Multimodal management of giant solid hemangioblastomas in two patients with preoperative embolization.

Background: Hemangioblastomas are benign vascular neoplasms, World Health Organization grade I, with the most frequent location in the cerebellum. Complete microsurgical resection can be a challenge due to excessive bleeding, which is why preoperative embolization takes importance. Case Description: Two clinical cases are presented, a 25-year-old woman and a 75-year-old man, who presented with intracranial hypertension symptoms due to obstructive hydrocephalus; a ventriculoperitoneal shunt was placed in both cases; in addition, they presented with cerebellar signs. Both underwent embolization with ethylene vinyl alcohol copolymer, with blood flow reduction. After that, they underwent microsurgical resection within the 1st-week post embolization, obtaining, in both cases, gross total resection without hemodynamic complications, with clinical improvement and good surgical outcome. It is worth mentioning that surgical management is the gold standard that allows a suitable surgical approach, like in our patients, for which a lateral suboccipital craniotomy was performed. Conclusion: Solid hemangioblastomas are less frequent than their cystic counterparts. The treatment is the surgical resection, which is a challenge and always has to be considered as an arteriovenous malformation in the surgical planning, including preoperative embolization to reduce perioperative morbidity and mortality and get good outcomes.

Trigeminal neuralgia secondary to vascular compression and neurocysticercosis: illustrative case.

BACKGROUND: Trigeminal neuralgia (TN) is a frequent neurosurgical problem negatively influencing the quality of life of patients. The standard surgical treatment is microvascular decompression for primary cases and decompression of the mass effect, mainly tumors, for secondary cases. Neurocysticercosis (NCC) in the cerebellopontine angle is a rare etiology of TN. The authors report a case in which NCC cysts around the trigeminal nerve coexisted with a vascular loop, which compressed the exit of the trigeminal nerve from the pons. OBSERVATIONS: A 78-year-old woman presented with a 3-year history of persistent severe pain in the left side of her face, refractory to medical treatment. On gadolinium-enhanced magnetic resonance imaging, cystic lesions were observed around the left trigeminal nerve and a vascular loop was also present and in contact with the nerve. A retrosigmoid approach for cyst excision plus microvascular decompression of the trigeminal nerve was successfully performed. There were no complications. The patient was discharged without facial pain. LESSONS: Albeit rare, TN secondary to NCC cysts should be considered in the differential diagnosis in NCC-endemic regions. In this case, the cause of the neuralgia was probably both problems, because when both were treated, the patient improved.

Transventricular endoscopic approach to the anterior interhemispheric fissure for neurocysticercosis: illustrative cases.

BACKGROUND: Neurocysticercosis (NCC) is a global public health problem. It is a complex disease to manage and a cause of great morbidity and mortality in affected patients. Conventional surgical approaches have been used for many years, but currently, minimally invasive approaches are being used with good results. The authors present a case of NCC in the anterior interhemispheric fissure that was treated with a transventricular endoscopic approach. OBSERVATIONS: A 32-year-old male patient was admitted for persistent moderate headache and dizziness. Gadolinium-enhanced magnetic resonance imaging (MRI) showed multiple parenchymal, ventricular, and subarachnoid cystic lesions, especially in the anterior interhemispheric space. A transventricular endoscopic approach was selected and applied. There were no complications during surgery. Pathological analysis confirmed the diagnosis of NCC. Control MRI demonstrated the absence of cysts in the anterior interhemispheric space. LESSONS: Minimally invasive approaches are an excellent alternative for patients with NCC, especially if a patient requires more than one surgery.

Sweet Immune Checkpoint Targets to Enhance T Cell Therapy.

Despite tremendous success against hematological malignancies, the performance of chimeric Ag receptor T cells against solid tumors remains poor. In such settings, the lack of success of this groundbreaking immunotherapy is in part mediated by ligand engagement of immune checkpoint molecules on the surface of T cells in the tumor microenvironment. Although CTLA-4 and programmed death-1 (PD-1) are well-established checkpoints that inhibit T cell activity, the engagement of glycans and glycan-binding proteins are a growing area of interest due to their immunomodulatory effects. This review discusses exemplary strategies to neutralize checkpoint molecules through an in-depth overview of genetic engineering approaches aimed at overcoming the inhibitory programmed death ligand-1 (PD-L1)/PD-1 axis in T cell therapies and summarizes current knowledge on glycoimmune interactions that mediate T cell immunosuppression.

Synthesis of Oligonucleotides containing the cis-Interstrand Crosslink Produced by Mitomycins in their Reaction with DNA.

Mitomycin C (MC) an antitumor drug and decarbamoylmitomycin C (DMC), a derivative of MC lacking the carbamoyl moiety, are DNA alkylating agents which can form DNA interstrand crosslinks (ICLs) between deoxyguanosine residues located on opposing DNA strands. MC forms primarily deoxyguanosine adducts with a 1"-R stereochemistry at the guanine-mitosene bond (1"-α, trans) whereas DMC forms mainly adducts with a 1"-S stereochemistry (1"-ß, cis). The crosslinking reaction is diastereospecific: trans-crosslinks are formed exclusively at CpG sequences, while cis-crosslinks are formed only at GpC sequences. Until now, oligonucleotides containing 1"-ß-deoxyguanosine adducts or ICL at a specific site could not be synthesized, thus limiting the investigation of the role played by the stereochemical configuration at C1'' in the toxicity of these compounds. Here, a novel biomimetic synthesis to access these substrates is presented. Structural proof of the adducted oligonucleotides and ICL were provided by enzymatic digestion to nucleosides, high resolution mass spectral analysis, CD spectroscopy and UV melting temperature studies. Finally, a virtual model of the 25-mer 1"-ß ICL synthesized was created to explore the conformational space and structural features of the crosslinked duplex.

Prevalencia y factores asociados a conducta suicida en estudiantes de la Universidad Nacional Mayor de San Marcos, Lima-Perú / Prevalence and associated factors of suicidal behavior in students of the Universidad Nacional Mayor de San Marcos, Lima-Peru

Introducción. La Organización Mundial de la Salud ha señalado el incremento de riesgo suicida en personas de 15 a 44 años, grupo etario en el que se ubican los estudiantes universitarios. Objetivo. Determinar prevalencias de conducta suicida y variables asociadas en estudiantes de pregrado de la Universidad Nacional Mayor de San Marcos (UNMSM), Lima-Perú. Métodos. Estudio analítico, transversal. La población objetivo fue de 24 118 estudiantes matriculados en 2015. Se aplicaron los instrumentos de conducta suicida de la Encuesta Nacional de Salud Mental en el Perú 2002 y 2012, las escalas de ansiedad y depresión de Zung y el cuestionario CAGE para problemas de alcohol, a una muestra de 1819 estudiantes obtenida mediante muestreo bietápico. Se estimaron prevalencias y se empleó regresión logística para determinar factores asociados. Resultados. Las prevalencias de vida, último año, últimos seis meses y último mes de los componentes de la conducta suicida fueron: deseos de morir (35%; 13,9%; 11% y 5,6%); ideación suicida (22,4%; 8,2%; 6% y 3,3%); plan suicida (17,7%; 4,4%; 3,5% y 1,6%); e intento suicida (11,1%; 3,7%; 2,8% y 1,4%). Los factores de riesgo en términos de odds ratio (OR) ajustados y sus IC 95% fueron: condición de mujer 1,48 (IC 95%: 1,03-2,12), depresión 2,46 (IC 95%: 1,49-4,06), angustia 2,5 (IC 95%: 1,38-4,6), y vivir en hogar no nuclear 2,51 (IC 95%: 1,70-3,72). De los estudiantes que intentaron suicidarse sólo 16% buscó ayuda profesional y 21% pensó repetir el intento. Conclusiones. Los estudiantes de la UNMSM tienen mayor riesgo de conducta suicida que los de la población en general, tanto por razones científicas como por responsabilidad moral se recomienda implementar estrategias de intervención para revertir esta tendencia y proteger a este valioso recurso humano.

Introduction. World Health Organization has pointed out the increasing suicidal risk in the 115 - 44 years of age. University students are inmerse in that age group risk. Objective. To estimate the prevalence of suicidal behavior and associated variables in undergraduate students of Universidad Nacional Mayor de San Marcos (UNMSM). Methodos. Transversal and analytic study. Target population: 24 118 students registered in 2015. The Suicide Behavior Questionnaire of the 2002, 2012 Mental Health National Survey, the Zung self-rated anxiety and depression scales, and the CAGE questionnaire for potential alcohol-related problems were applied to a sample of 1819 students obtained by a bietapic with probabililty proportional to size sampling procedure. Results. Life, last year, last 6 months, and last month prevalences of suicide behavior`s components of were, in that order: (i) death wish (35%; 13,9%; 11%; 5,6%); (ii) suicidal ideation (22,4%; 8,2%; 6%;3,3%); (iii) suicidal planning (17,7%; 4,4%; 3,5%; 1,6%); and (iv) suicidal attempt (11,1%; 3,7%; 2,8%; 1,4%), and higher than the prevalences of metropolitan Lima general population. Risk factors, in terms of OR and 95% CI were: being female 1,48 (1,03-2,12), depression 2,46 (1,49-4,06), anxiety 2,5 (1,38-4,6), and living in a non nuclear home 2,51 (1,70-3,72). Only 16% of the students who attempted suicide sought professional help and 21% considered repeating the attempt. Conclusions. UNMSM undergraduate students show a riskier suicide behavior tan the general population. Both for scientific reasons and moral responsibility it is highly recommended to implement intervention strategies in order to revert this trend and protect this valuable human resource.

Isolation and Rationale for the Formation of Isomeric Decarbamoylmitomycin C- N6-deoxyadenosine Adducts in DNA.

Mitomycin C (MC) is an anticancer agent that alkylates DNA to form monoadducts and interstrand cross-links. Decarbamoylmitomycin C (DMC) is an analogue of MC lacking the carbamate on C10. The major DNA adducts isolated from treatment of culture cells with MC and DMC are N2-deoxyguanosine (dG) adducts and adopt an opposite stereochemical configuration at the dG-mitosene bond. To elucidate the molecular mechanisms of DMC-DNA alkylation, we have reacted short oligonucleotides, calf thymus, and M. luteus DNA with DMC using biomimetic conditions. These experiments revealed that DMC is able to form two stereoisomeric deoxyadenosine (dA) adducts with DNA under bifuntional reduction conditions and at low temperature. The dA-DMC adducts formed were detected and quantified by HPLC analysis after enzymatic digestion of the alkylated DNA substrates. Results revealed the following rules for DMC dA alkylation: (i) DMC dA adducts are formed at a 48- to 4-fold lower frequency than dG adducts, (ii) the 5'-phosphodiester linkage of the dA adducts is resistant to snake venom diesterase, (iii) end-chain dA residues are more reactive than internal ones in duplex DNA, and (iv) nucleophilic addition by dA occurs on both faces of DMC and the ratio of stereoisomeric dA adducts formed is dependent on the end bases located at the 3' or 5' position. A key finding was to discover that temperature plays a determinant role in the regioselectivity of duplex DNA alkylation by DMC: at 0 °C, both dA and dG alkylation occur, whereas at 37 °C, DMC preferentially alkylates dG residues.

Conducta y personalidad disociales en estudiantes de medicina: implicancias para la educación médica peruana / Dyssocial behavior and personality in medical students: implications for Peruvian medical education

Investigaciones previas sobre conducta suicida realizadas en estudiantes de medicina hallaron, como variable asociada, una alta prevalencia de vida (PV) de indicadores de conducta disocial. Tal resultado obliga a sospechar presencia de personalidad de este tipo en dicha población. Con el objetivo de aportar nuevos elementos que complementen los estudios previos, el presente artículo analiza el concepto de personalidad disocial y discute los resultados de un estudio piloto que evaluó su presencia en una muestra de alumnos recién ingresados a la Escuela de Medicina de la Universidad Nacional Mayor de San Marcos. Se encontró que de 175 estudiantes, 33 resultaron positivos a indicadores de conducta disocial (19% de PV) durante una primera evaluación; de este grupo, 30 se presentaron a una segunda evaluación diagnóstica, de los cuales cinco superaron el punto de corte para personalidad disocial, y 11 obtuvieron puntaje de sospecha de tal desarrollo. Sobre estos resultados sugerimos que la universidad debiera aceptar la responsabilidad de continuar investigando esta área, crear intervenciones preventivo-terapéuticas tempranas e innovaciones curriculares para reducir el riesgo de producir profesionales tecnicamente bien entrenados pero con minusvalías morales.

Previous studies on medical students´suicidal behavior found, as an associated variable, a high life-prevalence (LP) of dissocial behavior indicators. Such findings compel to suspect the presence of dissocial personality in that population. On the purpose to add knowledge to this problem, the present paper analyses the concept of dissocial personality and discusses the results of a pilot-study that evaluated its presence in recently admitted students to San Marcos University´s School of Medicine. In the first evaluation, it was found that 33 out of 175 students resulted positive to dissocial behavior indicators (LP: 19%). From this group, 30 showed up for a second diagnostic evaluation; 5 exceeded the cut-off point to dissocial personality and 11 showed scores very close to it, raising suspiciousness of such development. Upon these results we claim the university must accept the responsibility to continue researching this area, create early preventive-therapeutic interventions and curricula innovations to reduce the risk of generating well trained professionals but morally handicapped.

Interdependent Sequence Selectivity and Diastereoselectivity in the Alkylation of DNA by Decarbamoylmitomycin†C.

Mitomycin C (MC), an antitumor drug, and decarbamoylmitomycin C (DMC), a derivative of MC, alkylate DNA and form deoxyguanosine monoadducts and interstrand crosslinks (ICLs). Interestingly, in mammalian culture cells, MC forms primarily deoxyguanosine adducts with a 1"-R stereochemistry at the guanine-mitosene bond (1"-α) whereas DMC forms mainly adducts with a 1"-S stereochemistry (1"-ß). The molecular basis for the stereochemical configuration exhibited by DMC has been investigated using biomimetic synthesis. Here, we present the results of our studies on the monoalkylation of DNA by DMC. We show that the formation of 1"-ß-deoxyguanosine adducts requires bifunctional reductive activation of DMC, and that monofunctional activation only produces 1"-α-adducts. The stereochemistry of the deoxyguanosine adducts formed is also dependent on the regioselectivity of DNA alkylation and on the overall DNA CG content. Additionally, we found that temperature plays a determinant role in the regioselectivity of duplex DNA alkylation by mitomycins: At 0 °C, both deoxyadenosine (dA) and deoxyguanosine (dG) alkylation occur whereas at 37 °C, mitomycins alkylate dG preferentially. The new reaction protocols developed in our laboratory to investigate DMC-DNA alkylation raise the possibility that oligonucleotides containing DMC 1"-ß-deoxyguanosine adducts at a specific site may be synthesized by a biomimetic approach.

A conserved transcriptional response to intranasal Ebola virus exposure in nonhuman primates prior to onset of fever.

Ebola virus disease (EVD), caused by Ebola virus (EBOV), is a severe illness characterized by case fatality rates of up to 90%. The sporadic nature of outbreaks in resource-limited areas has hindered the ability to characterize the pathogenesis of EVD at all stages of infection but particularly early host responses. Pathogenesis is often studied in nonhuman primate (NHP) models of disease that replicate major aspects of human EVD. Typically, NHP models use a large infectious dose, are carried out through intramuscular or aerosol exposure, and have a fairly uniform disease course. By contrast, we report our analysis of the host response to EBOV after intranasal exposure. Twelve cynomolgus macaques were infected with 100 plaque-forming units of EBOV/Makona through intranasal exposure and presented with varying times to onset of EVD. We used RNA sequencing and a newly developed NanoString CodeSet to monitor the host response via changes in RNA transcripts over time. When individual animal gene expression data were phased based on the onset of sustained fever, the first clinical sign of severe disease, mathematical models indicated that interferon-stimulated genes appeared as early as 4 days before fever onset. This demonstrates that lethal EVD has a uniform and predictable response to infection regardless of time to onset. Furthermore, expression of a subset of genes could predict disease development before other host-based indications of infection such as fever.

Sequence-Dependent Diastereospecific and Diastereodivergent Crosslinking of DNA by Decarbamoylmitomycin C.

Mitomycin C (MC), a potent antitumor drug, and decarbamoylmitomycin C (DMC), a derivative lacking the carbamoyl group, form highly cytotoxic DNA interstrand crosslinks. The major interstrand crosslink formed by DMC is the C1'' epimer of the major crosslink formed by MC. The molecular basis for the stereochemical configuration exhibited by DMC was investigated using biomimetic synthesis. The formation of DNA-DNA crosslinks by DMC is diastereospecific and diastereodivergent: Only the 1''S-diastereomer of the initially formed monoadduct can form crosslinks at GpC sequences, and only the 1''R-diastereomer of the monoadduct can form crosslinks at CpG sequences. We also show that CpG and GpC sequences react with divergent diastereoselectivity in the first alkylation step: 1"S stereochemistry is favored at GpC sequences and 1''R stereochemistry is favored at CpG sequences. Therefore, the first alkylation step results, at each sequence, in the selective formation of the diastereomer able to generate an interstrand DNA-DNA crosslink after the "second arm" alkylation. Examination of the known DNA adduct pattern obtained after treatment of cancer cell cultures with DMC indicates that the GpC sequence is the major target for the formation of DNA-DNA crosslinks in vivo by this drug.

Comparison of Transcriptomic Platforms for Analysis of Whole Blood from Ebola-Infected Cynomolgus Macaques.

Ebola virus disease (EVD) is a serious illness with mortality rates of 20-90% in various outbreaks. EVD is characterized by robust virus replication and strong host inflammatory response. Analyzing host immune responses has increasingly involved multimodal approaches including transcriptomics to profile gene expression. We studied cynomolgus macaques exposed to Ebola virus Makona via different routes with the intent of comparing RNA-Seq to a NanoString nCounter codeset targeting 769 non-human primate (NHP) genes. RNA-Seq analysis of serial blood samples showed different routes led to the same overall transcriptional response seen in previously reported EBOV-exposed NHP studies. Both platforms displayed a strong correlation in gene expression patterns, including a strong induction of innate immune response genes at early times post-exposure, and neutrophil-associated genes at later time points. A 41-gene classifier was tested in both platforms for ability to cluster samples by infection status. Both NanoString and RNA-Seq could be used to predict relative abundances of circulating immune cell populations that matched traditional hematology. This demonstrates the complementarity of RNA-Seq and NanoString. Moreover, the development of an NHP-specific NanoString codeset should augment studies of filoviruses and other high containment infectious diseases without the infrastructure requirements of RNA-Seq technology.

Acetone promoted 1,4-migration of an alkoxycarbonyl group on a syn-1,2-diamine.

A 2-protected cis-amino mitosene undergoes an irreversible acetone promoted isomerization and converts to the 1-isomer. Kinetic studies and DFT calculations of the reaction are reported. An organocatalytic mechanism is proposed, involving a covalent intermediate formed by reaction of the mitosene and acetone.