Recent Development in the Understanding of Molecular and Cellular Mechanisms Underlying the Etiopathogenesis of Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to dementia and patient death. AD is characterized by intracellular neurofibrillary tangles, extracellular amyloid beta (Aß) plaque deposition, and neurodegeneration. Diverse alterations have been associated with AD progression, including genetic mutations, neuroinflammation, blood-brain barrier (BBB) impairment, mitochondrial dysfunction, oxidative stress, and metal ion imbalance.Additionally, recent studies have shown an association between altered heme metabolism and AD. Unfortunately, decades of research and drug development have not produced any effective treatments for AD. Therefore, understanding the cellular and molecular mechanisms underlying AD pathology and identifying potential therapeutic targets are crucial for AD drug development. This review discusses the most common alterations associated with AD and promising therapeutic targets for AD drug discovery. Furthermore, it highlights the role of heme in AD development and summarizes mathematical models of AD, including a stochastic mathematical model of AD and mathematical models of the effect of Aß on AD. We also summarize the potential treatment strategies that these models can offer in clinical trials.

Current Landscape of Therapeutic Resistance in Lung Cancer and Promising Strategies to Overcome Resistance.

Lung cancer is one of the leading causes of cancer-related deaths worldwide with a 5-year survival rate of less than 18%. Current treatment modalities include surgery, chemotherapy, radiation therapy, targeted therapy, and immunotherapy. Despite advances in therapeutic options, resistance to therapy remains a major obstacle to the effectiveness of long-term treatment, eventually leading to therapeutic insensitivity, poor progression-free survival, and disease relapse. Resistance mechanisms stem from genetic mutations and/or epigenetic changes, unregulated drug efflux, tumor hypoxia, alterations in the tumor microenvironment, and several other cellular and molecular alterations. A better understanding of these mechanisms is crucial for targeting factors involved in therapeutic resistance, establishing novel antitumor targets, and developing therapeutic strategies to resensitize cancer cells towards treatment. In this review, we summarize diverse mechanisms driving resistance to chemotherapy, radiotherapy, targeted therapy, and immunotherapy, and promising strategies to help overcome this therapeutic resistance.

An Analysis of the Multifaceted Roles of Heme in the Pathogenesis of Cancer and Related Diseases.

Heme is an essential prosthetic group in proteins and enzymes involved in oxygen utilization and metabolism. Heme also plays versatile and fascinating roles in regulating fundamental biological processes, ranging from aerobic respiration to drug metabolism. Increasing experimental and epidemiological data have shown that altered heme homeostasis accelerates the development and progression of common diseases, including various cancers, diabetes, vascular diseases, and Alzheimer's disease. The effects of heme on the pathogenesis of these diseases may be mediated via its action on various cellular signaling and regulatory proteins, as well as its function in cellular bioenergetics, specifically, oxidative phosphorylation (OXPHOS). Elevated heme levels in cancer cells intensify OXPHOS, leading to higher ATP generation and fueling tumorigenic functions. In contrast, lowered heme levels in neurons may reduce OXPHOS, leading to defects in bioenergetics and causing neurological deficits. Further, heme has been shown to modulate the activities of diverse cellular proteins influencing disease pathogenesis. These include BTB and CNC homology 1 (BACH1), tumor suppressor P53 protein, progesterone receptor membrane component 1 protein (PGRMC1), cystathionine-ß-synthase (CBS), soluble guanylate cyclase (sGC), and nitric oxide synthases (NOS). This review provides an in-depth analysis of heme function in influencing diverse molecular and cellular processes germane to disease pathogenesis and the modes by which heme modulates the activities of cellular proteins involved in the development of cancer and other common diseases.

Compromiso ocular en pacientes con rosácea: Hospital Arzobispo Loayza: 2004-2005 / Ocular involvement in patients with rosacea: Hospital Arzobispo Loayza: 2004-2005

La rosácea es una de las pocas dermatosis con importante morbilidad ocular asociada y que es independiente de la severidad de la afección cutánea. El objetivo del presente estudio es conocer el compromiso ocular en los pacientes con rosácea y compararlo con otras enfemedades dermatológicas. Materiales: Se realizó un estudio prospectivo caso-control en el Servicio de Dermatología del Hospital Arzobispo Loayza, con 50 casos de rosácea y 50 pacientes con otras enfermedades dermatológicas como controles. Todo los casos y controles completaron un ficha demográfica, exámenes dermatológicos y oftalmológicos, medición agudeza visual, examen con lámpara de hendidura y test de Schirmer. Resultados: La edad promedio de los pacientes y controles fue de 35+/-15 y 34.8+/-15 años, respecticamente, con un porcentaje de 74% de mujeres en ambos grupos. Hubo significativamente mayor prevalencia de ojo rojo, sensación de cuerpo extraño, lagrimeo, molestías oculares después de las manifestaciones cutáneas, enrojecimiento palpebral, blefaritis, telangiectasias palpebrales, congestión periquerática, queratitis puntiforme y disminución de la función lagrimal en los pacientes con rosácea. Luego del análisis de regresión logística múltiple las variables que permanecieron independientemente asociadas a rosácea fueron: blefaritis (OR: 7.7, 95% IC: 1.6-33.5, p=0.007), congestión periquerática (OR:0.9, 95% IC: 1.1-74.5, p=0.04) y disminución de la función lagrimal en el ojo derecho (OR: 0.9, 95% IC: 0.87-1.0, p=0.04). Conclusiones: La rosácea presenta significativamente un mayor compromiso ocular que otras enfermedades dermatológicas. Esto sugiere que los pacientes con rosácea deben tener un control oftalmológico periódico asociado al control dermatológico.

Rosacea is one of the few dermatosis which can be associated with significant ocular morbidity regardless of the severity of the cutaneous involvement. The objective of the present study is to recognize the ocular involvement in patients with rosacea and to compare it with other common dermatologic diseases. Materials: A prospective case-control study was carried out at the Dermatology Unit of the Hospital Arzobispo Loayza among 50 cases of rosacea and 50 patients with other dermatologic diseases as controls. Demographic data, dermatologic and ophthalmologic examinations, visual acuity, slit lamp and Schirmer tests were registered for all patients. Results: The average age for cases and controls was 35+/- 15 and 34.8 +/- 15 years old respectively; with 74% of women in both groups. Prevalence of red eye, foreign body sensation, tearing, on set of ocular features following cutaneous disease, eyelid hyperemia, blepharitis, eyelid telangiectasia, perikeratic congestion, punctate keratitis and diminished tear function was significantly higher in patients with rosacea. Variables like blepharitis (OR: 7.7, 95% CI: 1.6-33.5, p=0.007), perikeratic congestion (OR: 9.0, 95% CI: 1.1-74.5, p=0.04), and impairment of tear function in the right eye (OR: 0.9, 95% CI: 0.87-1.0, p=0.04) remain independently associated with rosacea after the multiple logistic regression analysis. Conclusions: Ocular involvement is significantly more associated to rosacea than other dermatologic diseases. This suggests that patients with rosacea must have a periodic ophthalmologic examination besides dermatologic assessment.

Verruga peruana en fase involutiva presentándose como pseudolinfoma / Involution phase peruvian wart presenting as pseudolymphoma

El espectro clinico de la infección por Bartonella bacilliformis varia ampliamente desde una infección subclínica hasta una enfermedad aguda fulminante, con hemólisis severa o desarrollo insidioso de tumores vasculares de la piel, con poca o ninguna sintomatología. Se reporta un caso enfermedad de Carrión presentándose como una tumoración única de aspecto angiomatoso, sin antecedente de enfermedad aguda previa, y con hallazgos histológicos compatibles con pseudolinfoma cutáneo, en la que la coloración de Warthin Starry nos permitió visualizar al agente infeccioso.

The clinical spectrum of Bartonella bacilliformis infection varies widely from subclinical infection to acute fulminant disease with severe hemolysis or insidious development of vascular tumors of the skin, with little or no symptoms. We report a case of Carrion's disease presenting as a single angiomatous tumor, with no history of previous symptoms, and histological findings consistent with cutaneous pseudolymphoma in which Warthin Starry staining allowed us to visualize the infectious agent.

Increased efficacy of infliximab associated with methotrexate in ankylosing spondylitis.

OBJECTIVES: The aims of this study were to assess the efficacy of infliximab (IFX) combined with methotrexate (MTX) versus IFX alone in the treatment of ankylosing spondylitis (AS). METHODS: The study was a 30weeks open label and prospective study of parallel groups in 19 patients with active AS. These patients had shown incomplete therapeutic response to standard therapy (full dose of non-steroidal anti-inflammatory drugs: NSAIDs) and disease modifying antirheumatic drugs: DMARDs (MTX or sulfasalazine: SLZ) for a period of at least 12 weeks and were treated with IFX (5mg/kg). Patients were divided into two treatment groups according to the previous treatment: in Group A, 9 patients previously treated with 7.5mg/week of MTX were treated with IFX in addition to MTX (IFX+MTX); in Group B, 10 patients previously treated only with NSAIDs were treated with IFX (5mg/kg) as monotherapy (IFX). The primary outcome was improvement in disease activity shown by the BASDAI50 at week 30; the secondary outcome included comparison of the proportions of subjects in each group achieving response criteria proposed by the ASAS group. BASDAI, BASFI, ESR, CRP, pain, inflammation and Patient Global Assessment were also recorded. RESULTS: Both groups were similar in sex ratio, clinical forms and B27. Differences between groups occurred only in the disease duration and age of the patient. At 14 and 30 weeks only 50% and 10% respectively of the patients from the IFX group achieved BASDAI50 response compared to 89% of patients from the IFX+MTX group. The difference between groups at 30 weeks was statistically significant (p=0.001; percentage of difference: 79%; 95% confidence interval (CI): 26-93%:). ASAS50 was reached in 67% and 55.6% of patients from the IFX+MTX group at 14 and 30 weeks respectively, compared with 30% and 0% of patients from the IFX group The difference between groups at 30 weeks was statistically significant (p=0.011; percentage of difference: 57%; 95% CI: 8-84.7%). CONCLUSION: Infliximab in combination with MTX seems to increase the efficacy of the therapeutic response in active AS patients, but more wide-ranging studies are necessary, mainly long-term studies.

Efficacy of bosentan in treatment of unresponsive cutaneous ulceration in disabling pansclerotic morphea in children.

Disabling pansclerotic morphea (PM) of childhood is a rare and debilitating variant of localized scleroderma. We describe a 4-year-old girl with rapid progression of deep cutaneous fibrosis extending into the muscle fascia with disabling joint contractures of the hips, knees, ankles, and fingers and recalcitrant ischemic ulcerations. Within the first months of therapy with dual oral endothelin receptor antagonist bosentan (31.25 mg qd for 4 weeks [DOSAGE ERROR CORRECTED], then 31.25 mg bid) limb ulcers improved, with resolution of the widespread sclerotic skin lesions. Joint mobility improved, and a substantial decrease of skin thickness was noted. No side effects were noted. In the context of other data in scleroderma, bosentan may be a promising option in the treatment of PM.

Fracturas pélvicas por insuficiencia tras radioterapia. Diagnóstico mediante TC / Pelvic insufficiency fractures following radiotherapy. CT Diagnosis

Objetivo: Determinar la utilidad de la tomografía computarizada (TC) como método de elección para establecer el diagnóstico definitivo de fracturas pélvicas por insuficiencia (FIP) frente al de enfermedad ósea metastásica en pacientes oncológicos tratados con radioterapia. Material y métodos: Valoración de las TC pélvicas de 26 pacientes oncológicos que presentaron sintomatología aguda referida como dolor lumbar. Los hallazgos de TC recogidos fueron: esclerosis, línea de fractura y masa de partes blandas. Se correlacionaron con los estudios gammagráficos y se compararon con las TC previas. Se realizó además seguimiento clinicorradiológico. Resultados: Todos los pacientes fueron diagnosticados de forma correcta de fracturas por insuficiencia pélvica mediante estudio por TC de pelvis. Los estudios por TC mostraron esclerosis en todos los casos (100 por ciento); líneas de fractura sacras en 16 (65 por ciento) casos; fracturas púbicas (30 por ciento) en ocho casos; masa de partes blandas en los cinco casos de fractura sinfisal bilateral. Se pudo establecer seguimiento en 21 pacientes, y la TC mostró: ausencia de visualización de las líneas de fractura, tendencia a la normalización con disminución progresiva de la esclerosis y pocos cambios en las fracturas de la sínfisis púbica. Conclusión: La TC es la técnica de imagen de elección para establecer el diagnóstico definitivo de FIP. Conocer esta entidad y ser capaz de diagnosticarla correctamente permite realizar el tratamiento adecuado y evitar la realización de pruebas diagnósticas y terapéuticas innecesarias, costosas y en ocasiones contraindicadas (AU)

Lupus eritematoso discoide en varón con implante de silicona / Lupus erythematosus, discoid in male with silicone implant

El lupus eritematoso discoide (LED) es una enfermedad dermatológica de evolución crónica, caracterizada por la presencia de lesiones eritematosas sobreelevadas, que se extienden lentamente con un contorno irregular, mientras que en el centro de las lesiones se evidencia curación con descamación, atrofia y cicatrización. Se desconoce su etiología; sin embargo, existen diversos factores que inducen la aparición de lesiones de LED. En el presente artículo se describe el caso de un paciente en quien se ha observado manifestaciones cutáneas de lupus eritematoso discoide en un receptor de tratamiento anticonceptivo que, a su vez, es portador de implante de silicona en la región de la frente. Los resultados del estudio son controversiales, por lo cual la hipótesis de que los implantes de silicona pudieran condicionar o promover el LED se encuentra aún en estudio

Procedimientos quirúrgicos sencillos en cirugía dermatológica básica: el colgajo romboidal / Simple surgical procedures in surgery basic dermatológica: the torn piece romboidal

Un colgajo permite tanto la restauración de la piel como la protección adicional, gracias al tejido subcutáneo y al aporte sanguíneo a través de su pedículo. Para que sea efectivo, no deben olvidarse las reglas de la dimensión, la dirección general de los vasos sanguíneos y las líneas de tensión de la piel. Presentamos, por su versatilidad, la técnica del colgajo romboidal o Limberg y su variante, el congajo de dufourmentel.