Pharmacological Inhibition of Epidermal Growth Factor Receptor Prevents Intracranial Aneurysm Rupture by Reducing Endoplasmic Reticulum Stress.

BACKGROUND: Multiple pathways and factors are involved in the rupture of intracranial aneurysms. The EGFR (epidermal growth factor receptor) has been shown to mediate inflammatory vascular diseases, including atherosclerosis and aortic aneurysm. However, the role of EGFR in mediating intracranial aneurysm rupture and its underlying mechanisms have yet to be determined. Emerging evidence indicates that endoplasmic reticulum (ER) stress might be the link between EGFR activation and the resultant inflammation. ER stress is strongly implicated in inflammation and apoptosis of vascular smooth muscle cells, both of which are key components of the pathophysiology of aneurysm rupture. Therefore, we hypothesized that EGFR activation promotes aneurysmal rupture by inducing ER stress. METHODS: Using a preclinical mouse model of intracranial aneurysm, we examined the potential roles of EGFR and ER stress in developing aneurysmal rupture. RESULTS: Pharmacological inhibition of EGFR markedly decreased the rupture rate of intracranial aneurysms without altering the formation rate. EGFR inhibition also significantly reduced the mRNA (messenger RNA) expression levels of ER-stress markers and inflammatory cytokines in cerebral arteries. Similarly, ER-stress inhibition also significantly decreased the rupture rate. In contrast, ER-stress induction nullified the protective effect of EGFR inhibition on aneurysm rupture. CONCLUSIONS: Our data suggest that EGFR activation is an upstream event that contributes to aneurysm rupture via the induction of ER stress. Pharmacological inhibition of EGFR or downstream ER stress may be a promising therapeutic strategy for preventing aneurysm rupture and subarachnoid hemorrhage.

Therapy of childhood acute lymphoblastic leukemia in resource-poor geospaces.

The therapy of children with acute lymphoblastic leukemia (ALL) in limited resource geospaces is challenging and must balance safety, efficacy, availability, and affordability. We modified the control arm of the St. Jude Total XI protocol for outpatient delivery including once-weekly daunorubicin and vincristine in initial therapy, postponing intrathecal chemotherapy until day 22, prophylactic oral antibiotics/antimycotics, use of generic drugs, and no central nervous system (CNS) radiation. Data were interrogated from 104 consecutive children ≤12 years (median, 6 years [interquartile range (IQR), 3, 9 years]. All therapies were given in an outpatient setting in 72 children. Median follow-up is 56 months (IQR 20, 126 months). A total of 88 children achieved a hematological complete remission. Median event-free survival (EFS) is 87 months [95% confidence interval (CI), 39, 60], 7.6 years in low-risk children (3.4, 8 years) whereas 2.5 years (1, 10 years) in high-risk children. The 5-year cumulative incidence of relapse (CIR) is 28% (18, 35%), 26% (14, 37%) in low-risk children and 35% (14, 52%) in high-risk children. Median survival for all subjects is not reached but must exceed 5 years. A total of 36 children relapsed at a median of 12 months (5, 23 months). Outcomes were comparable to those reported in the control arm of the Total Therapy XI study, but inferior to current treatment protocols in high-income countries. The average cost of the first 2 years of therapy was $28,500 USD compared with an average cost of approximately $150,000 USD in the US, an 80% saving. In conclusion, using an outpatient-based modification of the St. Jude Total XI protocol, we obtained good results with relatively few hospitalizations or adverse events and at a substantial saving. This model can be applied in other resource-poor geospaces.

Impaired lung function in multiple sclerosis: a single-center observational study in 371 persons.

INTRODUCTION: Abnormal lung function in people with multiple sclerosis (PwMS) could be considered as the result of muscle weakness or MS-specific structural central nervous system (CNS) abnormalities as a precipitant factor for the worsening of motor impairment or cognitive symptoms. METHODS: This is a cross-sectional observational study in PwMS. Forced spirometry was conducted, and normative metrics of forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), and the relation FEV1/FVC were calculated. Qualitative and quantitative brain magnetic resonance imaging (MRI) examinations were carried out. RESULTS: A total of 371 PwMS were included in the study. Of those, 196 (53%) had RRMS, 92 (25%) SPMS, and 83 (22%) PPMS. Low FVC and FEV1 was present in 16 (8%), 16 (19%), and 23 (25%) of the patients in the RRMS, PPMS, and SPMS, respectively. PwMS with T2-FLAIR lesions involving the corpus callosum (CC) had a significantly higher frequency of abnormally low FVC and FEV1 (OR 3.62; 95% CI 1.33-9.83; p = 0.012) than patients without lesions in that region. This association remained significant in the RRMS group (OR 10.1; 95% CI 1.3-67.8; p 0.031) when the model excluded PPMS and SPMS. According to our study, for every increase of 1 z score of FVC, we observed an increase of 0.25 cm3 of hippocampal volume (ß 0.25; 95% CI 0.03-0.47; p 0.023) and 0.43 cm3 of left hippocampus volume (ß 0.43; 95% CI 0.16-0.71; p 0.002). CONCLUSIONS: We observed an incremental prevalence of abnormally low pulmonary function tests that parallels a sequence from more early relapsing courses to long-standing progressive courses (RRMS to PPMS or SPMS).

SARS-CoV-2 vaccination patterns in a private hematology and internal medicine outpatient clinic.

OBJECTIVE: Determine the proportion of vaccinated patients in a private hematology and internal medicine outpatient clinic and potential factors in adherence in at-risk patients (due to onco-hematological diseases). MATERIALS AND METHODS: This is a cross-sectional study of outpatients from a private clinic. We applied a non-validated instrument to all patients attending the outpatient clinic from May to October 2021. According to the primary diagnosis, we classified patients into onco-hematological and non-onco-hematological patients. Since national authorities exclusively executed and planned the rollout of vaccines, the order and eligibility defined by authorities of vaccination was considered when conducting the analysis and patients were classified according to the their corresponding group. RESULTS: 397 participants were accrued, 269 (68%) had an onco-hematological condition. In the whole group, 73 (18.3%) had a history of infection. Vaccination history was present in 286 persons (72%); 82% had two doses. In the subset of 269 persons with an onco-hematological condition, 191 (71%) were vaccinated, whereas 95 participants with non-hematological conditions (73%) had received the vaccine. Vaccination status was associated with age (OR 1.07, 95%CI: 1.03,1.10, p<0.0001) and body mass index (OR 1.11, 95%CI: 1.04,1.17, p<0.0001). CONCLUSIONS: According to our study, vaccination adherence at our center is significantly different from the nationwide proportion of vaccines.

Long-term results of the treatment of adolescents and adults with acute lymphoblastic leukemia with a pediatric-inspired regimen delivered on an outpatient basis: A single institution experience.

The results of treatment of adolescents and adults with acute lymphoblastic leukemia (ALL) remain unsatisfactory. Pediatric-inspired treatments seem to be related with better outcomes. 126 adolescent and adult patients with ALL were treated in a 37-year period with a pediatric inspired combined chemotherapy (PICC) schedule, delivered on an outpatient basis and based on the St. Jude´s TOTAL XI pediatric protocol employing vincristine, prednisone, asparaginase, daunorubicin, etoposide, cytarabine, methotrexate, mercaptopurine and triple intrathecal therapy. 80 % of patients were able to receive the initial seven-week period of induction / consolidation fully as outpatients and 77 % achieved a complete remission. In adolescents and young adults (AYAs) the median probability of overall survival (OS) was 44 months, whereas the 5-year OS was 48 %. In adults, the median probability of OS was 24 months, and the 5-year OS was 32 %. Patients with T-cell ALL did significantly worse than those with a B cell phenotype (OS at 5 years 17 versus 40 %, respectively). These figures are better than those informed in our country employing more aggressive, in-hospital schedules such as the hyper-CVAD. We found that, in AYAs and adult patients with ALL, the use of an asparaginase-containing PICC delivered on an outpatient basis renders acceptable results, better than those obtained in similar socioeconomic circumstances employing adult-oriented schedules. Additional studies are needed to assess the usefulness of these PICC treatments in adult individuals with ALL treated in underprivileged circumstances, such as those prevailing in LMIC.

High dose melphalan is an adequate preparative regimen for autologous hematopoietic stem cell transplantation in relapsed/refractory lymphoma.

INTRODUCTION: High-dose melphalan (HD-Mel) has been successfully employed in autografting patients with multiple myeloma. An advantage of this regimen is that the total dose of Mel can be delivered in a single day, being particularly useful when non-frozen hematopoietic stem cells are employed in the autograft. MATERIAL AND METHODS: All consecutive patients with R/R lymphomas, both HL and NHL studied and treated at two different centers were prospectively included in a study of ASCT employing a single dose of HD-Mel (200 mg/m2). A group of R/R HL or NHL autografted employing BEAM-like preparative regimens was constructed matched by diagnosis and age. The primary endpoint of the study was overall survival (OS), the secondary endpoint was event-free survival (EFS). RESULTS: Twenty-five R/R HL/NHL patients were prospectively accrued in the study. There were 8 (32%) females, 13 (52%) patients had at least 1 adverse effect: 7 (28%) developed mucositis, 5 (20%) neutropenic fever, and 6 (24%) grade IV nausea. In the HD-Mel group, median overall survival (OS) was not achieved and OS at 36 months was 71%, the transplant-related mortality being 0%. In the control group, median OS was not achieved and the 36-month OS was 76%, results not statistically significant (p 0.5). The EFS was also similar in both groups (p 0.5). CONCLUSION: HD-Mel alone is non-inferior to a BEAM-like regimen as a preparative regimen for autografting patients with R/R HL and NHL. The regimen is adequate to graft persons with non-frozen stem cells.

Long term survival in multiple myeloma: a single institution experience in underprivileged circumstances.

There is data suggesting that the clinical behavior of multiple myeloma (MM) may be different in Latin Americans than in Caucasian or African-Americans, consistent with a less aggressive course of MM in Latinos. We analyzed the overall survival (OS) of 139 persons with MM in a single institution in México, as well the variables which were associated with long-term OS. Of all patients, the median OS was 11 years whereas the 5-year and 10-year OS were 75% and 55% respectively. The analysis of variables showed that the variable related with five-year survival was having hematopoietic stem cell transplantation (HSCT), whereas the variables related with 10-year survival were HSCT, age at diagnosis (patients younger than 50 survived longer), light chain type (kappa survived longer) and ISS stage (stage I patients survived longer). The only variable associated with both 5 and 10-year survival was HSCT. A plateau in the OS was reached after 10 years, both in grafted and non-grafted patients. We have confirmed the critical role of HSCT in the prognosis of persons with MM, independent of the induction treatment or the maintenance post-transplant, and we have identified a better prognosis in this cohort, as compared with African-Americans or Caucasians, since the proportion of long-term survivors in our group is seemingly better than those in other populations.

Hemophagocytic Lymphohistiocytosis: Management and Special Consideration in Human Immunodeficiency Virus Positive Patients with Immune Reconstitution Syndrome.

The human body is capable of reacting to multiple aggressors by developing an inflammatory response with the secretion of inflammatory cytokines. The worrisome clinical manifestations occur when this inflammatory response is disproportionate. Hemophagocytic lymphohistiocytosis (HLH) is a rare and severe condition characterized by an overwhelming inflammatory response that may result in end-organ damage and might be fatal. Correspondingly, immune reconstitution inflammatory syndrome (IRIS) is another well-known disorder, seen commonly in human immunodeficiency virus (HIV)-infected patients after the commencement of highly active antiretroviral therapy (HAART). Both entities share a similar clinical presentation and a dismal prognosis. Due to widespread clinical manifestations and laboratory abnormalities, diagnosis is often missed at the time of presentation. There is little consensus on the treatment of secondary HLH, which is usually handled on a case-by-case basis. Rapid curbing of the widespread inflammatory response is the main goal of treatment. To the best of our knowledge, there is scarce literature available on the coexistence of HLH and IRIS; therefore, medical management in the co-occurrence of these two conditions needs to be further investigated.

A Fatal Case of Large Cell Neuroendocrine Lung Cancer Metastatic to the Brain: A Case Report.

Large cell neuroendocrine carcinoma (LCNEC) is part of lung neuroendocrine tumors. LCNEC represents an extremely rare entity with aggressive behavior and poor prognosis. Primary surgery is the mainstream of treatment, although it is rarely amenable due to local or systemic tumor metastasis at the time of the diagnosis. We present a case report of a female patient diagnosed with large cell neuroendocrine lung cancer metastatic to the brain. Noting the low incidence of the disease, the lack of relevant clinical data has resulted in a challenge in diagnosis and management.

An Aggressive Case of Sinonasal Squamous Cell Carcinoma, Invasive to Bone, Arising Within Inverted Papilloma with Intracranial Extension: A Case Report.

Sinonasal squamous cell carcinoma represents a rare and aggressive disease. Clinical presentation usually mimics other benign entities and consequently this malignancy is seldom diagnosed in early stages. Surgical management, although is standard of care, is rarely amenable due to the structures involved, usually intracranially. This article encompasses a case report of squamous cell carcinoma involving the ethmoidal, maxillary, and sphenoid sinuses invasive to bone and extending intracranially.

Bilateral Basal Ganglia Infarction After Intranasal Use of Cocaine: A Case Report.

We present a case of a young man who developed bilateral basal ganglia infarct after intranasal use of cocaine. Cerebral ischemic infarcts are a known complication of cocaine use. This complication is rare and has been reported in the past with cocaine and concomitant use of other drugs such as heroin and amphetamines.

Cerebellar Cavernous Malformation (Cavernoma): A Case Report.

Cavernous malformations are congenital or acquired vascular abnormalities. They are uncommon entities with an incidence of 0.5% of the general population and usually are unnoticed until a hemorrhagic event occurs. Cavernomas can be concurrently seen with developmental venous anomalies (DVAs) in 20% (range 20%-40%) of cases, in which case they are known as mixed vascular malformations. We report a case of a healthy young adult, who presented with acute onset of headache, dizziness, and nausea with intermittent episodes of vomiting for four days. Brain tomography imaging at presentation revealed likely multiple foci of intracranial hemorrhage; however, magnetic resonance imaging (MRI) showed findings suggestive of an underlying cavernoma that had bled, in addition to a coexisting DVA. The patient was discharged home with no deficits. Outpatient follow-up five months later revealed no symptoms or neurologic deficits.

Prevalencia de enfermedades no definitorias de SIDA en pacientes VIH/SIDA en el Hospital Edgardo Rebagliati Martins en el año 2014 / Prevalence of not-defining-diseases of AIDS in patients with HIV/AIDS at the Hospital Edgardo Rebagliati Martins in 2014

Introducción: En la actual epidemia por VIH/SIDA que vivimos se está presentando un aumento del número de pacientes con enfermedad no definitoria de SIDA, sin embargo aún no se establecen las causas de este aumento, más aún estas enfermedades presentan un comportamiento distinto en cada cohorte de estudio. En nuestro país no se ha realizado un estudio que las evalúe como tal. Objetivo: Determinar las proporciones de enfermedades no definitorias de SIDA presentes en los pacientes infectados por el VIH del Hospital Edgardo Rebagliati Martins durante el año 2014. Diseño: Estudio observacional, exploratorio, retrospectivo, de corte transversal. Mediante un muestreo aleatorio sistemático se seleccionaron 137 pacientes infectados con VIH, de entre todos aquellos diagnosticados con infección por VIH. Se recolectó información de las fichas de registro y de las historias clínicas y se registraron en fichas electrónicas codificadas, luego, con la base de datos se utilizó Microsoft Excel 2013 para el análisis exploratorio de los datos. Resultados: Se encontraron 5 pacientes (3.65 por ciento) infectaos con enfermedad vascular periférica (EVP), 2 (3.65 por ciento) con ictus, 1 (0.73 por ciento) con cirrosis hepática, 1 (0.73 por ciento) con falla renal, 1 (0.73 por ciento) con linfoma de Hodgkin y 127 (92.7 por ciento) sin enfermedad (NE). Las medianas para los valores de CD4 más bajos fueron Ic: 294.5, EHC: 282, LH: 216, EVP: 178, ERC: 78 y NE: 143.5 cel/uL. De los pacientes con SIDA y enfermedad los pacientes con EHC fueron el 100 por ciento, ERC el 100 por ciento, HTA el 92.86 por ciento, EVP el 80 por ciento, NE el 77.17 por ciento respecto de sus pares con enfermedad. Conclusiones: Entre las enfermedades no definitorias de SIDA la enfermedad vascular periférica se determinó como la más frecuente, seguida luego de ictus. Comparativamente se encontró mayor presencia de enfermedad en pacientes con mayores niveles de CD4, sin embargo hubo mayor proporción de enfermedades...

Introduction: In the actual HIV/AIDS epidemic we live, it is being presenting an increase of the number of patients with non-AIDS defining illnesses, however there are not yet established the causes of this increase, also, these diseases have a different presentation in each study cohort. In our country it has not been performed a study that evaluate these diseases as such. Objective: To determine the frequencies of non-AIDS defining illnesses in HIV patients of the Edgardo Rebagliati Martins Hospital in the 2014 year. Design: Observational, exploratory, retrospective, transversal study. Throught ramdom systematic sampling it has been selected 137 HIV patients, among all HIV diagnosed patients. It has been collected information from registration cards and medical records of HIV patients. The information was registered in codified electronical cards, then, with the database it has been used Microsoft Excel 2013 for the exploratory analysis of data. Results: It has been found 5 patients (3.65 per cent) with peripheral vascular disease (EVP), 2 (3.65 per cent) with stroke, 1 (0.73 per cent) with hepatic cirrhosis, 1 (0.73 per cent) with kidney failure, 1 (0.73 per cent) with Hodgkin lymphoma and 127 (92.7 per cent) without disease (NE). The medians for the lowest CD4 values were: IC: 294.5, EHC: 282, LH: 216, EVP: 178, ERC: 78 y NE: 143.5 cel/uL. The patients with AIDS and illness who had EHC were the 100 per cent, ERC the 100 per cent, EVP the 80 per cent, NE the 77.17 per cent, IC the 50 per cent respect of its pairs with illness. Conclusions: Among non-aids defining illnesses the vascular peripheral disease was the most frequent, followed by stroke. It has been found, comparatively, a greater presence of disease in patients with higher CD4 cells levels, however, there was more proportion of diseases in AIDS patients. The study accomplished its objective of study the diseases proportions, moreover it contributes to the generation of hypotheses and mentions its...

Age class influence on the yield of edible fungi in a managed Mediterranean forest.

Lack of information and difficulty in predicting wild edible sporocarp yields is blocking its integration in forest management. In the Mediterranean area, this nontimber forest product has increased its market value, consumption demand, and interest over the last decade. In this work, sampling year and stand age effects are analyzed in order to advance knowledge of edible fungi community structure, dynamics, and production. Weekly autumnal sporocarp monitoring was performed from 1997 to 2011 in a Pinus pinaster managed forest in central Spain. After applying a random stand age-stratified survey, 21 plots of 150 m(2) have been set with three per stand age class. The forest age classes have been defined as follows: 0-10 years, mixture of parent and regenerated trees, 11-20, 21-40, 41-60, 61-90, and over 90 years. A total of 153 species belonging to 56 genera were recorded, 55 of which are edible. The production of edible sporocarps was 19.8 kg ha(-1), representing 31 % of total production. Sporocarp production presents a sharp interannual variability with autumns 62 times more productive than others. The most abundant edible species in terms of fresh weight per hectare has been Lactarius deliciosus with 7.0 kg ha(-1). Edible fungi yields registered a significant decline in 10 years following regenerative cutting. The presence of parent trees significantly increases production with regard to the first class. The highest production of edible species occurs in the middle age, 41-60 years, and in the following classes, a decrease is produced. L. deliciosus production registered differences with age, manifesting in a high yield in young stands (11-20 years) and significant recovery in woodlands near to the cutting.

Driving position field study, differences with the whiplash protocol and biomechanics experimental responses.

Rear-impact collisions at low speed are a leading cause of economic costs among motor vehicle accidents. Recently, EuroNCAP has incorporated in its protocol the whiplash test, to reproduce a low-speed rear impact. This paper presents a field driving study to assess the potential differences between the EuroNCAP dummy tests and actual drivers in the field, focusing on occupant position and biomechanics experimental results. A total of 182 drivers were randomly selected in two geographical areas in Spain. The driving position of each driver was recorded with a focus on the most relevant measurements for rear impact. Statistical analysis was performed to obtain means, standard deviations and density functions to compare observational seating position with that of the EuroNCAP testing protocol. The observational data showed a similar seatback angle to that used in the EuroNCAP protocol (24° in front of 25° for the protocol), a greater distance between the head vertex and the top of the head restraint (53mm compared to 39.5mm), and less distance between the occipital bone of the head and the headrest (67.9 compared to 89.3mm). Based on these data, 4 dummy tests were conducted using the dummy BioRID IIg. The baseline test was designed to reproduce the dummy position according to EuroNCAP 3.0 whiplash protocol. Three different additional tests were defined to reproduce the actual observed driving position as well as to assess a "worst case" scenario in terms of reduced seatback angle. These variations in initial driver position, comparing the EuroNCAP protocol to the observational study results, were not observed to cause significant differences in the biomechanical values measured in the BioRID IIg, The T1 acceleration was reduced less than 8%, the NIC was increased about 8%, and the NKm presented a reduction of 20%. Reducing the seat angle was observed to be more harmful in terms of NIC.

Mycorrhizal synthesis between Boletus edulis species complex and rockroses (Cistus sp.).

Ectomycorrhizas of Boletus aereus, Boletus edulis, and Boletus reticulatus were synthesized with Cistus sp. under laboratory conditions using synthesis tubes filled with a mixture of sterilized peat-vermiculite and nutrient solution. The fungal strains isolated from sporocarps were identified by molecular techniques. The inoculated seedlings were grown for 4-5 months. The ectomycorrhizas formed were described based on standard morphological and anatomical characters. The three ectomycorrhizas described were very similar, with white monopodial-pinnate morphology, a three-layered plectenchymatous mantle on plan view and boletoid rhizomorphs.