilms by means of cell viability and confocal microscopy. Finally, the best biofilm protocol was used for the treatment of S. aureus in a murine-infected wound model. A high NewPS-bacteria cell interaction was achieved since 0.5 nM and 30 J/cm2 was able to kill S. pneumoniae suspension. In the S. aureus biofilm, enhanced efficacy of NewPS-aPDT was achieved when 100 µM of NewPS was applied with longer periods of incubation at the light dose of 60 J/cm2. The best single and double-session protocol reduced 5.56 logs and 6.03 logs, respectively, homogeneous NewPS distribution, resulting in a high number of dead cells after aPDT. The in vivo model showed that one aPDT session enabled a reduction of 6 logs and faster tissue healing than the other groups. In conclusion, NewPS-aPDT may be considered a safe and effective anti-biofilm antimicrobial photosensitizer.

Finding a Needle in a Haystack: Producing Antimicrobial Cutin-Derived Oligomers from Tomato Pomace.

Agro-industrial residues comprise a rich diversity of plant polymers and bioactive compounds, constituting promising sources for the development of materials, including bioplastics, and food supplements, among other applications. In particular, the polyester cutin is abundant in fruit peel, a plentiful constituent of pomace agro-industrial residues. The potential of diverse fruit pomaces as a source for the development of cutin-derived materials/products has been extensively sought out. This study expands the established knowledge: it sets proof of concept for the production of antimicrobial oligomers from cutin-rich materials isolated in a single step from tomato pomaces generated by two remote agro-industries. Specifically, it first analyzed how the chemical signature (nuclear magnetic resonance (NMR) and gas chromatography-mass spectrometry (GC-MS)) of a pomace (and of its major constituents) mirrors that of the corresponding cutin-rich material isolated using an ionic liquid extractant. The cutin-rich materials were then deconstructed (using mild hydrolyses), and the resultant mixtures were chemically characterized and screened for bactericidal activity against Escherichia coli and Staphylococcus aureus. The presence of esterified structures, linear and/or branched, likely comprising dioic acids as a major building block (but not exclusively) is a prerequisite for activity against E. coli but not against S. aureus that was susceptible to monomers as well. Further studies are required to optimize the production of broad bactericidal oligomers from any cutin-rich pomace source, moving ahead toward their circular usage.

Life-threatening rupture of interstitial ectopic pregnancy: a rare presentation of metastatic invasive mole.

An invasive mole is an uncommon type of gestational trophoblastic disease, and if considering its implantation in an interstitial extrauterine location, we are facing a rarer condition.There are 14 cases described of interstitial ectopic gestational trophoblastic disease. As far as we know, we present the third case of invasive mole within interstitial location, in this case with pulmonary metastases.The diagnosis of an interstitial implantation is challenging. Our patient was initially diagnosed with an intrauterine hydatidiform molar pregnancy, and a uterine aspiration was performed. Two weeks later, she presented with haemodynamical instability due to a severe haemoperitoneum. A laparotomy was immediately performed and revealed a ruptured interstitial pregnancy with molar vesicle extrusion. Besides its rarity, we highlight the clinical presentation with hypovolaemic shock due to rupture of ectopic pregnancy in a young nulliparous woman, which required an emergent surgical approach with lifesaving purpose while preserving future fertility.

Quantification of Structure-Property Relationships for Plant Polyesters Reveals Suberin and Cutin Idiosyncrasies.

Polyesters, as they exist in planta, are promising materials with which to begin the development of "green" replacements. Cutin and suberin, polyesters found ubiquitously in plants, are prime candidates. Samples enriched for plant polyesters, and in which their native backbones were largely preserved, were studied to identify "natural" structural features; features that influence critical physical properties. Quantitative nuclear magnetic resonance (NMR), differential scanning calorimetry (DSC), and X-ray scattering methods were used to quantify structure-property relationships in these polymeric materials. The degree of esterification, namely, the presence of acylglycerol linkages in suberin and of secondary esters in cutin, and the existence of mid-chain epoxide groups defining the packing of the aliphatic chains were observed. This packing determines polymer crystallinity, the resulting crystal structure, and the melting temperature. To evaluate the strength of this rule, tomato cutin from the same genotype, studying wild-type plants and two well-characterized mutants, was analyzed. The results show that cutin's material properties are influenced by the amount of unbound aliphatic hydroxyl groups and by the length of the aliphatic chain. Collectively, the acquired data can be used as a tool to guide the selection of plant polyesters with precise structural features, and hence physicochemical properties.

Clinical Characteristics, Treatment and Evolution of Splenic and Nodal Marginal Zone Lymphomas-Retrospective and Multicentric Analysis of Portuguese Centers.

INTRODUCTION: Treatment of Splenic (SMZL) and Nodal (NMZL) Marginal Zone Lymphoma is not consensual. Histologic transformation (HT) to aggressive lymphoma is a poorly understood event, with an unfavorable outcome. OBJECTIVES: Describe the clinical characteristics, treatment, outcomes and incidence of HT. METHODS: Characteristics of patients with SMZL and NMZL consecutively diagnosed in 8 Portuguese centers were retrospectively reviewed. Endpoints were overall survival (OS), time to first systemic treatment (TTFST), frequency of HT and time to transformation (TTT). RESULTS: This study included 122 SMZL and 68 NMZL, most of them received systemic treatment: 55.4% and 76.5%, respectively. Splenectomy was performed in 58.7% of patients with SMZL. Different treatment protocols were used. OS or TTFST did not differ significantly according to treatments. Given the small sample size, no conclusion can be made concerning the role of Rituximab in the treatment of NMZL and SMZL based in these results. HT was documented in 18 patients, mainly in SMZL, with a cumulative incidence at 5 years of 4.2%. We confirmed that age is a prognostic factor. CONCLUSION: Randomized prospective trials are needed to standardize treatment in MZL. Patients with HT did appear to have shorter OS in comparison with those who did not experience HT (OS 5 years of 68.4% vs. 80.4%), but the number of HT was too small to reach statistical significance.

Brain Connectivity Studies on Structure-Function Relationships: A Short Survey with an Emphasis on Machine Learning.

This short survey reviews the recent literature on the relationship between the brain structure and its functional dynamics. Imaging techniques such as diffusion tensor imaging (DTI) make it possible to reconstruct axonal fiber tracks and describe the structural connectivity (SC) between brain regions. By measuring fluctuations in neuronal activity, functional magnetic resonance imaging (fMRI) provides insights into the dynamics within this structural network. One key for a better understanding of brain mechanisms is to investigate how these fast dynamics emerge on a relatively stable structural backbone. So far, computational simulations and methods from graph theory have been mainly used for modeling this relationship. Machine learning techniques have already been established in neuroimaging for identifying functionally independent brain networks and classifying pathological brain states. This survey focuses on methods from machine learning, which contribute to our understanding of functional interactions between brain regions and their relation to the underlying anatomical substrate.

Efficacy of vitamin D in the treatment of depression: a systematic review and meta-analysis.

Vitamin D is a fat-soluble vitamin that performs multiple functions in the body. In addition to regulating calcium and phosphate levels in the body and contributing to bone mineralization, it participates in various brain and neurocognitive processes. In fact, the deficiency of this vitamin has also been linked to various psychiatric disorders, including depression.

Eficacia de la vitamina D en el tratamiento de la depresión: revisión sistemática y metaanálisis / Efficacy of vitamin D in the treatment of depression: a systematic review and meta-analysis

INTRODUCCIÓN: La vitamina D es una vitamina liposoluble que desempeña múltiples funciones en el organismo. Además de regular los niveles de calcio y fosfato y contribuir a la mineralización ósea, participa en diversos procesos cerebrales y neurocognitivos. De hecho, el déficit de esta vitamina también se ha relacionado con diversos trastornos psiquiátricos, incluida la depresión. OBJETIVO: Revisar si la administración de la vitamina D es eficaz en el tratamiento de la depresión en adultos frente a placebo. METODOLOGÍA: Se realizó una búsqueda bibliográfica en 4 bases de datos (PubMed, Embase, Web of Science-Science Citation Index y Scopus) de ensayos clínicos aleatorizados (ECA) para valorar la eficacia de la vitamina D en adultos con depresión frente a placebo, desde 2013 hasta septiembre de 2019. La medida de resultado utilizada para el cálculo del tamaño del efecto fue la puntuación de los síntomas depresivos. Los tamaños del efecto para los ensayos se calcularon utilizando la diferencia de media estandarizada y la prueba I2 se utilizó para evaluar la heterogeneidad de la muestra. La evaluación crítica de los artículos se realizó mediante la herramienta del funnel plot. RESULTADOS: Un total de 10 ECA que implicaron 1.393 participantes fueron incluidos en el estudio. Dada la heterogeneidad de los estudios se utilizó el modelo de efectos aleatorios. El resultado del metaanálisis indica que la administración oral de vitamina D no obtuvo un efecto significativo en la disminución de las puntuaciones de depresión postintervención. La diferencia de media estandarizada para los datos agrupados fue de -0,91 (intervalo de confianza del 95 %: -2,02 - 0,19).Conclusiones. Este estudio no ha detectado un efecto terapéutico significativo en la administración de la vitamina D en la depresión

INTRODUCTION: Vitamin D is a fat-soluble vitamin that per-forms multiple functions in the body. In addition to regulating calcium and phosphate levels in the body and contributing to bone mineralization, it participates in various brain and neurocognitive processes. In fact, the deficiency of this vitamin has also been linked to various psychiatric disorders, including depression. OBJECTIVE: To review if the administration of vitamin D is effective in the treatment of depression in adults compared to placebo. METHODOLOGY: An electronic search was carried out in 4 databases (PubMed, Embase, Web of Science-Science Citation Index and Scopus) of randomized clinical trials (RCT) to assess the efficacy of vitamin D, in adults with depression compared to placebo, from 2013 to date of search (2019). The outcome measure used for the effect size calculation was the depressive symptom score. The effect sizes for the trials were calculated using the standardized mean difference and the I2 test was used to assess sample heterogeneity. The critical evaluation of the articles was carried out using the funnel plot tool. RESULTS: A total of 10 RCTs involving 1.393 participants were included in the study. Given the heterogeneity of the studies, the random effects model was used. The result of the meta-analysis indicates that oral administration of vita-min D did not have a significant effect on the reduction of post-intervention depression scores. The standardized mean difference for the pooled data was -0,91 (95% confidence interval -2,02 - 0,19). CONCLUSIONS: This study has not detected a significant therapeutic effect in the administration of vitamin D in depression

Invaginación apendicular como manifestación infrecuente de endometriosis / No disponible

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Appendicular invagination as a rare manifestation of endometriosis.

Appendicular invagination is a rare situation, with an incidence of 0.01 %. The clinical presentation can be variable from acute appendicitis to chronic abdominal pain, intestinal obstruction by intussusception or simply appear as a radiologic or intraoperative finding. Endometriosis is the underlying cause of appendicular invagination in one-third of cases but the possibility of neoplastic pathology should always be considered in these cases.