Arthrogryposis Multiplex Congenita and the Importance of Orthoses: A Case Report.

Arthrogryposis multiplex congenita (AMC) is a group of conditions characterized by multiple joint contractures. This rare disorder causes stiffness of joints, limiting the range of motion and negatively impacting activities of daily living (ADL). This case reports a 45-year-old male with AMC who was referred to physical medicine and rehabilitation (PMR). He had a limited range of movement in multiple joints and global muscle weakness. However, ADL were feasible, including walking. The patient had an unsteady barefoot gait, causing claudication, which improved significantly with adapted shoes. The primary goal of treatment is to improve the quality of life (QoL), and proper management should be promptly initiated. AMC requires a multidisciplinary approach to care with three mainstays of treatment: rehabilitation, orthoses, and corrective surgeries. Patients should be followed up periodically by their family doctors, and PMR evaluations and rehabilitation should be provided as needed. An orthopedic surgery consultation may be required for surgical interventions to provide optimal outcomes and augment the QoL.

Intranasal irbesartan reverts cognitive decline and activates the PI3K/AKT pathway in an LPS-induced neuroinflammation mice model.

BACKGROUND: New strategies are urgently needed to manage and delay the development of Alzheimer's disease (AD). Neuroinflammation is a significant contributor to cognitive decline in neurodegenerative diseases, including AD. Angiotensin receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEIs) protect hypertensive patients against AD, but the cellular and molecular mechanisms underlying these effects remain unknown. In light of this, the protective effects of three ARBs and three ACEIs against neuroinflammation and cognitive decline were investigated through comprehensive pharmacologicalin vitro/in vivoscreening. METHODS: BV-2 microglia cells were exposed tolipopolysaccharide (LPS) and treated with ARBs and ACEIs to provide initial insights into the anti-inflammatory properties of the drugs. Subsequently, irbesartan was selected, and its efficacy was evaluated inC57/BL6 male miceintranasally administered with irbesartan and injected with LPS. Long-term memory and depressive-like behavior were evaluated; dendritic spines were measured as well as neuroinflammation, neurodegeneration and cognitive decline biomarkers. RESULTS: Irbesartan mitigated memory loss and depressive-like behavior in mice treated with LPS, probably because itincreased spine density, ameliorated synapsis dysfunction and activated the PI3K/AKT pathway. Irbesartan elevated the levels of hippocampalsuperoxide dismutase2 andglutathione peroxidaseandsuppressed LPS-induced astrogliosis. CONCLUSIONS: Overall, this study provides compelling evidence that multiple intranasal administrations of irbesartan can effectively prevent LPS-induced cognitive decline by activating pathways involved in neuroprotection and anti-inflammatory events. These findings underscore the potential of irbesartan as a preventive strategy against the development of AD and other neurodegenerative conditions associated with neuroinflammation.

Intrathecal baclofen for the management of hereditary spastic paraparesis: a systematic review.

This systematic review aims to evaluate the use of intrathecal baclofen (ITB) for hereditary spastic paraparesis (HSP) treatment. An extensive search in two electronical databases was performed. We identified articles published between 1990 and 2022 (PubMed, Scopus), and applied the following inclusion criteria: diagnosis of HSP at the time of the intervention, either familial or sporadic; report on the effect of ITB in patients with HSP; test trial via either bolus injections or continuous infusion tests; and ITB pump implantation. A data extraction sheet based on the Cochrane Consumers and Communication Review Group's data extraction template was created and adapted to collect relevant data. A qualitative analysis was performed to present the results in narrative summary fashion. A total of 6 studies met our inclusion criteria. 51 patients with HSP had a pre-implantation ITB trial. The time since the diagnosis until the pump implantation ranged from 5 to 30 years. The initial bolus ranged from 20 to 50 µg and the mean doses used at steady state ranged from 65 to 705 µg. An improvement in spasticity was observed on the modified Ashworth Scale in patients treated with ITB. Although all studies reported a subjective gait improvement, not all found an objective improvement in gait. The most common side effect reported was catheter-related problems. The findings of this review support the use of ITB as an effective and a viable option for the treatment of spasticity in HSP refractory to conservative therapies.

Post-stroke dysphagia: Clinical characteristics and evolution in a single-primary stroke center.

BACKGROUND: Dysphagia is a common manifestation after stroke and seems to play a major role in clinical and functional outcomes. OBJECTIVES: To identify clinical predictors of higher degrees of dysphagia, as well as assess its burden in our hospital, in order to understand how to improve the approach to this symptom. METHODS: We included 311 patients admitted in an acute stroke unit in a year-long period. The relationship of dysphagia with different outcomes, both in acute phase and within the first year after stroke, were investigated. RESULTS: Using the Pearson Correlation Coefficient, NIHSS score at admission was positively correlated with the degree of dysphagia (r = 0,783; p < 0,001) and total anterior circulation infarcts and age (> 70 years) were also associated with higher risk of dysphagia (p < 0.001). During hospitalization both respiratory infections and mortality occurred at significantly higher rates for dysphagic patients (p < 0.001) and we observed an increasing trend towards a higher mortality rate, the higher the degree of dysphagia. These patients stayed longer in the stroke unit, with less chance to be discharged home and more frequently transferred to inpatient rehabilitation care. One year after admission, dysphagic patients were more frequently readmitted due to pneumonia and we observed a higher mortality rate compared to patients without dysphagia (p < 0.001). CONCLUSION: The presence of the above-mentioned dysphagia predictive factors should alert us to the need for an early approach, starting in the stroke unit, but also after discharge, taking into account its impact on clinical outcomes, mortality and healthcare costs.

Horseback Riding-Related Injuries in Portugal and Prevention Strategies.

CONTEXT: Horse riding (HR) has gain popularity in Portugal, thereby increasing the number of related injuries. This study identifies frequently occurring injuries in Portuguese riders, the conditions under which they occur, and preventive measures. DESIGN: A retrospective cohort study. METHODS: We included 216 Portuguese riders practicing HR at the time of the study with ≥1 year of experience. Data were obtained from a questionnaire that characterized first and second rider injuries; we opted for a systematic method to assess the riders' injuries, in a temporal order. Questions regarding demographic data, sports-related background, systematic training workload, number and characteristics of the first 2 injuries, and the need for treatment were included in the questionnaire. RESULTS: Most first and second injuries were musculoskeletal, occurred from falling off the horse during training, and primarily affected the lower limb. Rehabilitation was required in almost 50% of all cases. The occurrence of injury was significantly associated with the number of days of training per week, years of experience, height and weight of the rider, and practice of another sport. Riding different horses was also significantly associated with the number of injuries. CONCLUSIONS: The most frequently occurring injuries during HR are musculoskeletal and in the extremities. Injury prevention is essential in HR, as most riders have at least one injury while practicing. Rehabilitation should involve a physiatrist and core strengthening exercises.

Targeting brain Renin-Angiotensin System for the prevention and treatment of Alzheimer's disease: Past, present and future.

Alzheimer's disease (AD) is a well-known neurodegenerative disease characterized by the presence of two main hallmarks - Tau hyperphosphorylation and Aß deposits. Notwithstanding, in the last few years the scientific evidence about the drivers of AD have been changing and nowadays age-related vascular alterations and several cardiovascular risk factors have been shown to trigger the development of AD. In this context, drugs targeting the Renin Angiotensin System (RAS), commonly used for the treatment of hypertension, are evidencing a high potential to delay AD development due to their action on brain RAS. Indeed, the ACE 1/Ang II/AT1R axis is believed to be upregulated in AD and to be responsible for deleterious effects such as increased oxidative stress, neuroinflammation, blood-brain barrier (BBB) hyperpermeability, astrocytes dysfunction and a decrease in cerebral blood flow. In contrast, the alternative axis - ACE 1/Ang II/AT2R; ACE 2/Ang (1-7)/MasR; Ang IV/ AT4R(IRAP) - seems to counterbalance the deleterious effects of the principal axis and to exert beneficial effects on memory and cognition. Accordingly, retrospective studies demonstrate a reduced risk of developing AD among people taking RAS medication as well as several in vitro and in vivo pre-clinical studies as it is herein critically reviewed. In this review, we first revise, at a glance, the pathophysiology of AD focused on its classic hallmarks. Secondly, an overview about the impact of the RAS on the pathophysiology of AD is also provided, focused on their four essential axes ACE 1/Ang II/AT2R; ACE 2/Ang (1-7)/MasR; Ang IV/ AT4R(IRAP) and ACE 1/Ang II/AT1R. Finally, the therapeutic potential of available drugs targeting RAS on AD, namely angiotensin II receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEIs), is highlighted and data supporting this hope will be presented, from in vitro and in vivo pre-clinical to clinical studies.

A combo-strategy to improve brain delivery of antiepileptic drugs: Focus on BCRP and intranasal administration.

The breast cancer resistance protein (BCRP) is an efflux transporter expressed at the apical surface of human brain endothelial cells of the blood-brain barrier (BBB). It was proposed as one of the transporters responsible for the development of drug resistance to several central nervous system (CNS) drugs, including antiepileptic drugs (AEDs). In this context, the present work aimed to characterize the interaction between new-generation AEDs, lacosamide, levetiracetam and zonisamide, and BCRP, in order to investigate whether intranasal administration can successfully avoid the impact of BCRP on brain drug distribution, preventing the development of refractory epilepsy. Firstly, BCRP substrates and/or inhibitors were identified resorting to intracellular accumulation and bidirectional transport assays on Madin-Darby canine kidney (MDCK) cells and the transfected cell line with human ABCG2 (MDCK-BCRP). Furthermore, in vivo pharmacokinetic studies were carried out for BCRP substrates with and without elacridar, a well-known P-gp and BCRP modulator, to assess the impact of efflux inhibition on brain drug distribution. The extent of drug equilibration between plasma and brain was compared after intravenous (IV) and intranasal administration to mice. Among the three tested AEDs, zonisamide was the only AED identified as BCRP substrate in vitro, as demonstrated by the net flux ratio of 2.73, which decreased 53.85 % in the presence of a BCRP inhibitor, Ko143. Lacosamide revealed to inhibit BCRP in all tested concentrations (2.5-75 µM), exhibiting a significant increase (p < 0.001) of the intracellular accumulation of a BCRP substrate (Hoechst 33342) in MDCK-BCRP cells. Levetiracetam did not behave as a BCRP substrate nor inhibitor. After IV administration, the plasma concentrations of zonisamide were unaffected by elacridar, but its extent of brain exposure increased three-fold (as assessed by AUCt, 674.12 vs 284.47 µg.min/mL). These results corroborate the previous in vitro findings, suggesting that BCRP is involved in the transport of zonisamide through the BBB. In opposition, no significant changes were found in plasma or brain concentrations after the administration of zonisamide by intranasal route, indicating that the influence of BCRP is less relevant than for IV route. In addition, direct nose-to-brain delivery of zonisamide, given by the direct transport percentage, was approximately 49 %. Altogether, these assays demonstrated that the impact of BCRP on the delivery of zonisamide to the brain is lower after intranasal administration, probably due to direct nose-to-brain transport. Therefore, the intranasal administration of AEDs may be a relevant strategy to avoid the impact of efflux transporters at the BBB and the development of drug resistance.

QbD-driven development of intranasal lipid nanoparticles for depression treatment.

Depression is a life-threatening psychiatric disorder and a multifactorial global public health concern. Current pharmacological treatments present limited efficacy, and are associated with several harmful side effects and development of pharmacoresistance mechanisms. Developing more effective therapeutic options is therefore a priority. This work aims at efficiently designing an antidepressant therapeutic surrogate relying on a dual strategy supported on lipid nanoparticles and intranasal delivery. For that purpose, the formulation was comprehensively optimized following a quality by design perspective. Critical quality attributes (CQAs) ranged from physicochemical to intranasal performance features. The optimized formulation was administered to mice in order to assess the antidepressive and anxiolytic effects by applying the forced swimming and marble-burying tests, respectively. A cross-analysis of the predictive models established for the set of 12 CQAs elicited the formulation containing similar proportion of solid and liquid lipids and lower surfactant concentration as the optimal one. Despite increasing the liquid lipid amount yielded smaller and more homogeneous particle size, and higher release rate, nanostructured lipid carriers (NLCs) provided an earlier and superior pig nasal mucosa permeability than nanoemulsions, along with better stability and cytotoxic profiles. Importantly, the intranasal delivery of the optimal lipid nanoparticle formulation reduced both depressive and anxiety-like behaviors, which positions these intranasal nanosystems in line with the hypothesis of provisioning timely and better acting antidepressant therapies.

Development, validation and application of a new HPLC-DAD method for simultaneous quantification of apixaban, dabigatran, edoxaban and rivaroxaban in human plasma.

Direct oral anticoagulants (DOACs) have been commonly used for the treatment of venous thromboembolism and for the prevention of stroke in patients with atrial fibrillation. Despite not being initially recommended, monitoring DOACs plasma concentrations is now recognized as essential in emergency situations and in special populations. Moreover, the inter-individual variability found in real studies as well as the high reported non-adherence are corroborating the importance of determining the individual relationship between administered doses, plasma concentrations and pharmacological effects. Therefore, accurate but user-friendly bioanalytical techniques are required to monitor DOACs plasma concentrations in routine clinical practice and phase IV clinical trials. Herein, a fast and simple high performance liquid chromatography (HPLC) method coupled to diode array detection (DAD) was developed, validated and applied to quantify the four currently marketed DOACs (apixaban, edoxaban, dabigatran and rivaroxaban). Sample preparation was performed by solid phase extraction followed by evaporation and concentration of the analytes. Chromatographic separation was accomplished within 6 min on a reversed-phase column (octadecyl-silica packing material; 55 mm × 4 mm, 3 µm particle size), applying a mobile phase composed of an aqueous solution of formic acid (0.1 %, v/v) and acetonitrile, pumped with a gradient elution at 30 °C. The proposed method was linear (r2 ≥ 0.993) within the concentration ranges of 0.017-5.28 µg mL-1, 0.066-5.28 µg mL-1, 0.033-5.28 µg mL-1 and 0.017-5.28 µg mL-1 for apixaban, dabigatran, edoxaban and rivaroxaban, respectively, all of them including the expected range of therapeutic concentrations. Overall, intra- and inter-day trueness of quality control samples, including at the lower limit of quantification (LLOQ), varied between -12.98 to 5.79 %, while imprecision was lower than 16.43 %, supporting that the method is accurate and precise in accordance to international guidelines. Recovery and stability were also assessed and allowed the method to be applied in clinical practice, during therapeutic drug monitoring.

Liquid chromatographic methods for the determination of direct oral anticoagulant drugs in biological samples: A critical review.

Direct oral anticoagulants (DOACs) are first-line drugs used for the treatment of venous thromboembolism and prevention of stroke in patients with atrial fibrillation. These drugs do not require the regular biochemical monitoring that is mandatory for warfarin, and they exhibit shorter half-lives and have a faster onset of action. Since recent real-world studies evidence a higher prevalence of adverse side effects than what was anticipated in clinical trials, monitoring the plasma concentrations of DOACs is being used to personalize their pharmacotherapy, in accordance to the characteristics of the patient, and to evaluate the adherence to therapy. In order to fulfill the aforementioned clinical unmet needs, there are specific coagulation assays that indirectly assess the plasma concentrations of DOACs. Nevertheless, these assays are not sufficiently accurate or sensitive. For this reason, liquid chromatography techniques coupled to mass spectrometry detection, are considered the gold standard method to accurately determine plasma concentrations of DOACs. Therefore, the present paper provides the first comprehensive review of the current analytical methods that were developed and validated for the quantitative determination of apixaban, dabigatran, rivaroxaban and/or edoxaban and their main metabolites in biological samples. The chromatographic methods will be particularly highlighted and an emphasis will be placed on the major difficulties faced during optimization and development steps. In addition, the physicochemical, pharmacokinetic and pharmacodynamic characteristics of each drug will be critically related to chromatographic conditions. Their influence on the pre-treatment procedures and storage conditions of DOACs will be examined, suggesting strategies that should be applied to accurately quantify DOACs in biological samples.

Nose-to-brain delivery of levetiracetam after intranasal administration to mice.

Despite being one of the most commonly prescribed antiepileptic drugs, levetiracetam is marketed in oral and intravenous dosage forms, which are associated to drug-drug interactions and drug-resistant epilepsy (DRE). The purpose of the present study was to assess the potential of the intranasal route to deliver levetiracetam into the brain, due to the particular anatomical features of the nasal cavity. After development and characterization of the drug formulation, a thermoreversible gel loaded with levetiracetam was administered to CD-1 male mice by intranasal route and its pharmacokinetics compared to those observed after intravenous administration. Similar plasma pharmacokinetic profiles were obtained and the intranasal absolute bioavailability was 107.44%, underscoring that a high drug fraction was systemically absorbed. In brain tissue, maximum drug concentrations were 4.48 and 4.02 µg/g (intranasal vs intravenous) and the mean cerebral concentrations were significantly higher after intranasal administration. The percentage of drug targeting efficiency was 182.35% while direct transport percentage was 46.38%, suggesting that almost 50% of levetiracetam undergoes direct nose-to-brain delivery. Complementarily, an in vivo intranasal repeated dose toxicity study was performed and no relevant histopathological alterations were observed. The herein proposed non-invasive and safe intranasal administration route allowed a direct nose-to-brain delivery of levetiracetam and is a promising strategy for the treatment of DRE.

[Chronic Pain After Outpatient Inguinal Hernioplasty: Retrospective Cohort Study]. / Dor Crónica Pós-Hernioplastia Inguinal em Regime de Ambulatório: Estudo de Coorte Retrospetivo.

INTRODUCTION: Chronic postoperative pain is the most frequent late complication of inguinal hernia repair surgery. The aim of this study is to evaluate the incidence of chronic post-hernioplasty pain in outpatient care at Centro Hospitalar do Porto, describe it, analyse its relation with other variables defined in the literature and study its functional interference. MATERIAL AND METHODS: We performed a retrospective cohort study between February and May 2016, using a structured telephone interview composed of questions from the authors and sections of published questionnaires, two of which are validated for the Portuguese language and culture. We included men who underwent ambulatory inguinal hernioplasty, by laparotomy or laparoscopy, at Centro Hospitalar do Porto, between January 2011 and October 2015. RESULTS: In a final sample of 829 surgeries, the incidence of chronic post-hernioplasty pain was 24.0% [confidence interval: 21.2 - 27.1]. The development of chronic post-hernioplasty pain was higher in patients with pre-surgical pain and younger age and was related with the presence of pain during the first month after surgery. No relationship was found between surgical technique and the development of chronic post-hernioplasty pain. Of the individuals with chronic pain, 65.0% mentioned moderate-severe 'pain on the average' and 37.7% presented descriptors suggestive of neuropathic pain. The only parameter evaluated with which chronic post-hernioplasty pain 'did not interfere completely' was sleep. DISCUSSION: The prevalence found for chronic posthernioplasty pain with significant functional interference is in line with data retrieved from literature. The predictive potential of pre-surgical pain and young age for the development of chronic posthernioplasty pain is also in agreement with previous studies. Limitations were found to this study given its retrospective nature. CONCLUSION: The high prevalence of chronic post-hernioplasty pain raises the urgent need for raising awareness regarding this issue among health care professionals. The main areas for improvement are diagnosis, follow-up and treatment of pain.

Introdução: A dor crónica pós-cirúrgica é a complicação tardia mais frequente da cirurgia de reparação de hérnia inguinal. Este trabalho visa determinar a incidência de dor crónica pós-hernioplastia inguinal em ambulatório no Centro Hospitalar do Porto, estudar a sua relação com determinadas variáveis descritas na literatura, avaliar as suas características e interferência funcional.Material e Métodos: Realizámos um estudo de coorte retrospetivo, entre fevereiro e maio de 2016, por entrevista telefónica estruturada composta por perguntas dos autores e secções de três questionários publicados, dois dos quais validados para a língua e cultura portuguesas. Incluímos os homens submetidos a hernioplastia inguinal, por laparotomia ou laparoscopia, em ambulatório, no Centro Hospitalar do Porto, entre janeiro de 2011 e outubro de 2015.Resultados: Na amostra final de 829 hernioplastias, a incidência de dor crónica pós-hernioplastia foi de 24,0% [intervalo de confiança: 21,2 - 27,1]. O desenvolvimento de dor crónica foi superior nos doentes com dor pré-cirúrgica, nos doentes mais jovens e relacionou-se com o momento de início da dor pós-cirúrgica. Não encontrámos relação com a via de abordagem, clássica ou laparoscópica. Dos indivíduos com dor crónica, 65,0% apresentaram dor 'em média' moderada ou forte e 37,7% apresentavam descritores sugestivos de dor de origem neuropática. A dor crónica pós-hernioplastia do ponto de vista funcional apenas 'não interferiu completamente' com o sono.Discussão: A prevalência encontrada de dor crónica pós-hernioplastia, com interferência funcional importante, é congruente com os dados disponíveis na literatura. O potencial preditor da presença de dor pré-cirúrgica e idade jovem do doente para o desenvolvimento de dor crónica pós-hernioplastia é também corroborado pela literatura. Tratando-se de um estudo de coorte retrospetivo, o estudo apresenta as limitações inerentes.Conclusão: A elevada prevalência de dor crónica pós-hernioplastia encontrada apontam para a urgência na sensibilização dos profissionais de saúde para esta problemática e otimização do follow-up, diagnóstico e tratamento da dor.