Preclinical Studies with Glioblastoma Brain Organoid Co-Cultures Show Efficient 5-ALA Photodynamic Therapy.

BACKGROUND: The high recurrence of glioblastoma (GB) that occurs adjacent to the resection cavity within two years of diagnosis urges an improvement of therapies oriented to GB local control. Photodynamic therapy (PDT) has been proposed to cleanse infiltrating tumor cells from parenchyma to ameliorate short long-term progression-free survival. We examined 5-aminolevulinic acid (5-ALA)-mediated PDT effects as therapeutical treatment and determined optimal conditions for PDT efficacy without causing phototoxic injury to the normal brain tissue. METHODS: We used a platform of Glioma Initiation Cells (GICs) infiltrating cerebral organoids with two different glioblastoma cells, GIC7 and PG88. We measured GICs-5-ALA uptake and PDT/5-ALA activity in dose-response curves and the efficacy of the treatment by measuring proliferative activity and apoptosis. RESULTS: 5-ALA (50 and 100 µg/mL) was applied, and the release of protoporphyrin IX (PpIX) fluorescence measures demonstrated that the emission of PpIX increases progressively until its stabilization at 24 h. Moreover, decreased proliferation and increased apoptosis corroborated the effect of 5-ALA/PDT on cancer cells without altering normal cells. CONCLUSIONS: We provide evidence about the effectiveness of PDT to treat high proliferative GB cells in a complex in vitro system, which combines normal and cancer cells and is a useful tool to standardize new strategic therapies.

Cost savings associated with early initiation of pregabalin in the management of peripheral neuropathic pain.

OBJECTIVE: Peripheral neuropathic pain (PNP) is associated with significant economic burden. Guidelines recommend the early adoption of appropriate pharmacological interventions. The aim of this study was to explore whether early initiation of pregabalin was associated with lower economic burden, than later initiation, in the management of refractory chronic PNP. METHODS: A secondary analysis of a multicenter, observational cost-of-illness study was carried out in adults older than 18 years of age with refractory chronic PNP. Patients were pregabalin naive, with a poor response to previous analgesic therapy, defined as pain >40 in a 0 to 100 mm visual analog scale after, at least, 1 analgesic. The total costs, health care and indirect, assessed 12 weeks before the initiation of pregabalin were analyzed according to the time elapsed since diagnosis. RESULTS: One thousand one hundred thirty-nine outpatients, 59.3 (12.8) years old, 59.3% women, 2.0 (3.5) years with a diagnosis of PNP, fulfilled the criteria for analysis. Adjusted (pain intensity, sex, age, and body mass index) mean total costs 12 weeks before the baseline visit were significantly lower when pregabalin was initiated early (<6 mo; n=389) in comparison with later initiation; 6 to 12 months (n=328), or >12 months (n=422) after diagnosis; €2439 (2197; 2681) versus €3011 (2758; 3264) and €2945 (2717; 3173), respectively (P<0.01 in both cases). Lower health care costs and fewer lost-workday equivalents with early initiation of pregabalin were the main factors contributing to these findings. DISCUSSION: Early initiation of pregabalin treatment after diagnosis in patients with refractory chronic PNP may result in substantial cost savings from a societal perspective in daily practice in Spain.

Gastroprotección en usuarios de AINEs y aspirina a dosis bajas: estudio transversal en atención primaria / Gastroprotection in NSAID and low-dose aspirin users: A cross-sectional study in primary care

Las complicaciones gastrointestinales (GI) son un efecto secundario habitual relacionado con el uso de antiinflamatorios no esteroideos (AINE) y aspirina a dosis bajas (ADB). Las directrices para prevenir las complicaciones GI establecen que los pacientes con elevado riesgo deben recibir alguna forma de protección gástrica. Sin embargo, diversos informes sugieren que dichas estrategias no se llevan a cabo. Para determinar la prevalencia en la atención primaria española del uso de estrategias preventivas para reducir las complicaciones GI en los pacientes a los que se les ha prescrito AINE y ADB, se realizó un estudio observacional, transversal y multicéntrico en el que participaron médicos de atención primaria. Desde enero a mayo de 2009, los médicos recogieron datos demográficos, clínicos y sobre tratamiento procedentes de la última visita en 2008 de los 5 primeros pacientes consecutivos que cumplían los criterios de selección. Se llevó a cabo una regresión logística multivariante para identificar los predictores independientes de las estrategias preventivas utilizadas. Un total de 713 médicos de atención primaria incluyeron a 3357 pacientes: el 68% tomaba AINE, el 19,1% ADB y el 12,9% recibía AINE y ADB. El 31,5% de los pacientes no presentaba factores de riesgo de complicaciones GI, el 25,6% tenia uno y el 42,9% 2 o más factores de riesgo. La prevalencia total de uso de estrategias de prevención fue del 75,8%. La prevalencia del uso de gastroprotección incrementó con el número de factores de riesgo. La infrautilización de protección GI en pacientes con alto riesgo tratados con AINE es baja y no es tan marcada como la que se notifica en la atención primaria de otros países. También se observó un uso elevado de gastroprotección en los pacientes que toman ADB (AU)

Gastrointestinal (GI) complications are common side effects related to non-steroidal anti-inflammatory drugs (NSAID) and low-dose aspirin (LDA) use. The guidelines to prevent GI complications establish that patients at high risk should receive gastroprotection. However, different reports have suggested that these strategies are not greatly executed. To determine the prevalence of use of preventive strategies to reduce GI complications in NSAID and/or LDA users in primary care in Spain, we performed an observational, cross-sectional, multicentre study in which primary care physicians from Spain participated. From January 2009 to May 2009, physicians collected demographic, clinical and treatment data from the last visit in 2008 of the first 5 consecutive patients who met the selection criteria. A multivariate logistic regression was carried out to identify independent predictors of the preventive strategies used. A total of 713 primary care physicians included 3357 patients: 68% NSAID users, 19.1% LDA users and 12.9% NSAID/LDA users. 31.5% of patients did not have a risk factor for GI complications, 25.6% had one risk factor and 42.9% had 2 or more risk factors. The overall prevalence of preventive strategy use was 75.8%. The prevalence of gastroprotection use increased with the number of risk factors. The underutilization of gastroprotection in at-risk patients treated with NSAIDs is low and not as marked as those previously reported at the primary care level in other countries. We also found high rates of gastroprotection use in LDA users (AU)

Gastroprotection in NSAID and low-dose aspirin users: a cross-sectional study in primary care.

Gastrointestinal (GI) complications are common side effects related to non-steroidal anti-inflammatory drugs (NSAID) and low-dose aspirin (LDA) use. The guidelines to prevent GI complications establish that patients at high risk should receive gastroprotection. However, different reports have suggested that these strategies are not greatly executed. To determine the prevalence of use of preventive strategies to reduce GI complications in NSAID and/or LDA users in primary care in Spain, we performed an observational, cross-sectional, multicentre study in which primary care physicians from Spain participated. From January 2009 to May 2009, physicians collected demographic, clinical and treatment data from the last visit in 2008 of the first 5 consecutive patients who met the selection criteria. A multivariate logistic regression was carried out to identify independent predictors of the preventive strategies used. A total of 713 primary care physicians included 3357 patients: 68% NSAID users, 19.1% LDA users and 12.9% NSAID/LDA users. 31.5% of patients did not have a risk factor for GI complications, 25.6% had one risk factor and 42.9% had 2 or more risk factors. The overall prevalence of preventive strategy use was 75.8%. The prevalence of gastroprotection use increased with the number of risk factors. The underutilization of gastroprotection in at-risk patients treated with NSAIDs is low and not as marked as those previously reported at the primary care level in other countries. We also found high rates of gastroprotection use in LDA users.

Season of birth affects short- and long-term survival.

Recent research findings have highlighted the importance of early life conditions as risk factors for adult diseases and therefore determinants of subsequent survival. Given that individuals born during different seasons in seasonal environments experience different early-developmental conditions, an analysis of the effects of the season of birth on survival is considered an effective approach in clarifying the influence of early life conditions on survival in later life. In the present study, we analyzed the long-term effects of early developmental conditions in a historical population in which both nutritional levels and the burden of infectious diseases showed a seasonal variation. Using a semi-computerized linkage process, we were able to match birth and death data for 4,646 individuals born between 1634 and 1870 in the village of Es Mercadal (Minorca Island, Spain). To determine ecological differences associated with the season of birth, we first evaluated the association between season of birth and early life survival. This analysis helped us to determine seasonal variations in early life conditions such as infectious burden and nutritional levels. The season of birth had a significant effect on long-term survival in the birth cohort 1800-1870: summer births had a lower risk of death after age 15. We explain these results in terms of lower susceptibility to degenerative diseases in adult years due to superior in utero nutrition for summer births. These findings support the fetal origin hypothesis which states that the early life environment plays a key role in shaping the subsequent phenotype and risk of adult disease.