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Plasma-derived von Willebrand factor-containing factor VIII concentrates (pd-VWF/FVIII-C) are the mainstay of treatment in von Willebrand disease (VWD). Real-world data on efficacy and safety of these pd-VWF/FVIII-C are required. To retrospectively evaluate the efficacy and safety of pd-VWF/FVIII-C (Fanhdi® and Alphanate®, Grifols) in clinical practice in Italy. A multicentric, observational, retrospective study at 10 Italian centers was conducted. Eligible patients diagnosed with inherited VWD (ISTH criteria) were treated with either Fanhdi® or Alphanate® for bleeding episodes, prevention of surgical bleeding and secondary long-term prophylaxis (SLTP) according to clinical practice with medical records collected from January 2007 to December 2019. Efficacy/safety of pd-VWF/FVIII-C was assessed according to FDA-agreed objective criteria following regulatory procedures. Fifty-seven patients (M/F: 21/36) were enrolled in the study with the following VWD types: VWD1 (n = 29, 52%), VWD2A (n = 10, 18%), VWD2B (n = 7, 12%), VWD2M (n = 2, 4%), VWD2N (n = 1, 2%), VWD2 unclassified (n = 1, 2%), and VWD3 (n = 7, 12%). These pd-VWF/FVIII-C were used to manage 58 bleeding episodes (n = 24 patients), 100 surgeries (n = 47 patients), and 7 SLTP (n = 6 patients). Global clinical efficacy with these pd-VWF/FVIII-C was reported to be excellent/good in 85% of bleeding episodes, 98% of surgeries, and 100% of SLTP. As far as safety, no adverse-drug-related episodes, immunogenic or thrombotic events were reported. This study confirmed that Fanhdi® and Alphanate® were effective and safe in the management of bleeding episodes, the prevention of bleeding during surgeries and for SLTP in Italian patients with inherited VWD.

Background: The first case of coronavirus 2019 (COVID-19) in Latin America was detected on February 26th, 2020, in Brazil. Later, in June, the World Health Organization announced that the focus of the outbreak had shifted to Latin America, where countries already had poor control of indicators of noncommunicable diseases (NCDs). Concerns about coronavirus infection led to a reduced number of visits and hospitalizations in patients with NCDs, such as cardiovascular disease, diabetes, and cancer. There is a need to determine the impact of the COVID-19 pandemic on patients who have cardiometabolic diseases but do not have clinical evidence of COVID-19 infection. Methods: The CorCOVID LATAM is a cross-sectional survey of ambulatory cardiometabolic patients with no history or evidence of COVID-19 infection. The study will be conducted by the Interamerican Society of Cardiology. An online survey composed of 38 questions using Google Forms will be distributed to patients of 13 Latin American Spanish-speaking countries from June 15th to July 15th, 2020. Data will be analyzed by country and regions. Seven clusters of questions will be analyzed: demographics, socioeconomic and educational level, cardiometabolic profile, lifestyle and habits, body-weight perception, medical follow-up and treatments, and psychological symptoms. Results: Final results will be available upon completion of the study. Conclusions: The present study will provide answers regarding the impact of the COVID-19 pandemic on noninfected cardiometabolic patients. Data on this topic are scarce, as it is an unprecedented threat, without short-term solutions. Résumé: Contexte: Le premier cas de maladie à coronavirus 2019 (COVID-19) en Amérique latine a été détecté le 26 février 2020 au Brésil. En juin, l’Organisation mondiale de la Santé a annoncé que le foyer de l’épidémie s’était déplacé en Amérique latine, où le suivi des indicateurs relatifs aux maladies non transmissibles est déjà déficient. Les préoccupations relatives à l’infection par le coronavirus ont entraîné une diminution du nombre de consultations et d’hospitalisations des patients atteints d’une maladie non transmissible, comme une ma-ladie cardiovasculaire, le diabète ou un cancer. Il est donc nécessaire d’évaluer l’incidence de la pandémie de COVID-19 chez les patients atteints d’une maladie cardiométabolique ne présentant aucun signe clinique d’une infection au virus de la COVID-19. Méthodologie: L’étude CorCOVID LATAM est une enquête transversale menée auprès des patients ambulatoires atteints d’une maladie cardiométabolique n’ayant pas d’antécédents d’infection au virus de la COVID-19 et ne présentant aucun signe d’une telle infection. L’étude est réalisée par la Société interaméricaine de cardiologie. Du 15 juin au 15 juillet 2020, on a demandé aux patients de 13 pays hispanophones d’Amérique latine de répondre à un questionnaire en ligne de 38 questions dans Google Forms. Les données seront analysées par pays et par région. Les réponses aux questions seront examinées selon sept grands thèmes : caractéristiques démographiques, caractéristiques socioéconomiques et niveau de scolarité, profil cardiométabolique, mode de vie et habitudes, perception quant au poids corporel, suivi et traitements médicaux et symptômes psychologiques. Résultats: Les résultats seront publiés à la fin de l’étude. Conclusions: L’étude fournira des renseignements sur l’incidence de la pandémie de COVID-19 chez les patients atteints d’une maladie cardiométabolique non infectés. Les données sur cette question sont rares, puisqu’il s’agit d’une menace sans précédent, à laquelle il n’existe de surcroît pas de solution à court terme.

Summary: Vasculitic ulcers are caused by numerous disorders and may be chronic if not well treated. Various modalities of treatment, both medical and surgical, are available. We describe the case of a 63-year-old patient with a vasculitic ulcer treated with platelet-derived growth factors and noncultured autologous cell suspension collected by an innovative single-use device (ReCell).

Alterations in pH are a hallmark in several pathologies including cancer, ischemia, and inflammation. Non-invasive magnetic resonance methods to measure pH offer a new approach for early diagnosis of diseases characterized by acid-base imbalances. The hyperpolarization with parahydrogen-induced polarization (PHIP) enhances inherently low signals in magnetic resonance experiments by several orders of magnitude and offers a suitable platform to obtain biocompatible markers in less than one minute. Here, we present an optimized preparation of an hyperpolarized H 13 CO 3 - / 13 CO 2 pH sensor via non-enzymatic decarboxylation with H 2 O 2 of [1- 13 C]pyruvate-d 3 obtained by PHIP at 7 T. An improved 13 C polarization of purified [1- 13 C]pyruvate-d 3 in water with 36.65 ± 0.06% polarization was obtained starting from 50 mM precursor. Subsequent decarboxylation, H 13 CO 3 - / 13 CO 2 exhibited 12.46 ± 0.01% of polarization at physiological pH, 45 seconds after the reaction start. Considering the dilution factor that [1- 13 C]pyruvate-d 3 exhibits in vivo , we optimized our methodology to test the accuracy of the pH sensor at single digit millimolar concentration. In vitro pH estimations on phantoms and cell culture media demonstrated accurate pH calculations with uncertainties of less than 0.08 units. These promising results highlight the efficiency of a pH sensor generated via PHIP in less than one minute, with remarkable polarization, and biocompatibility suitable for future in vivo studies.

Magnetic resonance with hyperpolarized contrast agents is one of the most powerful and noninvasive imaging platforms capable for investigating in vivo metabolism. While most of the utilized hyperpolarized agents are based on 13 C nuclei, a milestone advance in this area is the emergence of 15 N hyperpolarized contrast agents. Currently, the reported 15 N hyperpolarized agents mainly utilize the dissolution dynamic nuclear polarization (d-DNP) protocol. The parahydrogen enhanced 15 N probes have proven to be elusive and have been tested almost exclusively in organic solvents. Herein, we designed a reaction based reactive oxygen sensor 15 N-boronobenzyl-2-styrylpyridinium ( 15 N-BBSP) which can be hyperpolarized with para-hydrogen. Reactive oxygen species plays a vital role as one of the essential intracellular signalling molecules. Disturbance of the H 2 O 2 level usually represents a hallmark of pathophysiological conditions. This H 2 O 2 probe exhibited rapid responsiveness toward H 2 O 2 and offered spectrally resolvable chemical shifts. We also provide strategies to bring the newly developed probe from the organic reaction solution into a biocompatible injection buffer and demonstrate the feasibility of in vivo 15 N signal detection. The present work manifests its great potential not only for reaction based reactive sensing probes but also promises to serve as a platform to develop other contrast agents., (© 2024 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Head and neck squamous cell carcinoma (HNSCC) is painful, and perineural invasion (PNI) has been associated with the worst pain. Pain due to HNSCC is diverse and may vary based on clinicopathological factors. This study aims to characterize different pain patterns linked with PNI, its influence on daily functioning, and gain insights into molecular changes and pathways associated with PNI-related pain in HNSCC patients. We conducted a cross-sectional study across 3 medical centers (n = 114), assessing pain phenotypes and their impact on daily functioning using 2 self-reported pain questionnaires, given to patients prior to their cancer surgery. Furthermore, we conducted RNA-seq analysis utilizing the The Cancer Genome Atlas dataset of HNSCC tumor from patients (n = 192) to identify genes relevant to both PNI and pain. Upon adjusting for demographic and clinicopathological variables using linear regression models, we found that PNI independently predicted function-evoked pain according to the University of Calfornia San Francisco Oral Cancer Pain Questionnaire, as well as the worst pain intensity reported in the Brief Pain Inventory. Distinct pain patterns were observed to be associated with daily activities in varying manners. Our molecular analyses revealed significant disruptions in pathways associated with the extracellular matrix structure and organization. The top differentially expressed genes linked to the extracellular matrix are implicated in cancer development, pain, and neurodegenerative diseases. Our data underscore the importance of properly categorizing pain phenotypes in future studies aiming to uncover mechanistic underpinnings of pain. Additionally, we have compiled a list of genes of interest that could serve as targets for both cancer and cancer pain management. PERSPECTIVE: PNI independently predicts function-evoked pain. Different pain phenotypes affect daily activities differently. We identified a list of candidate genes involved in the extracellular matrix structure and function that can be targeted for both cancer and cancer pain control., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Hydroalcoholic extracts from Malbec and Torrontés wine pomaces ( Vitis vinifera L.) originating from the high-altitude vineyards of Argentina's Calchaquí Valleys were characterized. Total phenolics, hydroxycinnamic acids, orthodiphenols, anthocyanins, non-flavonoid phenolics, total flavonoids, flavones/flavonols, flavanones/dihydroflavonols, and tannins were quantified through spectrophotometric methods, with the Malbec extract exhibiting higher concentrations in most of phytochemical groups when compared to Torrontés. HPLC-DAD identified more than 30 phenolic compounds in both extracts. Malbec displayed superior antiradical activity (ABTS cation, nitric oxide, and superoxide anion radicals), reduction power (iron, copper, and phosphomolybdenum), hypochlorite scavenging, and iron chelating ability compared to Torrontés. The cytotoxicity assessments revealed that Torrontés affected the viability of HT29-MTX and Caco-2 colon cancer cells by 70% and 50%, respectively, at the highest tested concentration (1 mg/mL). At the same time, both extracts did not demonstrate acute toxicity in Artemia salina or in red blood cell assays at 500 µg/mL. Both extracts inhibited the lipoxygenase enzyme (IC 50 : 154.7 and 784.7 µg/mL for Malbec and Torrontés), with Malbec also reducing the tyrosinase activity (IC 50 : 89.9 µg/mL), and neither inhibited the xanthine oxidase. The substantial phenolic content and diverse biological activities in the Calchaquí Valleys' pomaces underline their potentialities to be valorized for pharmaceutical, cosmetic, and food industries.

Alzheimer's disease (AD) involves a neurodegenerative process that has not yet been prevented, reversed, or stopped. Continuing with the search for natural pharmacological treatments, flavonoids are a family of compounds with proven neuroprotective effects and multi-targeting behavior. The American genus Dalea L. (Fabaceae) is an important source of bioactive flavonoids. In this opportunity, we tested the neuroprotective potential of three prenylated flavanones isolated from Dalea species in a new in vitro pre-clinical AD model previously developed by us. Our approach consisted in exposing neural cells to conditioned media (3xTg-AD ACM) from neurotoxic astrocytes derived from hippocampi and cortices of old 3xTg-AD mice, mimicking a local neurodegenerative microenvironment. Flavanone 1 and 3 showed a neuroprotective effect against 3xTg-AD ACM, being 1 more active than 3. The structural requirements to afford neuroprotective activity in this model are a 5'-dimethylallyl and 4'-hydroxy at the B ring. In order to search the mechanistic performance of the most active flavanone, we focus on the flavonoid-mediated regulation of GSK-3β-mediated tau phosphorylation previously reported. Flavanone 1 treatment decreased the rise of hyperphosphorylated tau protein neuronal levels induced after 3xTg-AD ACM exposure and inhibited the activity of GSK-3β. Finally, direct exposure of these neurotoxic 3xTg-AD astrocytes to flavanone 1 resulted in toxicity to these cells and reduced the neurotoxicity of 3xTg-AD ACM as well. Our results allow us to present compound 1 as a natural prenylated flavanone that could be used as a precursor to development and design of future drug therapies for AD., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Oral cancer pain remains a significant public health concern. Despite the development of improved treatments, pain continues to be a debilitating clinical feature of the disease, leading to reduced oral mobility and diminished quality of life. Opioids are the gold standard treatment for moderate-to-severe oral cancer pain; however, chronic opioid administration leads to hyperalgesia, tolerance, and dependence. The aim of this review is to present accumulating evidence that epidermal growth factor receptor (EGFR) signaling, often dysregulated in cancer, is also an emerging signaling pathway critically involved in pain and opioid tolerance. We presented preclinical and clinical data to demonstrate how repurposing EGFR inhibitors typically used for cancer treatment could be an effective pharmacological strategy to treat oral cancer pain and to prevent or delay the development of opioid tolerance. We also propose that EGFR interaction with the µ-opioid receptor and glutamate N-methyl-D-aspartate receptor could be two novel downstream mechanisms contributing to pain and morphine tolerance. Most data presented here support that repurposing EGFR inhibitors as non-opioid analgesics in oral cancer pain is promising and warrants further research.

Oral cancer causes pain associated with cancer progression. We report here that the function of the Ca 2+ channel ORAI1 is an important regulator of oral cancer pain. ORAI1 was highly expressed in tumor samples from patients with oral cancer, and ORAI1 activation caused sustained Ca 2+ influx in human oral cancer cells. RNA-seq analysis showed that ORAI1 regulated many genes encoding oral cancer markers such as metalloproteases (MMPs) and pain modulators. Compared with control cells, oral cancer cells lacking ORAI1 formed smaller tumors that elicited decreased allodynia when inoculated into mouse paws. Exposure of trigeminal ganglia neurons to MMP1 evoked an increase in action potentials. These data demonstrate an important role of ORAI1 in oral cancer progression and pain, potentially by controlling MMP1 abundance.

Neurodegenerative diseases such as Alzheimer's disease have been classically studied from a purely neuronocentric point of view. More recent evidences support the notion that other cell populations are involved in disease progression. In this sense, the possible pathogenic role of glial cells like astrocytes is increasingly being recognized. Once faced with tissue damage signals and other stimuli present in disease environments, astrocytes suffer many morphological and functional changes, a process referred as reactive astrogliosis. Studies from murine models and humans suggest that these complex and heterogeneous responses could manifest as disease-specific astrocyte phenotypes. Clear understanding of disease-associated astrocytes is a necessary step to fully disclose neurodegenerative processes, aiding in the design of new therapeutic and diagnostic strategies. In this work, we present the transcriptomics characterization of neurotoxic astrocytic cultures isolated from adult symptomatic animals of the triple transgenic mouse model of Alzheimer's disease (3xTg-AD). According to the observed profile, 3xTg-AD neurotoxic astrocytes show various reactivity features including alteration of the extracellular matrix and release of pro-inflammatory and proliferative factors that could result in harmful effects to neurons. Moreover, these alterations could be a consequence of stress responses at the endoplasmic reticulum and mitochondria as well as of concomitant metabolic adaptations. Present results support the hypothesis that adaptive changes of astrocytic function induced by a stressed microenvironment could later promote harmful astrocyte phenotypes and further accelerate or induce neurodegenerative processes., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Chemotherapy-induced neuropathic pain (CINP) is a debilitating and difficult-to-treat side effect of chemotherapeutic drugs. CINP is marked with oxidative stress and neuronal hypersensitivities. The peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor that regulates genes involved in oxidative stress and inflammation. We hypothesize that PPARγ agonists are protective against CIPN by reducing oxidative stress and inhibiting neuronal hypersensitivities. To test our hypothesis, acute or chronic CIPN was introduced by short or long-term treatment of oxaliplatin in BALB/c mice. CIPN mice were treated with either a novel blood-brain barrier (BBB) penetrable PPARγ agonist ELB00824, or a BBB non-penetrable PPARγ agonist pioglitazone, or vehicle. Cold allodynia, mechanical allodynia, motor coordination, sedation and addiction were measured with dry ice, von Frey filaments, beam-walking tests, and conditioned place preference, respectively. Oxidative stress was accessed by measuring byproducts of protein oxidation (carbonyl and 3-Nitrotyrosine) and lipid peroxidation [Thiobarbituric acid reactive substances (TBARS)], as wells as gene expression of Cat, Sod2, Ppargc1a. The effects of ELB00824 on nociceptor excitability were measured using whole-cell electrophysiology of isolated dorsal root ganglion neurons. Preemptive ELB00824, but not pioglitazone, reduced oxaliplatin-induced cold and mechanical allodynia and oxidative stress. ELB0824 suppressed oxaliplatin-induced firing in IB4 - neurons. ELB00824 did not cause motor discoordination or sedation/addiction or reduce the antineoplastic activity of oxaliplatin (measured with an MTS-based cell proliferation assay) in a human colon cancer cell line (HCT116) and a human oral cancer cell line (HSC-3). Our results demonstrated that ELB00824 prevents oxaliplatin-induced pain, likely via inhibiting neuronal hypersensitivities and oxidative stress., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Alzheimer's disease has been considered mostly as a neuronal pathology, although increasing evidence suggests that glial cells might play a key role in the disease onset and progression. In this sense, astrocytes, with their central role in neuronal metabolism and function, are of great interest for increasing our understanding of the disease. Thus, exploring the morphological and functional changes suffered by astrocytes along the course of this disorder has great therapeutic and diagnostic potential. In this work we isolated and cultivated astrocytes from symptomatic 9-10-months-old adult 3xTg-AD mice, with the aim of characterizing their phenotype and exploring their pathogenic potential. These "old" astrocytes occurring in the 3xTg-AD mouse model of Alzheimer's Disease presented high proliferation rate and differential expression of astrocytic markers compared with controls. They were neurotoxic to primary neuronal cultures both, in neuronal-astrocyte co-cultures and when their conditioned media (ACM) was added into neuronal cultures. ACM caused neuronal GSK3β activation, changes in cytochrome c pattern, and increased caspase 3 activity, suggesting intrinsic apoptotic pathway activation. Exposure of neurons to ACM caused different subcellular responses. ACM application to the somato-dendritic domain in compartmentalised microfluidic chambers caused degeneration both locally in soma/dendrites and distally in axons. However, exposure of axons to ACM did not affect somato-dendritic nor axonal integrity. We propose that this newly described old 3xTg-AD neurotoxic astrocytic population can contribute towards the mechanistic understanding of the disease and shed light on new therapeutical opportunities., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Head and neck cancer (HNC) is the seventh most common cancer worldwide, the majority being oral squamous cell carcinoma. Despite advances in cancer diagnosis and treatment, the survival rate of patients with HNC remains stagnant. The cancer-nerve interaction has been recognized as an important driver of cancer progression. Schwann cells, a type of peripheral glia, have been implicated in promoting cancer cell growth, migration, dispersion, and invasion into the nerve in many cancers. Here, it is demonstrated that the presence of Schwann cells makes oral cancer cells more aggressive by promoting their proliferation, extracellular matrix breakdown, and altering cell metabolism. Furthermore, oral cancer cells became larger, more circular, with more projections and nuclei following co-culturing with Schwann cells. RNA-sequencing analysis in oral cancer cells following exposure to Schwann cells shows corresponding changes in genes involved in the hallmarks of cancer and cell metabolism; the enriched KEGG pathways are spliceosome, RNA transport, cell cycle, axon guidance, signaling pathways regulating pluripotency of stem cells, cAMP signaling, WNT signaling, proteoglycans in cancer and PI3K-Akt signaling. Taken together, these results suggest a significant role for Schwann cells in facilitating oral cancer progression, highlighting their potential as a target to treat oral cancer progression., (© 2022 Wiley-VCH GmbH.)

Multidrug resistance (MDR) in the opportunistic pathogen Candida albicans is defined as non-susceptibility to at least one agent in two or more drug classes. This phenomenon has been increasingly reported since the rise in the incidence of fungal infections in immunocompromised patients at the end of the last century. After the discovery of efflux pump overexpression as a principal mechanism causing MDR in Candida strains, drug discovery targeting fungal efflux transporters has had a growing impact. Chemosensitization aims to enhance azole intracellular concentrations through combination therapy with transporter inhibitors. Consequently, the use of drug efflux inhibitors combined with the antifungal agent will sensitize the pathogen. As a result, the use of lower drug concentrations will reduce possible adverse effects on the host. Through an extensive revision of the literature, this review aims to provide an exhaustive and critical analysis of the studies carried out in the past two decades regarding the chemosensitization strategy to cope with multidrug resistance in C. albicans. This work provides a deep analysis of the research on the inhibition of drug-efflux membrane transporters by prenylated flavonoids and the interactions of these phytocompounds with azole antifungals as an approach to chemosensitize multidrug-resistant C. albicans strains. We highlight the importance of prenylflavonoids and their particular chemical and pharmacological characteristics that make them excellent candidates with therapeutic potential as chemosensitizers. Finally, we propose the need for further research on prenyl flavonoids as inhibitors of drug-efflux mediated fungal resistance., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Neurodegenerative diseases (NDs) represent a global problem on public health, with a growing incidence as human longevity increases. Currently, although there are palliative strategies available for most of these diseases, there is a lack of effective therapies for their cure. Flavonoids are extensively studied for their multi-target behavior. Among numerous biological activities, it has been reported that they act at the CNS level, presenting neuroprotective activity through different mechanisms of action. Dalea L. (Fabaceae) is an American genus, with about 172 species. Dalea elegans Gillies ex. Hook. & Arn and Dalea pazensis Rusby, both South American species, are the important source of natural compounds of the prenylated flavanones type. In the present study, five prenylated flavanones isolated from Dalea species were assayed for their neuroprotective activity in two in vitro models of neurodegeneration. Flavanones 1 and 2 exhibited neuroprotective effects against oxidative stress-induced death in both models, granular cerebellar neurons and (NGF)-differentiated PC12 cells. Structure-activity relationships were also reported. Our results indicated that an 8-prenyl group at the A-ring accompanied by an unsubstituted B-ring, or a 2',4'-dihydroxy-5'-dimethylallyl substitution, lead to the most potent flavanones. Furthermore, in silico studies were performed, and several putative targets in NDs were identified for compounds 1 and 2. Between them, the enzyme acetylcholinesterase was selected for its validation in vitro. The present in vitro and in silico results imply that prenylated flavanones 1 and 2 may be useful in the development and design of future strategies for the treatment of NDs diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

The lack of secure therapies for hyperpigmentation disorders, without serious adverse effects, and the latest reports relating melanogenic disorders with development of neurodegenerative diseases, encourage the continuing search for new drugs for the treatment of such disorders. In this sense, the plant kingdom is an important source of bioactive natural products with great potential for the research and development of new therapeutics. The present study evaluated the anti-melanogenic activity of the natural methoxylated chalcone, 2',6'-dihydroxy-4'-methoxy-3'-methylchalcone (Triangularin, T), on diphenolase activity from mushroom tyrosinase and on murine B16F0 melanoma cell model. In addition, molecular modelling studies were carried out in order to understand the inhibitory activity observed. T showed a potent anti-melanogenic activity being more active than kojic acid (KA) on tyrosinase isolated of both sources and on intracellular tyrosinase. Molecular docking studies displayed important interactions between T and the active site of tyrosinase. Our results suggest that T may be useful for the treatment of hyperpigmentary disorders., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Hyperpigmentation disorders are difficult to treat without causing permanent depigmentation or irritation. The most effective hypopigmenting agents are tyrosinase inhibitors, however some of those currently used have shown serious side effects. As several classes of flavonoids have already demonstrated ability to inhibit tyrosinase, a library of natural polymethoxyflavones isolated (1-7) from the bud exudate of Gardenia oudiepe and semi-synthetic derivatives (8,9) were evaluated. IC 50 of the most active compounds were in the micromolar range. The strongest inhibitors 1, 2 and 3 all shared a 3',4'-dimethoxy-5'-hydroxy trisubstituted B ring. These SAR conclusions were confirmed by molecular docking studies. The mode of interaction with the enzyme was elucidated, and important interactions between the most active compounds and catalytic residues of tyrosinase were observed. All of these data provided a library of compounds as potential leaders for the design of new depigmenting agents and formulations., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Xanthine oxidase (XO), an enzyme widely distributed among mammalian tissues, is associated with the oxidation of xanthine and hypoxanthine to form uric acid. Reactive oxygen species are also released during this process, leading to oxidative damages and to the pathology called gout. Available treatments mainly based on allopurinol cause serious side effects. Natural products such as flavonoids may represent an alternative. Thus, a series of polymethoxyflavones isolated and hemisynthesized from the bud exudates of Gardenia oudiepe has been evaluated for in vitro XO inhibitory activity. Compounds 1, 2 and 3 were more active than the reference inhibitor, Allopurinol (IC 50  = 0.25 ± 0.004 μM) with IC 50 values of (0.004 ± 0.001) μM, (0.05 ± 0.01) μM and (0.09 ± 0.003) μM, respectively. Structure-activity relationships were established. Additionally, a molecular docking study using MOE™ tool was carried out to establish the binding mode of the most active flavones with the enzyme, showing important interactions with its catalytic residues. These promising results, suggest the use of these compounds as potential leads for the design and development of novel XO inhibitors., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background Childhood trauma has been significantly associated with first-episode psychosis, affective dysfunction and substance use. Aims To test whether people with first-episode psychosis who had experienced childhood trauma, when compared with those who had not, showed a higher rate of affective psychosis and an increased lifetime rate of substance use. Method The sample comprised 345 participants with first-episode psychosis (58% male, mean age 29.8 years, s.d. = 9.7). Results Severe sexual abuse was significantly associated with a diagnosis of affective psychosis (χ 2 = 4.9, P = 0.04) and with higher rates of lifetime use of cannabis (68% v 41%; P = 0.02) and heroin (20% v 5%; P = 0.02). Severe physical abuse was associated with increased lifetime use of heroin (15% v 5%; P = 0.03) and cocaine (32% v 17%; P = 0.05). Conclusions Patients with first-episode psychosis exposed to childhood trauma appear to constitute a distinctive subgroup in terms of diagnosis and lifetime substance use., Competing Interests: Declaration of interestNone., (© The Royal College of Psychiatrists 2017.)

Background The GET UP multi-element psychosocial intervention proved to be superior to treatment as usual in improving outcomes in patients with first-episode psychosis (FEP). However, to guide treatment decisions, information on which patients may benefit more from the intervention is warranted. Aims To identify patients' characteristics associated with (a) a better treatment response regardless of treatment type (non-specific predictors), and (b) a better response to the specific treatment provided (moderators). Method Some demographic and clinical variables were selected a priori as potential predictors/moderators of outcomes at 9 months. Outcomes were analysed in mixed-effects random regression models. (Trial registration: ClinicalTrials.gov, NCT01436331) Results Analyses were performed on 444 patients. Education, duration of untreated psychosis, premorbid adjustment and insight predicted outcomes regardless of treatment. Only age at first contact with the services proved to be a moderator of treatment outcome (patients aged ⩾35 years had greater improvement in psychopathology), thus suggesting that the intervention is beneficial to a broad array of patients with FEP. Conclusions Except for patients aged over 35 years, no specific subgroups benefit more from the multi-element psychosocial intervention, suggesting that this intervention should be recommended to all those with FEP seeking treatment in mental health services., Competing Interests: Declaration of interestNone., (© The Royal College of Psychiatrists 2017.)

Two new prenylated flavanones, pazentin A (3',4'-dihydroxy-6,2'-diprenylpinocembrin, 1) and pazentin B [4'-hydroxy-2'-methoxy-5'-(1‴, 1‴-dimethylallyl)-6-prenylpinocembrin, 2] together with two known ones (3 and 4) previously isolated from other Dalea species were obtained from the benzene extract of Dalea pazensis Rusby roots. The compounds were evaluated in vitro for their inhibition on mushroom tyrosinase enzyme and in relation to their effect on melanogenesis in B16 murine melanoma cells, by using a spectrophotometric method. The information obtained could be relevant to the knowledge of the structure-activity relationship for these flavonoids with the aim to explore the rational design for skin-whitening agents., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Considerable variations in the incidence of psychosis have been observed across countries, in terms of age, gender, immigration status, urbanicity and socioeconomic deprivation., Aims: To evaluate the incidence rate of first-episode psychosis in a large area of north-eastern Italy and the distribution of the above-mentioned risk factors in individuals with psychoses., Method: Epidemiologically based survey. Over a 3-year period individuals with psychosis on first contact with services were identified and diagnosed according to ICD-10 criteria., Results: In total, 558 individuals with first-episode psychosis were identified during 3,077,555 person-years at risk. The annual incidence rate per 100,000 was 18.1 for all psychoses, 14.3 for non-affective psychoses and 3.8 for affective psychoses. The rate for all psychoses was higher in young people aged 20-29 (incidence rate ratio (IRR) = 4.18, 95% CI 2.77-6.30), immigrants (IRR = 2.26, 95% CI 1.85-2.75) and those living in the most deprived areas (IRR = 2.09, 95% CI 1.54-2.85)., Conclusions: The incidence rate in our study area was lower than that found in other European and North American studies and provides new insights into the factors that may increase and/or decrease risk for developing psychosis., (Royal College of Psychiatrists.)

In the operative reattachment of an avulsed or lacerated tendon, additional tendon length is occasionally needed to reach the proposed reinsertion site. This is encountered when there is loss of distal tendon substance or when muscle shortening and tendon retraction has occurred. The following describes a technique of lengthening the terminal portion of the tendon to facilitate reattachment.

A variety of clinical presentations can be encountered following compartment syndrome of the leg and foot. Deformity and functional impairment in the foot and ankle secondary to ischemia are determined by: 1) which leg compartments have been affected and to what degree extrinsic flexor or extensor "overpull" is exhibited, 2) degree of nerve injury sustained causing weakness or paralysis of extrinsic or intrinsic foot and ankle muscles, 3) which foot compartments have been affected and to what degree intrinsic "overpull" is exhibited, and 4) degree of sensory nerve injury leading to anesthesia, hypoesthesia, or hyperesthesia of the foot. Nonoperative therapy attempts to obtain or preserve joint mobility, increase strength, and provide corrective bracing and accommodative foot wear. Operative management is undertaken for treatment of residual nerve compression or refractory problematic deformities. Established surgical protocols are performed in a stepwise fashion, and include: 1) release of residual or secondary nerve compression; 2) release of fixed contractures, using infarct excision, myotendinous lengthening, muscle recession, or tenotomy; 3) tendon transfers or arthrodesis to increase function; and 4) osteotomy or amputation for severe, non-salvageable deformities.

Fibrotic contracture of skeletal muscle can follow weeks or months after the severe ischemic insult of compartment syndrome. Commonly known as Volkmann's ischemic contracture, the affected limb often becomes dysfunctional and painful, and may lose sensibility. The pathogenesis of the muscle contracture includes prolonged ischemia, myonecrosis, fibroblastic proliferation, contraction of the cicatrix, and myotendinous adhesion formation. Resultant shortening or overpull of involved muscles leads to stiffness and deformity. Simultaneously, nerve injury from initial ischemia or subsequent soft tissue fibrotic compression leads to muscle paresis or paralysis of the involved compartment and of those muscles more distally innervated. The resultant deformity is thus a combination of varying degrees of contracture and weakness depending on which muscles and nerves are affected. Deformity and functional impairment in the foot and ankle secondary to ischemia are determined by many factors, including: (1) which leg compartment, if any, has been affected and to what degree extrinsic flexor or extensor overpull is exhibited, (2) degree of nerve injury sustained causing weakness or paralysis of extrinsic or intrinsic foot and ankle muscles (3) which foot compartment, if any, has been affected and to what degree intrinsic overpull is exhibited, and (4) degree of sensory nerve injury leading to anesthesia, hypoesthesia, or hyperesthesia of the foot. Therefore, a variety of clinical presentations can be encountered following compartment syndrome of the leg and foot. Treatment is based on an appreciation of the pathoanatomy of the deformity. Nonoperative therapy is aimed at obtaining or preserving joint mobility, increasing strength, and providing corrective bracing and accommodative footwear. Operative management is usually reserved for treatment of residual nerve compression or severe and problematic deformities. Established surgical protocols are performed in a stepwise fashion, to include: (1) release of residual or secondary nerve compression, (2) release of fixed contractures, using infarct excision, myotendinous lengthening, muscle recession, or tenotomy, (3) tendon transfers or arthrodesis to increase function, and (4) ostectomy or amputation for severe, refractory deformities.

Twenty-eight patients who had reconstructions of the anterior cruciate ligament with a ligament augmentation device in the semitendinosus and gracilis tendons were compared with 32 patients who had reconstructions with semitendinosus and gracilis tendons alone. Preoperatively, there was no significant difference between the 2 groups with respect to age, sex, Tegner activity level, and time from injury to operation. Mean postoperative followup was 31.4 months for the augmentation group and 32.3 months for the nonaugmentation group. At postoperative evaluation, there was no difference in the 2 groups with respect to Lysholm knee scores, return to activity as measured by Tegner levels, KT-1000 arthrometer laxity testing, presence of pivot shift or Lachman sign, range of motion, and the patient's subjective overall rating of the surgery. Twenty-six of the 28 patients (93%) with augmentation rated their results as either "good" or "excellent" compared with 30 of the 32 patients (94%) with no ligament augmentation who rated their results as good or excellent. Four patients with the ligament augmentation devices needed reoperation for recurrent effusions and pain. No patients in the nonaugmentation group had recurrent effusions.

Twelve infants born to mothers who received i.v. magnesium sulfate for > 6 weeks for the cessation of preterm labor were evaluated radiographically shortly after birth. All infants were born at > 33 weeks gestational age. All twelve infants demonstrated consistent and unique radiographic abnormalities in the metaphyses of their long bones. The extent of abnormality was at least partially related to the length of magnesium sulfate exposure, and appeared to completely resolve within the first few months of life.

Giant sacral schwannomas (GSS) are extremely rare. Complete resection of benign but neurologically devastating tumors has been recommended. A 48-year-old man with GSS had a tumor so large that a total sacrectomy was necessary. A special method of lumbar iliac fixation was devised. Two years and nine months after surgery, the patient was free of pain and ambulating with bilateral orthoses.

The results of 94 initially successful, partial foot amputations in dysvascular patients were reviewed with survivorship analysis at a minimum of 6.5 years after surgery. Partial foot amputations were divided into three types: transmetatarsal amputations, metatarsophalangeal disarticulations, and ray resections. No amputation type was more or less likely to be treated with subsequent amputation of the foot or to develop recurrent ulceration. Taking all groups together, the chance of retaining the foot after an initially healed partial foot amputation was 86% at four years after operation and 76% at eight years after operation. Of these surviving feet, however, 53.8% developed ulceration or needed local reoperation. The chance of completely avoiding any surgery after an initially healed partial foot amputation was 71% at four years after operation and 52% at eight years after operation. In properly selected patients, partial foot amputations have significant longevity.

A female volleyball player with a Marfanoid habitus had bilateral symptomatic anomalous insertions of the medial meniscus. Arthroscopic resection of the anomalous portions of the medial menisci as they attached to the anterior cruciate ligament successfully eliminated her symptoms.