What is the Philosophy of Neurosurgery? Systematic Review and Defining the Discipline.

INTRODUCTION: Despite centuries of joint investigation of philosophy and neurological interventions, a founding account for the philosophy of neurosurgery has yet to be rigorously constructed or defended. This paper reviews recent work on the philosophy of neurosurgery, spanning metaphysics, epistemology, and value theory, to establish a framework and clinical relevance for study in the philosophy of neurosurgery. METHODS: A systematic review of an online database was conducted using the broad search terms, "Philosophy AND (Neurosurgery OR Neurological Surgery)." Records were included if they demonstrated relevance to the philosophy of neurosurgery and analytical rigor, but were excluded if solely legal, clinical, or ethical principles were considered without substantive discussion of underlying ethical frameworks and philosophical principles. RESULTS: Of 8025 candidates from online and print records, 16 records (14 from online sources and 2 from an edited volume) met inclusion criteria for the systematic review. Three dealt with metaphysics, 3 dealt with epistemology, 4 dealt with value theory, 5 dealt with metaphysics/epistemology, and 1 dealt with value theory/metaphysics. Questions of free will, consciousness, personal identity, neurosurgical knowledge, ascription of other minds, deontology, and minimalism, among others, were considered. DISCUSSION: Based on identified studies, the philosophy of neurosurgery is defined as the discipline of rigorously and methodically addressing metaphysical, epistemological, and value-theoretic questions arising from physically intervening in the nervous system. We discuss future directions for questions within the philosophy of neurosurgery and consider their relevance for patient care and the practice of neurosurgery.

Endoscopic Anterior Lumbar Interbody Fusion: Systematic Review and Meta-Analysis.

Laparoscopic anterior lumbar interbody fusion (L-ALIF), which employs laparoscopic cameras to facilitate a less invasive approach, originally gained traction during the 1990s but has subsequently fallen out of favor. As the envelope for endoscopic approaches continues to be pushed, a recurrence of interest in laparoscopic and/or endoscopic anterior approaches seems possible. Therefore, evaluating the current evidence base in regard to this approach is of much clinical relevance. To this end, a systematic literature search was performed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines using the following keywords: "(laparoscopic OR endoscopic) AND (anterior AND lumbar)." Out of the 441 articles retrieved, 22 were selected for quantitative analysis. The primary outcome of interest was the radiographic fusion rate. The secondary outcome was the incidence of perioperative complications. Meta-analysis was performed using RStudio's "metafor" package. Of the 1,079 included patients (mean age, 41.8±2.9 years), 481 were males (44.6%). The most common indication for L-ALIF surgery was degenerative disk disease (reported by 18 studies, 81.8%). The mean follow-up duration was 18.8±11.2 months (range, 6-43 months). The pooled fusion rate was 78.9% (95% confidence interval [CI], 68.9-90.4). Complications occurred in 19.2% (95% CI, 13.4-27.4) of L-ALIF cases. Additionally, 7.2% (95% CI, 4.6-11.4) of patients required conversion from L-ALIF to open surgery. Although L-ALIF does not appear to be supported by studies available in the literature, it is important to consider the context from which these results have been obtained. Even if these results are taken at face value, the failure of endoscopy to have a role in the ALIF approach does not mean that it should not be incorporated in posterior approaches.

Structural brain differences in essential tremor and Parkinson's disease deep brain stimulation patients.

BACKGROUND: Essential tremor (ET) and Parkinson's disease (PD) are the most common tremor disorders and are common indications for deep brain stimulation (DBS). In some patients, PD and ET symptoms overlap and diagnosis can be challenging based on clinical criteria alone. The objective of this study was to identify structural brain differences between PD and ET DBS patients to help differentiate these disorders and improve our understanding of the different brain regions involved in these pathologic processes. METHODS: We included ET and PD patients scheduled to undergo DBS surgery in this observational study. Patients underwent 3T brain MRI while under general anesthesia as part of their procedure. Cortical thicknesses and subcortical volumes were quantified from T1-weighted images using automated multi-atlas segmentation. We used logistic regression analysis to identify brain regions associated with diagnosis of ET or PD. RESULTS: 149 ET and 265 PD patients were included. Smaller volumes in the pallidum and thalamus and reduced thickness in the anterior orbital gyrus, lateral orbital gyrus, and medial precentral gyrus were associated with greater odds of ET diagnosis. Conversely, reduced volumes in the caudate, amygdala, putamen, and basal forebrain, and reduced thickness in the orbital part of the inferior frontal gyrus, supramarginal gyrus, and posterior cingulate were associated with greater odds of PD diagnosis. CONCLUSIONS: These findings identify structural brain differences between PD and ET patients. These results expand our understanding of the different brain regions involved in these disorders and suggest that structural MRI may help to differentiate patients with these two disorders.

External Validation of the Global Alignment and Proportion Score as Prognostic Tool for Corrective Surgery in Adult Spinal Deformity: A Systematic Review and Meta-Analysis.

BACKGROUND: Since its proposal, the Global Alignment and Proportion (GAP) score has been the topic of several external validation studies, which have yielded conflicting results. Given the lack of consensus regarding this prognostic tool, the authors aim to assess the accuracy of GAP scores for predicting mechanical complications following adult spinal deformity correction surgery. METHODS: A systematic search was performed using PubMed, Embase, and Cochrane Library for the purpose of identifying all studies evaluating the GAP score as a predictive tool for mechanical complications. GAP scores were pooled using a random-effects model to compare patients reporting mechanical complications after surgery versus those reporting no complications. Where receiver operator curves were provided, the area under the curve (AUC) was pooled. RESULTS: A total of 15 studies featuring 2092 patients were selected for inclusion. Qualitative analysis using Newcastle-Ottawa criteria revealed moderate quality among all included studies (5.99/9). With respect to sex, the cohort was predominantly female (82%). The pooled mean age among all patients in the cohort was 58.55 years, with a mean follow-up of 33.86 months after surgery. Upon pooled analysis, we found that mechanical complications were associated with higher mean GAP scores, albeit minimal (mean difference = 0.571 [ 95% confidence interval: 0.163-0.979]; P = 0.006, n = 864). Additionally, age (P = 0.136, n = 202), fusion levels (P = 0.207, n = 358), and body mass index (P = 0.616, n = 350) were unassociated with mechanical complications. Pooled AUC revealed poor discrimination overall (AUC = 0.69; n = 1206). CONCLUSIONS: GAP scores may have a minimal-to-moderate predictive capability for mechanical complications associated with adult spinal deformity correction.

Resident Training in Spine Surgery: A Systematic Review of Simulation-Based Educational Models.

OBJECTIVE: With the increasing prevalence of spine surgery, ensuring effective resident training is becoming of increasing importance. Training safe, competent surgeons relies heavily on effective teaching of surgical indications and adequate practice to achieve a minimum level of technical proficiency before independent practice. American Council of Graduate Medical Education work-hour restrictions have complicated the latter, forcing programs to identify novel methods of surgical resident training. Simulation-based training is one such method that can be used to complement traditional training. The present review aims to evaluate the educational success of simulation-based models in the spine surgical training of residents. METHODS: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, the PubMed, Web of Science, and Google Scholar databases were systematically screened for English full-text studies examining simulation-based spine training curricula. Studies were categorized based on simulation model class, including animal-cadaveric, human-cadaveric, physical/3-dimensional, and computer-based/virtual reality. Outcomes studied included participant feedback regarding the simulator and competency metrics used to evaluate participant performance. RESULTS: Seventy-two studies were identified. Simulators displayed high face validity and were useful for spine surgery training. Objective measures used to evaluate procedural performance included implant placement evaluation, procedural time, and technical skill assessment, with numerous simulators demonstrating a learning effect. CONCLUSIONS: While simulation-based educational models are one potential means of training residents to perform spine surgery, traditional in-person operating room training remains pivotal. To establish the efficacy of simulators, future research should focus on improving study quality by leveraging longitudinal study designs and correlating simulation-based training with clinical outcome measures.

Radiation modulated spin coupling in a double-stranded DNA model.

The spin activity in macromolecules such as DNA and oligopeptides, in the context of the chiral induced spin selectivity has been proposed to be due to the atomic spin-orbit coupling (SOC) and the associated chiral symmetry of the structures. This coupling, associated with carbon, nitrogen and oxygen atoms in biological molecules, albeit small (meV), can be enhanced by the geometry, and strong local polarization effects such as hydrogen bonding. A novel way to manipulate the spin degree of freedom is by modifying the spectrum using a coupling to the appropriate electromagnetic radiation field. Here we use the Floquet formalism in order to show how the half filled band Hamiltonian for DNA, can be modulated by the radiation to produce up to a tenfold increase of the effective SOC once the intrinsic coupling is present. On the other hand, the chiral model, once incorporating the orbital angular momentum of electron motion on the helix, opens a gap for different helicity states (helicity splitting) that chooses spin polarization according to transport direction and chirality, without breaking time reversal symmetry. The observed effects are feasible in physically reasonable parameter ranges for the radiation field amplitude and frequency.

Exome sequencing and characterization of 49,960 individuals in the UK Biobank.

The UK Biobank is a prospective study of 502,543 individuals, combining extensive phenotypic and genotypic data with streamlined access for researchers around the world1. Here we describe the release of exome-sequence data for the first 49,960 study participants, revealing approximately 4 million coding variants (of which around 98.6% have a frequency of less than 1%). The data include 198,269 autosomal predicted loss-of-function (LOF) variants, a more than 14-fold increase compared to the imputed sequence. Nearly all genes (more than 97%) had at least one carrier with a LOF variant, and most genes (more than 69%) had at least ten carriers with a LOF variant. We illustrate the power of characterizing LOF variants in this population through association analyses across 1,730 phenotypes. In addition to replicating established associations, we found novel LOF variants with large effects on disease traits, including PIEZO1 on varicose veins, COL6A1 on corneal resistance, MEPE on bone density, and IQGAP2 and GMPR on blood cell traits. We further demonstrate the value of exome sequencing by surveying the prevalence of pathogenic variants of clinical importance, and show that 2% of this population has a medically actionable variant. Furthermore, we characterize the penetrance of cancer in carriers of pathogenic BRCA1 and BRCA2 variants. Exome sequences from the first 49,960 participants highlight the promise of genome sequencing in large population-based studies and are now accessible to the scientific community.

Back pain outcomes after minimally invasive anterior lumbar interbody fusion: a systematic review.

OBJECTIVE: Minimally invasive anterior lumbar interbody fusion surgery (MIS ALIF) is a technique that restores disc height and lumbar lordosis through a smaller exposure and less soft-tissue trauma compared to open approaches. The mini-open and laparoscopic assistance techniques are two main forms of MIS ALIF. The authors conducted a systematic review that sought to critically summarize the literature on back pain following MIS ALIF. METHODS: In March 2020, the authors searched the PubMed, Web of Science, and Cochrane Library databases for studies describing back pain visual analog scale (VAS) outcomes after MIS ALIF. The following exclusion criteria were applied to studies evaluated in full text: 1) the study included fewer than 20 patients, 2) the mean follow-up duration was shorter than 12 months, 3) the study did not report back pain VAS score as an outcome measure, and 4) MIS ALIF was not studied specifically. The methodology for the included studies were evaluated for potential biases and assigned a level of evidence. RESULTS: There were a total of 552 patients included from 13 studies. The most common biases were selection and interviewer bias. The majority of studies were retrospective. The mean sample size was 42.3 patients. The mean follow-up duration was approximately 41.8 months. The mean postoperative VAS reduction was 5.1 points. The mean VAS reduction for standalone grafts was 5.9 points, and 5.0 points for those augmented with posterior fixation. The most common complications included bladder or urinary dysfunction, infection, and hardware-related complications. CONCLUSIONS: This was a systematic review of back pain outcomes following MIS ALIF. Back pain VAS score was reduced postoperatively across all studies. The complication rates were low overall. MIS ALIF is safe and effective at reducing back pain in appropriate patient populations.

Microvascular Decompression for Trigeminal Neuralgia in Patients with Multiple Sclerosis: Predictors of Treatment Success.

BACKGROUND: Microvascular decompression (MVD) is highly effective in managing the neuropathic facial pain of trigeminal neuralgia (TN). Its utility in patients with TN and concurrent multiple sclerosis (MS) has been a subject of debate. The goal of this study was to identify demographic and perioperative variables associated with favorable outcome after MVD over the past 20 years in patients from our institution. METHODS: A retrospective analysis of our cohort of 33 patients diagnosed with MS and TN who underwent MVD between 1997 and 2017 to treat neuropathic facial pain was performed. Perioperative variables included MS disease burden, findings on preoperative magnetic resonance imaging (MRI), TN pain severity, and the presence of intraoperative neurovascular compression. MS disease burden was quantified using the Expanded Disability Status Scale. Preoperative and postoperative pain severity was quantified using the Barrow Neurological Institute (BNI) pain severity scale. RESULTS: A total of 33 patients with TN and MS were treated with MVD at our institution (out of the 632 total MVDs performed) between 1997 and 2017. Twenty-two patients (67%) maintained a reduction in pain at a mean follow-up of 53.5 months. Higher preoperative BNI pain intensity score was associated with unfavorable outcome after MVD (P = 0.006). No associations were identified between MS disease burden, presence of neurovascular compression or pontine demyelinating plaques on MRI, or intraoperative findings of neurovascular compression and treatment outcomes. CONCLUSIONS: MVD is a reasonable treatment option for patients with TN and MS, although the rate of freedom from pain is lower than that for the general TN population. Preoperative pain severity may be a predictor of treatment success.

Media improvement for 10 L bioreactor production of rPOXA 1B laccase by P. pastoris.

In this work, we statistically improved culture media for rPOXA 1B laccase production, expressed in Pichia pastoris containing pGAPZαA-LaccPost-Stop construct and assayed at 10 L bioreactor production scale (6 L effective work volume). The concentrated enzyme was evaluated for temperature and pH stability and kinetic parameter, characterized by monitoring oxidation of different ABTS [2, 20-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)] substrate concentrations. Plackett-Burman experimental design (PBED) implementation improved previous work results by 3.05-fold, obtaining a laccase activity of 1373.72 ± 0.37 U L-1 at 168 h of culture in a 500 mL shake flask. In contrast, one factor experimental design (OFED) applied after PBED improved by threefold the previous study, additionally increasing the C/N ratio. Employing OFED media at 10 L bioreactor scale was capable of producing 3159.93 ± 498.90 U L-1 at 192 h, representing a 2.4-fold increase. rPOXA 1B concentrate remained stable between 10 and 50 °C and retained over 70% residual enzymatic activity at 60 °C and 50% at 70 °C. Concerning pH stability, the enzyme was stable at pH 4.0 ± 0.2 with a residual activity greater than 90%. The lowest residual activity (60%) was obtained at pH 10.0 ± 0.2. Furthermore, the apparent kinetic parameters were V max of 3.163 × 10-2 mM min-1 and K m of 1.716 mM. Collectively, regarding enzyme stability our data provide possibilities for applications involving a wide range of pH and temperatures.

Testing the Testers: Are Young Men Who Have Sex With Men Receiving Adequate HIV Testing and Counseling Services?

BACKGROUND: The United States Centers for Disease Control and Prevention promote HIV testing every 6 months among young men who have sex with men (YMSM) to facilitate entry into the HIV prevention and care continuum. Willingness to be tested may be influenced by testing services' quality. Using a novel mystery shopper methodology, we assessed YMSM's testing experiences in 3 cities and recommend service delivery improvements. METHODS: We assessed YMSM's experiences at HIV testing sites in Philadelphia (n = 30), Atlanta (n = 17), and Houston (n = 19). YMSM (18-24) were trained as mystery shoppers and each site was visited twice. After each visit, shoppers completed a quality assurance survey to evaluate their experience. Data were pooled across sites, normed as percentages, and compared across cities. RESULTS: Across cites, visits averaged 30 minutes (SD = 25.5) and were perceived as welcoming and friendly (70.9%). YMSM perceived most sites respected their privacy and confidentiality (84.3%). YMSM noted deficiencies in providers' competencies with sexual minorities (63.4%) and comfort during the visit (65.7%). Sites underperformed on Lesbian, Gay, Bisexual, Transgender visibility (49.6%) and medical forms inclusivity (57.95%). Sites on average did not discuss YMSM's relationship context (49.8%) nor provide risk reduction counseling (56.8%) or safer sex education (24.3%). Sites delivered pre-exposure prophylaxis information and counseling inconsistently (58.8%). CONCLUSIONS: Testing sites' variable performance underscores the importance of improving HIV testing services for YMSM. Strategies are recommended for testing sites to promote cultural sensitivity: funding staff trainings, creating systems to assess adherence to testing guidelines and best practices, and implementing new service delivery models.

Anaerobic sulfatase maturase AslB from Escherichia coli activates human recombinant iduronate-2-sulfate sulfatase (IDS) and N-acetylgalactosamine-6-sulfate sulfatase (GALNS).

Maturation of type I sulfatases requires the conversion of the cysteine (Cys) or serine (Ser) present in the active site to formylglycine (FGly). This activation represents a limiting step during the production of recombinant sulfatases in bacteria and eukaryotic hosts. AslB, YdeM and YidF have been proposed to participate in the activation of sulfatases in Escherichia coli. In this study, we combined in-silico and experimental approaches to study the interaction between Escherichia coli BL21(DE3) AslB and human sulfatases, more specifically iduronate-2-sulfate sulfatase (IDS) and N-acetylgalactosamine-6-sulfate sulfatase (GALNS). In-silico results show that AslB has a higher affinity for the residual motif of GALNS (-9.4kcalmol-1), Cys- and Ser-type, than for the one of IDS (-8.0kcalmol-1). However, the distance between the AslB active residue and the target motif favors the interaction with IDS (4.4Å) more than with GALNS (5.5Å). Experimental observations supported in-silico results where the co-expression of AslB with GALNS Cys- and Ser-type presented an activity increment of 2.0- and 1.5-fold compared to the control cultures, lacking overexpressed AslB. Similarly, IDS activity was increased in 4.6-fold when co-expressed with AslB. The higher sulfatase activity of AslB-IDS suggests that the distance between the AslB active residue and the motif target is a key parameter for the in-silico search of potential sulfatase activators. In conclusion, our results suggest that AslB is involve in the maturation of heterologous human sulfatases in E. coli BL21(DE3), and that it can have important implications in the production of recombinant sulfatases for therapeutic purposes and research.

Electronic health record phenotype in subjects with genetic variants associated with arrhythmogenic right ventricular cardiomyopathy: a study of 30,716 subjects with exome sequencing.

PurposeArrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease. Clinical follow-up of incidental findings in ARVC-associated genes is recommended. We aimed to determine the prevalence of disease thus ascertained.MethodsIndividuals (n = 30,716) underwent exome sequencing. Variants in PKP2, DSG2, DSC2, DSP, JUP, TMEM43, or TGFß3 that were database-listed as pathogenic or likely pathogenic were identified and evidence-reviewed. For subjects with putative loss-of-function (pLOF) variants or variants of uncertain significance (VUS), electronic health records (EHR) were reviewed for ARVC diagnosis, diagnostic criteria, and International Classification of Diseases (ICD-9) codes.ResultsEighteen subjects had pLOF variants; none of these had an EHR diagnosis of ARVC. Of 14 patients with an electrocardiogram, one had a minor diagnostic criterion; the rest were normal. A total of 184 subjects had VUS, none of whom had an ARVC diagnosis. The proportion of subjects with VUS with major (4%) or minor (13%) electrocardiogram diagnostic criteria did not differ from that of variant-negative controls. ICD-9 codes showed no difference in defibrillator use, electrophysiologic abnormalities or nonischemic cardiomyopathies in patients with pLOF or VUSs compared with controls.ConclusionpLOF variants in an unselected cohort were not associated with ARVC phenotypes based on EHR review. The negative predictive value of EHR review remains uncertain.

Characterization of recombinant human lysosomal beta-hexosaminidases produced in the methylotrophic yeast Pichia pastoris / Caracterización de beta-hexosaminidasas lisosomales humanas recombinantes producidas en la levadura metilotrófica Pichia pastoris / Caracterização de beta-hexosaminidases lisossomais humanas recombinantes produzidas na levedura metilotrófica Pichia pastoris

Abstract β-hexosaminidases (Hex) are dimeric enzymes involved in the lysosomal degradation of glycolipids and glycans. They are formed by α- and/or β-subunits encoded by HEXA and HEXB genes, respectively. Mutations in these genes lead to Tay Sachs or Sandhoff diseases, which are neurodegenerative disorders caused by the accumulation of non-degraded glycolipids. Although tissue-derived Hex have been widely characterized, limited information is available for recombinant α-hexosaminidases. In this study, human lysosomal recombinant Hex (rhHex-A, rhHex-B, and rhHex-S) were produced in the methylotrophic yeast Pichia pastoris GS115. The highest specific enzyme activities were 13,124 for rhHexA; 12,779 for rhHex-B; and 14,606 U .mg-1 for rhHex-S. These results were 25- to 50-fold higher than those obtained from normal human leukocytes. Proteins were purified and characterized at different pH and temperature conditions. All proteins were stable at acidic pH, and at 4 °C and 37 °C. At 45 °C rhHex-S was completely inactivated, while rhHex-A and rhHex-B showed high stability. This study demonstrates P. pastoris GS115 potential for polymeric lysosomal enzyme production, and describes the characterization of recombinant β-hexosaminidases produced within the same host.

Resumen Las β-hexosaminidasas (Hex) son enzimas diméricas involucradas en la degradación lisosomal de glicolípidos y glicanos. Estas enzimas están formadas por las subunidades α- y/o β-codificadas por los genes HEXA and HEXB respectivamente. Las mutaciones de estos genes conducen a las enfermedades de Tay Sachs o Sandhoff, que son desórdenes neurodegenerativos causados por la acumulación de glicolípidos no degradados. Aunque las Hex derivadas de tejido han sido ampliamente caracterizadas, la información disponible sobre las p-hexosaminidasas recombinantes es limitada. En este estudio se produjeron Hex recombinantes lisosomales (rhHex-A, rhHex-B y rhHex-S) en la levadura metilotrófica Pichia pastoris GS115. Las actividades específicas más altas de las enzimas fueron 13.124, 12.779, 14.606 U .mg-1 para rhHex-A, rhHex-B y rhHex-S, respectivamente. Estos resultados fueron 25 a 50 veces más altos que los obtenidos de leucocitos humanos normales. Las proteínas se purificaron y se caracterizaron a diferentes condiciones de pH y temperatura. Todas las proteínas fueron estables a pH ácido y a 4°C y 37°C. A 45°C la rhHex-S se inactivó completamente, mientras que rhHex-A y rhHex-B mostraron alta estabilidad. Este estudio demuestra el potencial de P. pastoris GS115 para la producción de enzimas lisosomales poliméricas y presenta la caracterización de distintas β-hexosaminidasas recombinantes producidas en un único hospedero.

Resumen As β-hexosaminidases (Hex) são enzimas diméricas envolvidas na degradação lisossomal de glicolipídeos e glicanos. Essas enzimas são formadas por subunidades a- e/ou p-codificadas pelos genes HEXA e HEXB, respectivamente. As mutações nesses genes causam a doença de Sandhoff ou Tay Sachs, que são desordens neurodegenerativas causadas pela acumulação de glicolipídeos não degradados. Embora Hex derivadas de tecido hajam sido caracterizadas extensivamente, as informações disponíveis sobre as p-hexosaminidases recombinantes são limitadas. Esse estudo produziu Hex recombinantes lisossomais (rhHex-A, rhHex-B e rhHex-S) na levedura metilotrófica Pichia pastoris GS115. As atividades específicas mais altas das enzimas foram 13.124, 12.779, 14.606 U .mg-1 para rhHex-A, rhHex-B y rhHex-S, respectivamente. Esses resultados foram 25 a 50 vezes mais altos do que os obtidos a partir de leucócitos humanos normais. As proteínas foram purificadas e caracterizadas em diferentes condições de pH e temperatura. Todas as proteínas foram estáveis a pH ácido e a 4°C e 37°C. A 45°C a rhHex-S foi completamente inativada, enquanto rhHex rhHex-A e B se mostraram altamente estáveis. Esse estudo demonstra o potencial de P. pastoris GS115 para a produção de enzimas lisossomais poliméricas e apresenta a caracterização de diferentes p-hexosaminidases recombinantes produzidas em único hospedeiro.

Recombinant human N-acetylgalactosamine-6-sulfate sulfatase (GALNS) produced in the methylotrophic yeast Pichia pastoris.

Mucopolysaccharidosis IV A (MPS IV A, Morquio A disease) is a lysosomal storage disease (LSD) produced by mutations on N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Recently an enzyme replacement therapy (ERT) for this disease was approved using a recombinant enzyme produced in CHO cells. Previously, we reported the production of an active GALNS enzyme in Escherichia coli that showed similar stability properties to that of a recombinant mammalian enzyme though it was not taken-up by culture cells. In this study, we showed the production of the human recombinant GALNS in the methylotrophic yeast Pichia pastoris GS115 (prGALNS). We observed that removal of native signal peptide and co-expression with human formylglycine-generating enzyme (SUMF1) allowed an improvement of 4.5-fold in the specific GALNS activity. prGALNS enzyme showed a high stability at 4 °C, while the activity was markedly reduced at 37 and 45 °C. It was noteworthy that prGALNS was taken-up by HEK293 cells and human skin fibroblasts in a dose-dependent manner through a process potentially mediated by an endocytic pathway, without any additional protein or host modification. The results show the potential of P. pastoris in the production of a human recombinant GALNS for the development of an ERT for Morquio A.

Disección espontánea de la arteria vertebral / Spontaneous vertebral artery dissection

La disección arterial como causa de ataque cerebrovascular es infrecuente, presentándose más comúnmente en población joven asociado a un trauma menor que involucra la hiperextensión del cuello. Presentamos el reporte de un paciente hombre, joven, con un accidente cerebrovascular de fosa posterior y cuya etiología fue una disección espontánea de la arteria vertebral derecha.

Arterial dissection as a cause of stroke is uncommon, most commonly presenting in young people sometimes associated with trauma involving hyperextension of the neck as the only history which would suggest the traumatic origin. We present the case report of a young man with posterior stroke whose etiology was a spontaneous dissection of the right vertebral artery.

Proceso del sistema referencia, retorno e interconsulta, implementado a partir de la reforma de salud, en la Unidad Comunitaria de Salud Familiar Intermedia Periférica San Vicente y el Hospital Nacional Santa Gertrudis del departamento de San Vicente, durante el periodo del mes de julio a diciembre 2015 / Process of the referral, return and interconsultation system, implemented as of the health reform, in the San Vicente Peripheral Intermediate Family Health Community Unit and the Santa Gertrudis National Hospital of the department of San Vicente, during the period from July to December 2015

Propósito: Mejorar el proceso y el cumplimiento de los lineamientos de referencia, retorno e interconsulta, facilitando el continuo de atención de las personas bajo los criterios de continuidad, oportunidad, pertinencia e integralidad permitiendo la toma de decisiones para la referencia cuando las necesidades o complicaciones sobrepasan la oferta de servicios definida para el nivel de atención correspondiente, constituyéndose una pieza fundamental para el trabajo en red. Materiales y métodos: Es un estudio de tipo descriptivo de corte transversal con enfoque cuantitativo, se entrevistaron a 50 médicos de la Unidad Comunitaria de Salud Familiar Periférica y Hospital Nacional Santa Gertrudis, en el periodo de julio a diciembre de 2015. Resultados: Se observó que de los 50 médicos entrevistados el 94% refiere conocer la red de servicios de salud a la cual pertenece su institución y el 6% restante desconoce la red de servicios a la cual pertenece. El 98% de los 50 médicos entrevistados conocen los lineamientos del proceso de referencia, retorno e interconsulta y solamente el 2% restante no los conoce. El 70% de los 50 médicos entrevistados manifestaron que no se cumplen con los criterios de oportunidad y pertinencia. Un 30 % refieren que sí. Conclusiones: Los médicos conocen el instrumento oficial utilizado en el proceso de referencia, retorno e interconsulta, los mecanismos de coordinación en ambos niveles, no todos aplica correctamente los lineamientos dentro del proceso de referencia, retorno e interconsulta.

Impact of enzyme replacement therapy and hematopoietic stem cell transplantation in patients with Morquio A syndrome.

Patients with mucopolysaccharidosis IVA (MPS IVA) can present with systemic skeletal dysplasia, leading to a need for multiple orthopedic surgical procedures, and often become wheelchair bound in their teenage years. Studies on patients with MPS IVA treated by enzyme replacement therapy (ERT) showed a sharp reduction on urinary keratan sulfate, but only modest improvement based on a 6-minute walk test and no significant improvement on a 3-minute climb-up test and lung function test compared with the placebo group, at least in the short-term. Surgical remnants from ERT-treated patients did not show reduction of storage materials in chondrocytes. The impact of ERT on bone lesions in patients with MPS IVA remains limited. ERT seems to be enhanced in a mouse model of MPS IVA by a novel form of the enzyme tagged with a bone-targeting moiety. The tagged enzyme remained in the circulation much longer than untagged native enzyme and was delivered to and retained in bone. Three-month-old MPS IVA mice treated with 23 weekly infusions of tagged enzyme showed marked clearance of the storage materials in bone, bone marrow, and heart valves. When treatment was initiated at birth, reduction of storage materials in tissues was even greater. These findings indicate that specific targeting of the enzyme to bone at an early stage may improve efficacy of ERT for MPS IVA. Recombinant N-acetylgalactosamine-6-sulfate sulfatase (GALNS) in Escherichia coli BL21 (DE3) (erGALNS) and in the methylotrophic yeast Pichia pastoris (prGALNS) has been produced as an alternative to the conventional production in Chinese hamster ovary cells. Recombinant GALNS produced in microorganisms may help to reduce the high cost of ERT and the introduction of modifications to enhance targeting. Although only a limited number of patients with MPS IVA have been treated with hematopoietic stem cell transplantation (HSCT), beneficial effects have been reported. A wheelchair-bound patient with a severe form of MPS IVA was treated with HSCT at 15 years of age and followed up for 10 years. Radiographs showed that the figures of major and minor trochanter appeared. Loud snoring and apnea disappeared. In all, 1 year after bone marrow transplantation, bone mineral density at L2-L4 was increased from 0.372 g/cm(2) to 0.548 g/cm(2) and was maintained at a level of 0.48±0.054 for the following 9 years. Pulmonary vital capacity increased approximately 20% from a baseline of 1.08 L to around 1.31 L over the first 2 years and was maintained thereafter. Activity of daily living was improved similar to the normal control group. After bilateral osteotomies, a patient can walk over 400 m using hip-knee-ankle-foot orthoses. This long-term observation of a patient shows that this treatment can produce clinical improvements although bone deformity remained unchanged. In conclusion, ERT is a therapeutic option for MPS IVA patients, and there are some indications that HSCT may be an alternative to treat this disease. However, as neither seems to be a curative therapy, at least for the skeletal dysplasia in MPS IVA patients, new approaches are investigated to enhance efficacy and reduce costs to benefit MPS IVA patients.

ESTUDIO POBLACIONAL DE LA TORTUGA CAREY Eretmochelys imbricata (CHELONIIDAE)EN EL PACÍFICO SUR DE COLOMBIA / Population Study of the Hawksbill Turtle Eretmochelys imbricata (Cheloniidae) in the Southern Pacific region of Colombia

El objetivo de esta investigación fue conocer aspectos poblacionales, biológicos y ecológicos de las tortugas carey (Eretmochelys imbricata) presentes en el Pacífico sur de Colombia (Departamento del Cauca), para esto se tomó información de morfometría, se revisó el estado de salud de los individuos y se tomaron muestras de sangre para valoración de química sanguínea. Durante siete meses de muestreo se capturaron 25 tortugas carey (16 individuos diferentes) en los arrecifes del Parque Nacional Natural Gorgona, con un porcentaje de recaptura del 46 %. Aunque no se notaron problemas evidentes de salud, la mayoría de animales presentaron gran parte del caparazón cubierto de algas filamentosas y algunos epibiontes sobre el plastrón y el caparazón. La Longitud Curva Caparazón (LCC) mostró una mayor proporción de individuos con tallas entre 37 y 45 cm de longitud (prom. 42,3 cm; min. 37,5 cm; max. 58 cm). Por medio de la prueba de Mann Whitney U, se comparó la LCC de los 16 individuos diferentes capturados en el PNN Gorgona, con 11 individuos capturados en la zona del litoral del Departamento del Cauca, encontrándose diferencias significativas entre estos dos grupos, donde los animales presentes en el PNN Gorgona fueron de mayor talla que los presentes en el continente (Z = -2,59; p = 0,007). Los valores de ácido úrico se encontraron por encima de los valores de referencia.

The objective of this research was to determine biological and ecological population characteristics of the hawksbill turtle (Eretmochelys imbricata) found in the southern Colombian Pacific department of Cauca. Morphometric measurements were recorded, the health status of individuals was reviewed, and blood samples were taken for a biochemistry assessment. During the seven months of the investigation, 25 hawksbill turtles were caught (16 different individuals) on the reefs of Gorgona Natural National Park. Forty-six percent of the total numbers of turtles assessed were recaptured during the study period. While no obvious health problems were noted, most animals possessed epibionts and filamentous algae covering the carapace, some parts of the limbs, as well as on their neck. Curved carapace length (CCL) showed the highest proportion of individuals were between 37 and 45 cm. Sixteen individuals captured in Gorgona Natural National Park were compared with 11 individuals captured in the coastal zone of the department of Cauca. Using the Mann-Whitney U test, a significant difference in CCL was found between these two groups; the animals from Gorgona National Park were larger than those present on the coast of the mainland (Z = -2.59, p = 0.007). Uric acid concentrations were found to be higher than previously referenced values.

Tumor fibroso localizado de pleura: reporte de un caso / Localized fibrous tumor of pleura: a case report

Fundamento: los tumores fibrosos localizados de pleura son raros, de etiología incierta; la mayoría de los pacientes con esta enfermedad sobrepasan la quinta década de vida y más de la mitad están asintomáticos al diagnóstico, principalmente cuando los tumores son pequeños. Objetivo: describir el caso de una paciente con tumor fibroso localizado de pleura que, por su edad, sintomatología y por las características histológicas del tumor, representa una situación clínica infrecuente, con dificultades para el diagnóstico. Presentación de caso: mujer saludable, de 39 años, con dolor tóraco-lumbar persistente, de un año de evolución; en radiografía de tórax se visualizó imagen retro cardíaca izquierda corroborada por tomografía computarizada. Se realizó exéresis total de una masa de 4,8 cm, pedunculada, con origen en la pleura visceral, cuyo diagnóstico histopatológico fue un tumor fibroso localizado de pleura con características quísticas. Después de varios meses de seguimiento la paciente permanecía saludable y sin signos de recurrencia. Conclusiones: este caso constituye una forma infrecuente de presentación del tumor fibroso localizado de pleura por tratarse de una paciente menor de 40 años, con una sintomatología no frecuente y por el comportamiento benigno que ha tenido el tumor aunque presentó características quísticas.

Background: localized fibrous tumors of the pleura are rare, with uncertain etiology; most of the patients with this disease exceed the fifth decade of life and more than a half are without symptoms at the diagnosis, mainly when tumors are small. Objective: to describe a case of a female patient with a diagnosis of a localized fibrous tumor of pleura in which due to her age, the symptomatology and histological features of the tumor, it represents an infrequent clinical situation with difficulties for the diagnosis. Case presentation: a 39-year-old healthy woman with one year history of persistent thoracic lumbar pain; in chest radiography a left retrocardiac image was observed and it was corroborated by chest CT scan. Total exeresis was performed in a 4.8 cm mass, pedunculated, originating from the visceral pleura, whose histopathological diagnosis was a localized fibrous tumor of the pleura with cystic features. After several months of follow-up, the patient remained healthy and did not show recurrent signs. Conclusions: this case is an infrequent presentation of a localized fibrous tumor of the pleura for having been diagnosed in a patient under 40 years old, with an infrequent symptomatology and because the tumor has shown a benign behavior even with cystic features.