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Spinal muscular atrophy (SMA) is the most common inherited lethal disease in children. Confirmatory diagnosis is based on molecular genetic testing of survival motor neuron (SMN) genes. We aimed to describe the phenotypic presentation of Filipino infants and children with SMA based on the copy number analysis of SMN genes. Medical records of 17 Filipino children were reviewed from January 2017 to December 2019. De-identified clinical data fulfilled the diagnostic criteria defined by the International SMA Consortium. Among Filipino children, the predominant SMA type by copy number was type I having two copies of SMN2 gene. The clinical severity based on symptom onset and highest functional motor capacity attained correlated with SMN2 copy number congruent with existing data. A significant time lag between symptom onset to confirmation of genetic diagnosis was noted. Nine out of the 17 (52%) children did not have a family history of the disease, raising the possibility of mutation carriers in these families since the incidence of de novo mutations in literature is about 2%. These data offered the first epidemiological pattern of genetically confirmed SMA among Filipino children; provided additional information for genetic counselling; and an avenue to consider pre-symptomatic newborn screening and carrier testing that would change proactive measures and opportunities for therapy. These measures unavoidably will decrease the incidence and prevalence of disease in the future. Key words: Clinical profile, spinal muscular atrophy, genetically-confirmed, Filipino children, survival motor neuron

Rationale: Duchenne muscular dystrophy (DMD) is a disease that primarily manifests in the early stages of life and progressively affects muscle strength resulting in quadriparesis and ultimately resulting in premature death secondary to cardiac or respiratory failure. DMD is the most common x-linked genetic disorder in children that is because of an alteration of a protein called “dystrophin” which is responsible for strengthening muscle fibers and protecting them from injury as muscles contract and relax. Objective: To highlight the case of a 19-year-old male who was diagnosed with DMD at 8 years of age and treated with oral corticosteroid and rehabilitation. Case: We present the case of a 19-year-old male who developed difficulty climbing stairs and was diagnosed with DMD at 8 years old with the use of clinical exome sequencing. Corticosteroid therapy was initiated and rehabilitation perpetuated which dramatically improved his life expectancy. Discussion and Summary: Clinical exome sequencing was employed on our patient to confirm the diagnosis of DMD from other neuromuscular and neurodegenerative diseases. Most cases of DMD succumb to cardiopulmonary arrest before reaching adulthood; however, this case exemplifies DMD from other cases since our patient was able to prolong his life with continuation of oral corticosteroid and rehabilitation and in the absence of extensive life support. Key words: Progressive muscle weakness, Dystrophin, Premature death, DMD

POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes) also known as Crow-Fukase syndrome or Takatsuki syndrome is a rare and disabling paraneoplastic syndrome that frequently occurs in the fifth or sixth decade of life without a known standard first-line therapy. A 34-year-old Filipino male nurse, who presented with gradually progressive distal lower extremity weakness and sharp shooting pain in bilateral legs accompanied by mild joint effusion on the left knee, hypertrichosis, bilateral conjunctival injection, and gynecomastia underwent extensive workup and was diagnosed with POEMS syndrome. Complete blood count revealed erythrocytosis and thrombocytosis with elevated serum VEGF (vascular endothelial growth factor) and elevated monoclonal serum free lambda light chains. The electrophysiologic studies revealed chronic demyelinating sensorimotor polyneuropathy while bone marrow core biopsy and bone marrow aspirate smear immunohistochemical staining showed it to be positive for lambda and CD138. He had an initial unsuccessful treatment course with melphalan and prednisone. Hence, bortezomib and dexamethasone were given which gave significant improvement in symptoms from the overall neuropathy limitation score of 5 to 1.

Aim: This study is aimed to assess the health and well-being benefits of gardening between gardeners and non-gardeners. Methods: A total of 400 respondents participated in the study which was equally sampled between gardeners and non-gardeners. Criterion sampling was utilized in the participant selection. The study utilized standardized questionnaires and was conducted in Central Philippines. The study utilized a quasi-experimental post-test only design. T-test of independent samples was utilized in the analysis. Results: Results revealed that gardeners have considerably higher reports of good health (M=3.40, SD=0.48), higher resilience (M=3.82, SD=.51) and displayed significantly higher reports of coping (M=3.82, SD=.56) than non-gardeners. Non-gardeners on the other hand showed to be more fearful of COVID-19 than the gardener group (M=3.26.SD=.63). Conclusion: Gardening activity is beneficial in maintaining a person’s perceived health and well-being especially in times of distress and social isolation. People who engage in gardening activities are better at adapting to change, making them more resilient and adjusted from grief and loss of a loved one. It is recommended to incorporate gardening as an adaptive means in improving the public’s health and well-being especially at times of health crises.

The research focused on the practices of teachers and parents of learners with special educational needs during pandemic employing descriptive-correlational research design. It specifically sought the demographic profile of the teachers and parent-respondents. Using purposive sampling, the respondents of the study consisted of 22 teachers and 26 parents from Academia De Santiago of Tarlac, and Angel Beats Play and Development Center, Manila, Philippines. The frequency count, percentage weighted mean, and correlation analysis were used to treat the data gathered from the survey-questionnaire. Results revealed that that the teacher-respondents “greatly encountered” behavioral problems and “encountered” cognitive development problems in handling LSENs; parent-respondents “encountered” both behavioral and cognitive development problems. There was a “great extent” of practices of teachers while “little extent” in parents’ practices. There was a significant relationship between the demographic profile of the teacher-respondents and the extent of teachers’ practices. Based from the significant findings drawn, this study recommends to upskill teachers’ competencies in handling learners with special education needs. Finally, implementation of the action plan is hereby recommended to improve the behavioral and cognitive aspects of the learners and to further improve practices of teachers and parents of the home-schooled learners with special educational needs during a pandemic and its aftermath.

Background X-Linked dystonia-parkinsonism (XDP) is a movement disorder characterized by the presence of both dystonia and parkinsonism with one or the other more prominent in the initial stages and later on manifesting with more parkinsonian features towards the latter part of the disease. XDP patients show oculomotor abnormalities indicating prefrontal and striatal impairment. This study investigated oculomotor behavior in non-manifesting mutation carriers (NMC). We hypothesized that oculomotor disorders occur before the appearance of dystonic or parkinsonian signs. This could help to functionally identify brain regions already affected in the prodromal stage of the disease. Methods Twenty XDP patients, 13 NMC, and 28 healthy controls (HC) performed different oculomotor tasks typically affected in patients with parkinsonian signs. Results The error rate for two types of volitional saccades, i.e., anti-saccades and memory-guided saccades, was increased not only in XDP patients but also in NMC compared to HC. However, the increase in error rates of both saccade types were highly correlated in XDP patients only. Hypometria of reflexive saccades was only found in XDP patients. Initial acceleration and maintenance velocity of smooth pursuit eye movements were only impaired in XDP patients. Conclusions Despite being asymptomatic, NMC already showed some oculomotor deficits reflecting fronto-striatal impairments, typically found in XDP patients. However, NMC did not show saccade hypometria and impaired smooth pursuit as seen in advanced Parkinson’s disease and XDP, suggesting oculomotor state rather than trait signs in these mutation carriers. Neurodegeneration may commence in the striatum and prefrontal cortex, specifically the dorsolateral prefrontal cortex.

Background: Resting tremor is a prominent cardinal motor symptom of Parkinson’s disease (PD). In some cases, the tremor may be refractory to dopaminergic and anticholinergic treatment. Multiple studies were previously done to evaluate the effectiveness of Botulinum Neurotoxin A (BoNT/A) with essential tremors and dystonia, but data regarding its use on tremors of PD is still lacking. Objective: This meta-analytic study aims to determine the effectiveness of BoNT/A in treating tremors of patients with PD. Data Sources: Researches were searched at PubMed, ScienceDirect and EBSCO Host. Review Methods: Articles on the effect of BoNT/A on PD hand tremors were searched. Studies and data pertaining to non-PD tremors like essential tremors excluded in the analysis due to difference in pathophysiology. Standardized mean difference was used as the effect measure and was computed with Review Manager version 5.4 software. Results: Three open label studies were used for final analysis in this study. Studies included are those pertaining to tremors due to PD. Pooled estimates showed a significant change in decreasing tremor score after BoNT/A injection. Conclusion: Botulinum Toxin A injections can be used to manage PD tremors effectively. Keywords: Botulinum neurotoxin A, Botox A, Btx, tremors, Parkinson’s disease

Objectives. This study aimed to develop and validate a simple questionnaire for chronic neuropathic pain that can be administered as a screening tool by general practitioners and internists in order to help them identify patients with probable neuropathic pain. Methods. Following a development phase and a pilot study, the revised version of the screening tool which included eleven descriptors associated with neuropathic pain both in English and Filipino languages was validated on 120 consecutive patients with any type of pain except psychogenic pain, recruited in the out-patient clinics of six hospitals. The questionnaire was validated by assessing the sensitivity, specificity, positive and negative predictive value of each item and the overall questionnaire. The internal consistency of the questionnaire items was assessed using the Kuder-Richardson formula 20. Results. Overall, the internal consistency of the SigN-PQ using the Kuder-Richardson formula 20 was 0.7837; the sensitivity was 91.89% with specificity of 80.22%, PV (+) was 65.38% and PV(-) was 96.0%. For the English version, the descriptors with the highest scores were burning (Sensitivity: 100%, Specificity: 93%) and electricity-like (Sensitivity: 100%, Specificity: 93%). For the Filipino version, mainit (burning) has the highest sensitivity of 88% with specificity of 82.6%, followed by gumagapang (tingling) with sensitivity of 86.96% and specificity of 85.42%. The sensation of saksak (stabbing) and hiwa (lancinating) have the lowest sensitivity, 60% and 54% respectively, although their specificity scores are high. Since this study is a validation of a screening tool for neuropathic pain, the investigators decided to choose descriptors with higher sensitivity. Thus, in the final version of the SignN-PQ, the descriptors saksak and hiwa were removed. Conclusion. The SigN-PQ Neuropathic Pain Questionnaire has a high overall sensitivity of 91.89% and specificity of 80.22%. The pain descriptors in the questionnaire are consistent with the descriptors cited in the literature. It is a valid screening instrument for neuropathic pain that can be easily incorporated in the daily practice of general practitioners and internists.

Acute lymphoblastic leukemia (aLL) is a malignant cancer in the blood and bone marrow characterized by rapid expansion of lymphoblasts. It is a common pediatric cancer and the principal basis of cancer death in children. Previously, we reported that L-asparaginase, a key component of acute lymphoblastic leukemia chemotherapy, causes IP3R-mediated ER Ca2+ release, which contributes to a fatal rise in [Ca2+]cyt, eliciting aLL cell apoptosis via upregulation of the Ca2+-regulated caspase pathway (Blood, 133, 2222–2232). However, the cellular events leading to the rise in [Ca2+]cyt following L-asparaginase-induced ER Ca2+ release remain obscure. Here, we show that in acute lymphoblastic leukemia cells, L-asparaginase causes mitochondrial permeability transition pore (mPTP) formation that is dependent on IP3R-mediated ER Ca2+ release. This is substantiated by the lack of L-asparaginase-induced ER Ca2+ release and loss of mitochondrial permeability transition pore formation in cells depleted of HAP1, a key component of the functional IP3R/HAP1/Htt ER Ca2+ channel. L-asparaginase induces ER Ca2+ transfer into mitochondria, which evokes an increase in reactive oxygen species (ROS) level. L-asparaginase-induced rise in mitochondrial Ca2+ and reactive oxygen species production cause mitochondrial permeability transition pore formation that then leads to an increase in [Ca2+]cyt. Such rise in [Ca2+]cyt is inhibited by Ruthenium red (RuR), an inhibitor of the mitochondrial calcium uniporter (MCU) that is required for mitochondrial Ca2+ uptake, and cyclosporine A (CsA), an mitochondrial permeability transition pore inhibitor. Blocking ER-mitochondria Ca2+ transfer, mitochondrial ROS production, and/or mitochondrial permeability transition pore formation inhibit L-asparaginase-induced apoptosis. Taken together, these findings fill in the gaps in our understanding of the Ca2+-mediated mechanisms behind L-asparaginase-induced apoptosis in acute lymphoblastic leukemia cells.

Background: There are growing reports on the benefits of gardening on physical and mental health especially during lockdowns, but very limited studies presented how this affects a person’s fear of COVID-19 and coping from grief and loss.Purpose: This study aimed to assess the mediating effects of gardening on coronaphobia and bereavement coping.Methods: This study utilised a cross-sectional design using self-report scales. A total of 200 participants were selected through referral sampling following a set of criteria. Both researcher-made and standardized questionnaires were utilized in the collection of data. Multiple linear regression was utilized to analyse association between the study variablesResults: Results revealed that gardening has significant partial mediating effects in the relationship between fear of COVID-19 and coping (B=-0.078, z=-3.55, p=0.001). Fear of COVID-19 negatively affects gardening (β=-0.157, p=0.001), while gardening positively affects coping (β=0.497, p=0.001). Nevertheless, the results also indicate that even accounting for the mediating role of gardening, fear of COVID-19 still has a negative impact to coping (β=0.148, p=0.001).Conclusion: Gardening is an adaptive practice in ameliorating stress and improving a person’s resilience and bereavement coping. This study adds to the body of knowledge on the benefits of gardening particularly on its mediating role between fear of COVID-19 and bereavement coping. Gardening activities as a complementary intervention may be recommended to bereaved individuals to help them improve coping and grief.

Rationale: Entrapment neuropathies are peripheral nerve disorders at specific anatomical locations. They may be caused by trauma in a manner of sprains or bone fracture, but it is often caused by repetitive insults or compression of nerves as they travel through a narrow anatomic space. Pregnancy and pre-existing comorbidities such as diabetes, obesity, cancer, or autoimmune diseases may also cause nerve entrapment. Objective: To highlight the case of a 52-year-old female developing right foot dysesthesia and weakness after continuous restraint strapping from her previous hospitalization. Case: Here we have the case of a 52-year-old Filipino female consulted because of right foot dysesthesia, allodynia, and mild weakness. She had a history of bipolar disorder and recent onset of acute psychosis and overdosing with her irregularly taken maintenance olanzapine tablets. She was put on restraint strapping of the right lower limb in her one-week hospital stay. This resulted in developing restraint marks on her right ankle accompanied by difficulty walking on heels and toes, spontaneous dysesthesia, and touch allodynia of her entire right foot. An electrodiagnosis yielded right lower limb focal neuropathies involving the right fibular nerve, right tibial nerve, right superficial fibular, and right sural nerves. The prescribed amitriptyline and gabapentin for 6 months led to gradual improvement of neuropathic pain. Discussion and Summary: Our case exemplifies focal limb neuropathies from entrapment due to restraint strapping. Electrodiagnostic confirmation of neuropathies of the same limb sensory and motor nerves was mandated to corroborate clinical neuropathic pain and after ruling out other causes of entrapment neuropathies. Prolonged use of neuropathic pain medications were needed to attain relief in this present case. Restrictive strapping is an iatrogenic cause of entrapment neuropathy that is preventable, had there been proper medical attention applied.

The daily work life of physicians who function as clinicians, researchers, and academicians is focused on improving public health and patient outcomes in three usually compartmentalized settings: clinics, classrooms, and centers for research. In these settings, physicians are addressing patients’ medical concerns based on evidence, and at the same time, considering if new information could lead to research and discovery for better patient outcomes. The physician then proceeds to mentor, teach, and train medical students in quality evidence-based clinical practice and the conduct of scientific research. The importance of operationally blending these three disciplines with research as a common thread is not only a big challenge for these physicians but also an opportunity to innovate for better public health.

Developmental disorders characterized by small body size have been linked to CDK5RAP2 loss-of-function mutations, but the mechanisms underlying which remain obscure. Here, we demonstrate that knocking down CDK5RAP2 in human fibroblasts triggers premature cell senescence that is recapitulated in Cdk5rap2an/an mouse embryonic fibroblasts and embryos, which exhibit reduced body weight and size, and increased senescence-associated (SA)-β-gal staining compared to Cdk5rap2+/+ and Cdk5rap2+/an embryos. Interestingly, CDK5RAP2-knockdown human fibroblasts show increased p53 Ser15 phosphorylation that does not correlate with activation of p53 kinases, but rather correlates with decreased level of the p53 phosphatase, WIP1. Ectopic WIP1 expression reverses the senescent phenotype in CDK5RAP2-knockdown cells, indicating that senescence in these cells is linked to WIP1 downregulation. CDK5RAP2 interacts with GSK3β, causing increased inhibitory GSK3β Ser9 phosphorylation and inhibiting the activity of GSK3β, which phosphorylates β-catenin, tagging β-catenin for degradation. Thus, loss of CDK5RAP2 decreases GSK3β Ser9 phosphorylation and increases GSK3β activity, reducing nuclear β-catenin, which affects the expression of NF-κB target genes such as WIP1. Consequently, loss of CDK5RAP2 or β-catenin causes WIP1 downregulation. Inhibition of GSK3β activity restores β-catenin and WIP1 levels in CDK5RAP2-knockdown cells, reducing p53 Ser15 phosphorylation and preventing senescence in these cells. Conversely, inhibition of WIP1 activity increases p53 Ser15 phosphorylation and senescence in CDK5RAP2-depleted cells lacking GSK3β activity. These findings indicate that loss of CDK5RAP2 promotes premature cell senescence through GSK3β/β-catenin downregulation of WIP1. Premature cell senescence may contribute to reduced body size associated with CDK5RAP2 loss-of-function.

Introduction In patients with cervical dystonia (CD), pain is a major contributor to disability and social isolation and is often the main reason patients seek treatment. Surveys evaluating patient perceptions of their CD symptoms consistently highlight pain as a troublesome and disabling feature of their condition with significant impact on daily life and work. Areas covered In this article, the authors review the epidemiology, assessment, possible mechanisms and treatment of pain in CD, including a meta-analysis of randomized controlled trial data with abobotulinumtoxinA. Expert opinion Mechanisms of pain in CD may be muscle-based and non-muscle based. Accumulating evidence suggests that non-muscle-based mechanisms (such as abnormal transmission and processing of nociceptive stimuli, dysfunction of descending pain inhibitory pathways as well as structural and network changes in the basal ganglia, cortex and other areas) may also contribute to pain in CD alongside prolonged muscle contraction. Chemodenervation with botulinum toxin is considered the first-line treatment for CD. Treatment with botulinum toxin is usually effective, but optimization of the injection parameters should include consideration of pain as a core symptom in addition to the motor problems.

Scouting is one of the most prominent extra-curricular activities. It has a positive effect on an individual's character development and nurturing. It enables someone to use critical thinking abilities and be resilient. Moreover, it is notable in shaping adults to have self-esteem, self-reliance, and job satisfaction. This descriptive-survey research sought to determine the relationship between the teachers' level of participation in scouting activities and how it influenced their self-esteem and job satisfaction. The respondents of this study were the public elementary school boy scout coordinators in the 2nd Congressional District of Bohol, Philippines. From this population, 114 respondents were selected through cluster sampling. The researcher employed a researcher-made questionnaire (with internal consistency of alpha = 0.866) for the level of participation in scouting activities, the Self-esteem Scale survey questionnaire by Morris Rosenberg, and the Job Satisfaction Survey questionnaire by Richard Bellingham to obtain the necessary data. Results revealed that most respondents have an 'average' participation level in scouting activities, ‘low' self-esteem, and ‘very high’ job satisfaction. 'Sex' and 'length of service' were identified as predictors that influenced the level of participation in scouting. Thus, no significant relationship was found between the boy scout coordinators' participation level in scouting, self-esteem, and job satisfaction.

Loss of cyclin-dependent kinase 5 (Cdk5) in the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) increases ER–mitochondria tethering and ER Ca2+ transfer to the mitochondria, subsequently increasing mitochondrial Ca2+ concentration ([Ca2+]mt). This suggests a role for Cdk5 in regulating intracellular Ca2+ dynamics, but how Cdk5 is involved in this process remains to be explored. Using ex vivo primary mouse embryonic fibroblasts (MEFs) isolated from Cdk5−/− mouse embryos, we show here that loss of Cdk5 causes an increase in cytosolic Ca2+concentration ([Ca2+]cyt), which is not due to reduced internal Ca2+ store capacity or increased Ca2+ influx from the extracellular milieu. Instead, by stimulation with ATP that mediates release of Ca2+ from internal stores, we determined that the rise in [Ca2+]cyt in Cdk5−/− MEFs is due to increased inositol 1,4,5-trisphosphate receptor (IP3R)-mediated Ca2+ release from internal stores. Cdk5 interacts with the IP3R1 Ca2+ channel and phosphorylates it at Ser421. Such phosphorylation controls IP3R1-mediated Ca2+ release as loss of Cdk5, and thus, loss of IP3R1 Ser421 phosphorylation triggers an increase in IP3R1-mediated Ca2+ release in Cdk5−/− MEFs, resulting in elevated [Ca2+]cyt. Elevated [Ca2+]cyt in these cells further induces the production of reactive oxygen species (ROS), which upregulates the levels of Nrf2 and its targets, Prx1 and Prx2. Cdk5−/− MEFs, which have elevated [Ca2+]cyt, proliferate at a faster rate compared to wt, and Cdk5−/− embryos have increased body weight and size compared to their wt littermates. Taken together, we show that altered IP3R1-mediated Ca2+ dynamics due to Cdk5 loss correspond to accelerated cell proliferation that correlates with increased body weight and size in Cdk5−/− embryos.

La zorrita del desierto, Vulpes macrotris, es un carnívoro nocturno poco común a raro que habita las regiones desérticas y semiáridas del oeste de Norteamérica. A diferencia de las poblaciones más norteñas, en el centro-sur de su distribución geográfica existe menos información sobre esta especie. En esta nota, reportamos un registro notable de la zorrita del desierto en el noroeste de San Luis Potosí, México. El 12 de agosto de 2017, se realizó el registro de un ejemplar macho atropellado en una carretera del municipio de Charcas San Luis Potosí, México. Esta zorrita del desierto fue fotografiada y se le tomaron medidas somáticas externas. Adicionalmente, se tomaron las coordenadas geográficas y se determinaron las características del tipo de hábitat. Nuestro registro representa la primera evidencia confiable de la zorrita del desierto en el estado de San Luis Potosí, México y posiblemente también es el segundo registro más sureño de la especie en el centro-sur de su distribución histórica. El ejemplar fue registrado a 107 km al noroeste del registro anterior en 11.26 km al S de Real de Los Pinos, Zacatecas, México. Se confirma la presencia de la zorrita del desierto para el noroeste de San Luis Potosí, México, después de 65 años de su último registro en la localidad más cercana en el estado de Zacatecas. Se discuten las implicaciones biológicas de este registro, así como la necesidad de realizar un seguimiento efectivo a largo plazo para conocer la distribución y determinar los parámetros ecológicos de las poblaciones de la zorrita del desierto en la zona.

INTRODUCCIÓN: La pandemia por la enfermedad por el nuevo coronavirus (COVID-19) impactó en la organización y el funcionamiento del sistema de salud en su conjunto; aunque es muy poco lo descrito sobre lo ocurrido en los servicios de salud mental donde, además de atender la demanda habitual, se debe atender a la población afectada emocionalmente por la pandemia. El objetivo de este estudio fue caracterizar el efecto de la pandemia por COVID-19 en la provisión de servicios de salud mental en Argentina. MÉTODOS: Se realizó un estudio observacional transversal. Se entrevistó a 76 trabajadores de servicios de salud mental de cinco jurisdicciones del país, entre el 8 de mayo y el 30 de junio de 2020. Se indagó por cambios en la demanda, en el proceso de atención y en la estructura de los servicios. El análisis de datos fue mixto. RESULTADOS: La focalización de los servicios de salud en la pandemia implicó una reducción de la disponibilidad de atención en salud mental. La demanda de atención se modificó, con cambios en los motivos de contacto con los servicios, que pasaron a ser más críticos. Se observó una reconcentración de la atención en salud mental en los hospitales neuropsiquiátricos. La oferta de atención disminuyó y las intervenciones grupales se vieron especialmente afectadas. DISCUSIÓN: La situación de los servicios de salud mental muestra el impacto de la COVID-19 en el acceso de la población a la atención por necesidades no vinculadas de manera directa con la enfermedad

Apomorphine hydrochloride is used in the management of advanced Parkinson disease (PD), either as a rescue medication for off periods during levodopa therapy or as a maintenance pump medication. This is the first study to describe the effects of apomorphine in Filipino patients with PD.To evaluate the safety and efficacy of apomorphine ampules (APO-go®) pump infusion in the treatment of motor fluctuations in patients inadequately controlled on oral anti-Parkinson medications.Patients diagnosed with PD who developed motor fluctuations with levodopa were evaluated at baseline and at the end of the study using the Modified Hoehn and Yahr (HY) Scale, the Unified Parkinson's Disease Rating Scale (UPDRS) and the Abnormal Involuntary Movement Scale (AIMS). After initial assessment, patients were administered 20 ampules of apomorphine hydrochloride 10 mg/mL by infusion pump over 20 days. Intention-to-treat (ITT) analysis included all patients who completed at least one posttreatment assessment. Motor disability based on modified HY scores, motor function and complications of therapy pre- and posttreatment were compared using Wilcoxon Signed Rank test. Chi-squared test was used to compare outcomes by age and sex. Frequencies of adverse reactions were recorded to evaluate the tolerability of the medication.Ten patients (mean age 63 ± 9.7 years), 3 male and 7 female, were enrolled in the study. Patients were given apomorphine for at most 16 days. The doses used were 2.5 mg/0.50 mL (Apomorphine hydrochloride pump infusion therapy is potentially effective and safe in the treatment of motor fluctuations in Filipino patients with PD. This pilot study springboards safe engagements of Filipino PD patients in multicenter, large-scale trials.

The study investigated the mental health concerns, mental health states, and help-seeking behaviors of international graduate students by gender. Ninety-two respondents accomplished an online survey. The males’ main concerns were academics and finances while it was academics and other relationships for females. There is no significant gender difference in mental health states although, there are more males with 3-5 depression symptoms and moderate-severe anxiety. Both males and females were willing to seek help for their mental health concerns. Both males and females suggested the provision of university mental health services. Further, males added the need for better teacher/adviser-student relations while females added having social events. The depression and anxiety symptoms were higher for male master’s students and for female students who resided off-campus and have a family member/friend diagnosed with a mental health problem. Provision of appropriate university services to attend to the mental health needs of international students is necessary.

X-linked dystonia parkinsonism (XDP) is a neurodegenerative disorder that has received significant interest on several fronts. Although much still remains to be elucidated regarding the disease cause, a robust amount of data has been produced in recent years compared to when it was first described in 1976. The debilitating nature of the overlapping dystonia and parkinsonism that characterizes this disorder has fueled much of the interest in unraveling its cause, clinical presentation, symptom progression, treatment and impact on the afflicted patients as well as their caregivers. Having made several significant advances in genetic studies, neuropathology, neurophysiology and clinical characterization, we are entering a new threshold in the study of this disorder, hopefully bringing us closer to potential treatments and possible cures. This review will focus on new information gathered regarding the motor and non-motor features of XDP, deep brain stimulation (DBS) as a potential treatment for XDP and the utility of the recently validated XDP-Movement Disorder Society of the Philippines (MDSP)-rating scale.

RESUMEN Objetivo: evaluar la calidad de atención en servicios de internación psiquiátrica de hospitales generales desde los enfoques de derechos y comunitario. Métodos: estudio multicéntrico, observacional descriptivo. Se seleccionaron cuatro servicios de internación psiquiátrica de hospitales generales ubicados en centros urbanos de distinta población en Argentina. En cada uno de ellos se analizaron los registros estadísticos, se realizaron observaciones no participantes y se entrevistó a gestores, trabajadores y usuarios. La guía de observación y entrevista se elaboró a partir de la revisión de instrumentos de la OMS y del proyecto Idea. Los resultados se analizaron a partir de las categorías de enfoque de derechos y orientación comunitaria de los servicios. Resultados: respecto del enfoque de derechos se observa que el que requiere mayor desarrollo es el de capacidad jurídica. En relación a la orientación comunitaria, se observa un mayor desarrollo de esta perspectiva a través de la implementación de diversas estrategias y el trabajo con las familias como la más común. Conclusiones: en términos de procesos y resultados de la atención se observan algunas diferencias entre los servicios que cuentan con sala especializada y los que no, y que estos últimos requieren de otros estudios para poder ser analizados. ABSTRACT Objective: To evaluate, based on the human rights and community care frameworks, the quality of hospitalization psychiatric services in general hospitals. Methods: Multisite, descriptive observational study. There were analyzed four psychiatric hospitalization services, located in general hospitals of urban districts with different sizes in Argentina. Data collection included analysis of statistical records, non-participant observations of services, and interviews with service managers, service staff and users. The observation and interview guides were based on two international tools: Idea project interview guide, and QRTK of the WHO. Results were analyzed using two main categories: human rights-based care approach and community orientation of care delivery. Results: Regarding human rights-based care, legal capacity is the right that requires more improvement in services. About community orientation of care, different strategies were observed, with the work with the families as the most common. Conclusions: One aspect that requires further research is the specific type of psychiatric hospitalization service in the general hospital, given the fact that some differences in process and results were observed between general and specialized wards.

The search continues for improved therapy for acute lymphoblastic leukemia (aLL), the most common malignancy in children. Recently, d,l-methadone was put forth as sensitizer for aLL chemotherapy. However, the specific target of d,l-methadone in leukemic cells and the mechanism by which it induces leukemic cell apoptosis remain to be defined. Here, we demonstrate that d,l-methadone induces leukemic cell apoptosis through activation of the mu1 subtype of opioid receptors (OPRM1). d,l-Methadone evokes IP3R-mediated ER Ca2+ release that is inhibited by OPRM1 loss. In addition, the rate of Ca2+ extrusion following d,l-methadone treatment is reduced, but is accelerated by loss of OPRM1. These d,l-methadone effects cause a lethal rise in [Ca2+]i that is again inhibited by OPRM1 loss, which then prevents d,l-methadone-induced apoptosis that is associated with activation of calpain-1, truncation of Bid, cytochrome C release, and proteolysis of caspase-3/12. Chelating intracellular Ca2+ with BAPTA-AM reverses d,l-methadone-induced apoptosis, establishing a link between the rise in [Ca2+]i and d,l-methadone-induced apoptosis. Altogether, our findings point to OPRM1 as a specific target of d,l-methadone in leukemic cells, and that OPRM1 activation by d,l-methadone disrupts IP3R-mediated ER Ca2+ release and rate of Ca2+ efflux, causing a rise in [Ca2+]i that upregulates the calpain-1-Bid-cytochrome C-caspase-3/12 apoptotic pathway.

BackgroundWhile multiple genetic causes of movement disorders have been identified in the past decade, modifying factors of disease expression are still largely unknown for most conditions. X-linked dystonia-parkinsonism (XDP) is an inherited neurodegenerative disease caused by a SINE-VNTR-Alu (SVA)-type retrotransposon insertion that contains a hexanucleotide repeat within an intron of the TAF1 gene. To date, four putative genetic modifiers explain about 65% of variance in age at onset in XDP. However, additional genetic modifiers are conceivably at play in XDP and may include mismatches of the SVA hexanucleotide repeat motif. We aim to identify additional genetic modifiers of XDP expressivity and age at onset (AAO).MethodsThird-generation sequencing of PCR amplicons from XDP patients (n=202) was performed to assess potential repeat interruption and instability. Repeat-primed PCR and Cas9-mediated targeted enrichment were used to confirm the presence of identified repeat mismatches.ResultsAn increased frequency of deletions at the beginning of the hexanucleotide repeat (CCCTCT)n domain was found. Specifically, three deletions at positions 11, 14, and 17 of the TAF1 SVA repeat motif of somatic mosaic origins were detected in different combinations. The most common one was three deletions (1-2-3) at a median frequency 0.425 (IQR:0.42-0.43) and deletions within positions 11 and 14 (1-2-wt) at a median frequency 0.128 (IQR:0.12-0.13). The frequency of deletions at positions 11 and 14 correlated with repeat number (r=-0.48, p=9.5×10-13) and AAO (r=0.34, p=9.5×10-7). The association with AAO still stands when including other modifier genotypes (MSH3 and PMS2) in a regression model. However, the association dissipates when including repeat numbers.ConclusionWe present a novel mosaic repeat motif deletion within the hexanucleotide repeat (CCCTCT)n domain of TAF1 SVA. Our study illustrates: 1) the importance of somatic mosaic genotypes; 2) the biological plausibility of multiple modifiers (both germline and somatic) that can have additive effects on repeat instability; 3) that these variations may remain undetected without assessment of single molecules.

While many genetic causes of movement disorders have been identified, modifiers of disease expression are largely unknown. X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disease caused by a SINE-VNTR-Alu(AGAGGG)n retrotransposon insertion in TAF1, with a polymorphic (AGAGGG)n repeat. Repeat length and variants in MSH3 and PMS2 explain ∼65% of the variance in age at onset (AAO) in XDP. However, additional genetic modifiers are conceivably at play in XDP, such as repeat interruptions. Long-read nanopore sequencing of PCR amplicons from XDP patients (n = 202) was performed to assess potential repeat interruption and instability. Repeat-primed PCR and Cas9-mediated targeted enrichment confirmed the presence of identified divergent repeat motifs. In addition to the canonical pure SINE-VNTR-Alu-5′-(AGAGGG)n, we observed a mosaic of divergent repeat motifs that polarized at the beginning of the tract, where the divergent repeat interruptions varied in motif length by having one, two, or three nucleotides fewer than the hexameric motif, distinct from interruptions in other disease-associated repeats, which match the lengths of the canonical motifs. All divergent configurations occurred mosaically and in two investigated brain regions (basal ganglia, cerebellum) and in blood-derived DNA from the same patient. The most common divergent interruption was AGG [5′-SINE-VNTR-Alu(AGAGGG)2AGG(AGAGGG)n], similar to the pure tract, followed by AGGG [5′-SINE-VNTR-Alu(AGAGGG)2AGGG(AGAGGG)n], at median frequencies of 0.425 (IQR: 0.42–0.43) and 0.128 (IQR: 0.12–0.13), respectively. The mosaic AGG motif was not associated with repeat number (estimate = −3.8342, P = 0.869). The mosaic pure tract frequency was associated with repeat number (estimate = 45.32, P = 0.0441) but not AAO (estimate = −41.486, P = 0.378). Importantly, the mosaic frequency of the AGGG negatively correlated with repeat number after adjusting for age at sampling (estimate = −161.09, P = 3.44 × 10−5). When including the XDP-relevant MSH3/PMS2 modifier single nucleotide polymorphisms into the model, the mosaic AGGG frequency was associated with AAO (estimate = 155.1063, P = 0.047); however, the association dissipated after including the repeat number (estimate = −92.46430, P = 0.079). We reveal novel mosaic divergent repeat interruptions affecting both motif length and sequence (DRILS) of the canonical motif polarized within the SINE-VNTR-Alu(AGAGGG)n repeat. Our study illustrates: (i) the importance of somatic mosaic genotypes; (ii) the biological plausibility of multiple modifiers (both germline and somatic) that can have additive effects on repeat instability; and (iii) that these variations may remain undetected without assessment of single molecules.

Background: Several studies on clinical practice for Duchenne muscular dystrophy (DMD) have been conducted in Western countries. However, there have been only a few similar studies in Asia and Oceania. Here, we investigate the steroid therapy-related clinical practice for DMD among the local experts. In 2015, we conducted a DMD expert survey in Asia and Oceania to acquire information regarding patients with DMD and to assess current clinical practice with the cooperation of Asian and Oceanian Myology Centre, a neuromuscular disease research network. Results: We obtained survey responses from 87 out of 148 clinicians (62%) from 13 countries and regions. In China, 1385 DMD patients were followed-up by 5 respondent neurologists, and 84% were between 0 and 9 years of age (15% were 10-19 years, 1% > 19 years). While in Japan, 1032 patients were followed-up by 20 clinicians, and the age distribution was similar between the 3 groups (27% were 0-9 years, 35% were 10-19 years, 38% were >19 years). Most respondent clinicians (91%) were aware of DMD standard of care recommendations. Daily prednisolone/prednisone administration was used most frequently at initiation (N = 45, 64%). Inconsistent opinion on steroid therapy after loss of ambulation and medication for bone protection was observed. Conclusions: Rare disease research infrastructures have been underdeveloped in many of Asian and Oceanian countries. In this situation, our results show the snapshots of current medical situation and clinical practice in DMD. For further epidemiological studies, expansion of DMD registries is necessary Refereed/Peer-reviewed

We previously demonstrated that loss of Cdk5 in breast cancer cells promotes ROS-mediated cell death by inducing mitochondrial permeability transition pore (mPTP) opening (Oncogene 37, 1788–1804). However, the molecular mechanism by which Cdk5 loss causes mPTP opening remains to be investigated. Using primary mouse embryonic fibroblasts (MEFs) isolated from Cdk5−/− mouse embryos, we show that absence of Cdk5 causes a significant increase in both mPTP opening and mitochondrial Ca2+ level. Analysis of subcellular fractions of MEFs demonstrates that Cdk5 localizes in the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) and Cdk5 loss in MAMs causes increased ER-mitochondria tethering, a process required for Ca2+ transfer from the ER to the mitochondria. Loss of Cdk5 also causes increased ATP-mediated mitochondrial Ca2+ uptake from the ER. Inhibition of ER Ca2+ release or mitochondrial Ca2+ uptake in Cdk5−/− MEFs prevents mPTP opening, indicating that mPTP opening in Cdk5−/− MEFs is due to increased Ca2+ transfer from the ER to the mitochondria. Altogether, our findings suggest that Cdk5 in MAMs regulates mitochondrial Ca2+ homeostasis that is disturbed upon Cdk5 loss, which leads to mPTP opening.

X-linked dystonia–parkinsonism (XDP) is a severe neurodegenerative disorder that manifests as adult-onset dystonia combined with parkinsonism. A SINE-VNTR-Alu (SVA) retrotransposon inserted in an intron of the TAF1 gene reduces its expression and alters splicing in XDP patient-derived cells. As a consequence, increased levels of the TAF1 intron retention transcript TAF1-32i can be found in XDP cells as compared to healthy controls. Here, we investigate the sequence of the deep intronic region included in this transcript and show that it is also present in cells from healthy individuals, albeit in lower amounts than in XDP cells, and that it undergoes degradation by nonsense-mediated mRNA decay. Furthermore, we investigate epigenetic marks (e.g., DNA methylation and histone modifications) present in this intronic region and the spanning sequence. Finally, we show that the SVA evinces regulatory potential, as demonstrated by its ability to repress the TAF1 promoter in vitro. Our results enable a better understanding of the disease mechanisms underlying XDP and transcriptional alterations caused by SVA retrotransposons.

Loss of cyclin-dependent kinase 5 (Cdk5) in the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) increases ER-mitochondria tethering and ER Ca

Background The pathophysiology of abnormal temperature sensation in Parkinson's disease (PD) remains unclear. Abnormal thermal detection does not seem to depend on the dopaminergic deficit, suggesting that other systems play a role in these changes, probably both central and peripheral. Methods We measured thermal detection thresholds (TDT) using quantitative sensory testing (QST) in 28 patients with PD and compared them with 15 healthy controls. Results Of 28 patients, 21% had increased TDT according to the normative data. TDT were higher on the dominant side. No correlation between TDT and disease duration, severity of motor impairment, and dopaminergic therapy was observed. 50% of the patients had difficulty differentiating between warm and cold stimuli, as TDT were within the normal range in most of these patients. Conclusions 21% of the patients in our study had increased TDT according to the normative data. Abnormal thermal detection was more pronounced on the dominant side. Abnormal differentiation between the thermal stimuli suggest impaired central processing of thermal information.

Background Myoclonus-dystonia is a rare movement disorder with an autosomal dominant inheritance pattern characterized by a combination of myoclonic jerks and dystonia that may have psychiatric manifestations. Our aim is to present neurologic and psychiatric phenotypic characteristics in the first Filipino bi-ethnic myoclonus-dystonia patient and her father. Case presentation We investigated a Filipino myoclonus-dystonia patient with a positive family history. This 21-year-old woman of mixed Filipino-Greek ethnicity presented with involuntary jerking movements of her upper extremities, head, and trunk. Her symptoms affected her activities of daily living which led her to develop moderate depression, mild to moderate anxiety, and mild obsessive-compulsive disorder (OCD). Her 49-year-old Greek father suffered from adolescence-onset myoclonus-dystonia. Conclusion Genetic testing revealed a novel epsilon-sarcoglycan (SGCE) gene nonsense mutation c.821C > A; p.Ser274* that confirmed our clinical diagnosis. For co-morbid anxiety, depression, and OCD, this patient was given duloxetine, in addition to clonazepam for the myoclonus and dystonia.