Cholesterol efflux capacity (CEC) is of interest given its potential relationship with several important clinical conditions including Alzheimer's disease. The inactivation of the APOE locus in mouse models supports the idea that it is involved in determining the CEC. With that in mind, we examine the impact of the plasma metabolome profile and the APOE genotype on the CEC in cognitively healthy elderly subjects. The study subjects were 144 unrelated healthy individuals. The plasma CEC was determined by exposing cultured mouse macrophages treated with BODIPY-cholesterol to human plasma. The metabolome profile was determined using NMR techniques. Multiple regression was performed to identify the most important predictors of CEC, as well as the NMR features most strongly associated with the APOE genotype. Plasma 3-hydroxybutyrate was the variable most strongly correlated with the CEC (r = 0.365; p = 7.3 × 10-6). Male sex was associated with a stronger CEC (r = -0.326, p = 6.8 × 10-5). Most of the NMR particles associated with the CEC did not correlate with the APOE genotype. The NMR metabolomics results confirmed the APOE genotype to have a huge effect on the concentration of plasma lipoprotein particles as well as those of other molecules including omega-3 fatty acids. In conclusion, the CEC of human plasma was associated with ketone body concentration, sex, and (to a lesser extent) the other features of the plasma lipoprotein profile. The APOE genotype exerted only a weak effect on the CEC via the modulation of the lipoprotein profile. The APOE locus was associated with omega-3 fatty acid levels independent of the plasma cholesterol level.
Cholesterol , Fasting , Animals , Mice , Humans , Male , Adult , Aged , Magnetic Resonance Spectroscopy , Genotype , Apolipoproteins E/genetics , Cholesterol, HDL
Biomaterials can control cell and nuclear morphology. Since the shape of the nucleus influences chromatin architecture, gene expression and cell identity, surface topography can control cell phenotype. This study provides fundamental insights into how surface topography influences nuclear morphology, histone modifications, and expression of histone-associated proteins through advanced histone mass spectrometry and microarray analysis. The authors find that nuclear confinement is associated with a loss of histone acetylation and nucleoli abundance, while pathway analysis reveals a substantial reduction in gene expression associated with chromosome organization. In light of previous observations where the authors found a decrease in proliferation and metabolism induced by micro-topographies, they connect these findings with a quiescent phenotype in mesenchymal stem cells, as further shown by a reduction of ribosomal proteins and the maintenance of multipotency on micro-topographies after long-term culture conditions. Also, this influence of micro-topographies on nuclear morphology and proliferation is reversible, as shown by a return of proliferation when re-cultured on a flat surface. The findings provide novel insights into how biophysical signaling influences the epigenetic landscape and subsequent cellular phenotype.
Even today, the mortality rate for uveal melanoma (UM) remains very high. In our research, we sought to determine which pathological and clinical features were correlated with the prognosis of UM. BAP1 (BRCA1-Associated Protein 1) gene mutation has been analyzed as one of the strongest predictors for metastasis in UM. The BAP1 gene codifies the BAP1 protein which has a tumor suppressor function. The presence of this protein can be determined by BAP1 immunohistochemical staining. Eighty-four uveal melanoma patients and forty enucleated eyeballs were examined. Metastasis was present in 24 patients. Nuclear BAP1 staining was low in 23 patients. The presence of a higher large basal diameter tumor (p < 0.001), tumor infiltrating lymphocytes (p = 0.020), and a lack of nuclear BAP1 immunostaining (p = 0.001) ocurred significantly more often in the metastatic group. Metastasis-free survival was lower in patients with low nuclear BAP1 staining (p = 0.003). In conclusion, to the best of our knowledge, this is the first time that BAP1 staining has been studied in uveal melanoma in a Spanish community. We believe that this technique should become routine in the pathological examination of uveal melanoma in order to allow adequate classification of patients and to establish an individual follow-up plan.
Purpose: To report the case of a drug-induced uveitis during the treatment of a metastatic cutaneous melanoma.Case report: A 75-year-old female treated with Dabrafenib and Trametinib due to a cutaneous melanoma stage IV presented with blurriness in both eyes. The examination revealed bilateral intraocular signs of inflammation, and fundoscopy showed bilateral changes at the posterior pole, such as chorioretinal folds and Neurosensory Retinal Detachment (NRD). Due to a worsening of Visual Acuity (VA) and persistence of intraocular inflammation in spite of topical prednisolone acetate treatment, the therapy with Dabrafenib + Trametinib was interrupted, after having been administered for 4 months, and replaced by Nivolumab. Fundus abnormalities and intraocular inflammation improved, but VA remained low due to the presence of an epiretinal membrane in the right eye. Then, a decreasing course of prednisolone eye drops was introduced for one more month and finally interrupted without the cessation of Nivolumab.Conclusion: Drug-induced uveitis has been increasing in the last few years due to the development of new biological agents for treatment of different types of tumours. The management of these adverse events should be handled in collaboration with oncologists and ophthalmologists and must be individualised and based on the risk-benefit balance. A case report of an uveitis and subsequent development of an epiretinal membrane during the treatment with Dabrafenib, Trametinib and subsequent Nivolumab for a metastatic cutaneous melanoma is reported here, in order to note the importance of an adequate follow-up of patients treated with these drugs.
Antineoplastic Agents/adverse effects , Drug-Related Side Effects and Adverse Reactions/etiology , Epiretinal Membrane/chemically induced , Liver Neoplasms/drug therapy , Melanoma/drug therapy , Skin Neoplasms/drug therapy , Uveitis/chemically induced , Aged , Drug-Related Side Effects and Adverse Reactions/diagnosis , Epiretinal Membrane/diagnostic imaging , Epiretinal Membrane/drug therapy , Female , Glucocorticoids/therapeutic use , Humans , Imidazoles/adverse effects , Liver Neoplasms/secondary , Lymphatic Metastasis , Melanoma/secondary , Neoplasm Staging , Oximes/adverse effects , Prednisolone/therapeutic use , Pyridones/adverse effects , Pyrimidinones/adverse effects , Skin Neoplasms/pathology , Tomography, Optical Coherence , Uveitis/diagnosis , Uveitis/drug therapy
Purpose: To report a case of endogenous endophthalmitis caused by Haemophilus influenzae in an immunocompetent host.Case report: A 13-year-old male presented with pain, blurriness, and decreased Visual Acuity (VA) of Hand Motion in his right eye. Slit-lamp examination revealed hypopyon. Fundoscopy showed vitritis, vasculitis, and retinal infiltrates. Echography revealed vitreous condensations. Empirical treatment with intravitreal Ganciclovir, oral Valacyclovir, and Dexamethasone was initiated with no improvement. Vitreous culture revealed Haemophilus influenzae growth. Then, intravenous Ciprofloxacin and Cefotaxime and intravitreal Ceftazidime were administered with gradual improvement. Lensectomy with Pars Plana Vitrectomy and intraocular tamponade was performed. Nevertheless, the visual outcome was poor.Conclusion: Pediatric endogenous bacterial endophthalmitis is a rare but potentially devastating infection which is often misdiagnosed. Moreover, we want to highlight the importance of an adequate clinical suspicion in cases of H. influenzae to prevent the serious complications seen in this report.
Endophthalmitis/microbiology , Eye Infections, Bacterial/microbiology , Haemophilus Infections/microbiology , Haemophilus influenzae/isolation & purification , Adolescent , Anti-Bacterial Agents/therapeutic use , Cataract Extraction , Cefotaxime/therapeutic use , Ceftazidime/therapeutic use , Ciprofloxacin/therapeutic use , Drug Therapy, Combination , Endophthalmitis/diagnosis , Endophthalmitis/drug therapy , Endotamponade , Eye Infections, Bacterial/diagnosis , Eye Infections, Bacterial/drug therapy , Haemophilus Infections/diagnosis , Haemophilus Infections/drug therapy , Humans , Immunocompromised Host , Infusions, Intravenous , Intravitreal Injections , Male , Slit Lamp Microscopy , Visual Acuity/physiology , Vitreous Body/microbiology
Objective: To emphasize the importance of an early diagnosis and an adequate treatment in conjunctival tumors. Methods: We present two clinical cases and compare the course of each case: one of conjunctival intraepithelial neoplasia (CIN) which took a positive course, and a fatal case of squamous cell carcinoma (SCC) with intraocular and orbital extension. Results: Epithelial conjunctival malignancies are one of the most prevalent ocular surface tumors. Among these, CIN are the most common. CIN have an excellent prognosis, given adequate treatment. However, when the diagnosis of CIN is late, the epithelial basement membrane will be affected, resulting in SCC. SCC may have poorer results due to its capacity to infiltrate near tissues and create distant metastasis. Conclusion: It is not common today to treat patients with orbital extension of SCC; however, it is crucial to note the importance of an early diagnosis of conjunctival malignancies. An early diagnosis is essential to prevent the transformation to other life-threatening types.
No disponible
Humans , Female , Child , Adult , Trachoma/diagnosis , Trachoma , Meibomian Glands/injuries , Lymphadenitis/pathology , Macrolides/administration & dosage , Fluorescent Antibody Technique, Indirect/methods , Bartonella Infections/diagnosis , Lymphadenitis , Bartonella henselae/isolation & purification , Bartonella henselae/drug effects , Amoxicillin-Potassium Clavulanate Combination/administration & dosage , Bartonella/isolation & purification , Bartonella Infections/diagnosis
Objective: To report the occurrence and management of an eyelashes infestation by Phthirus pubis. Methods: A 27-year-old female presented with itching in her right eye and head after she had been traveling in southern Italy five days earlier. Visual acuity (VA) was 20/20 in both eyes. Slit-lamp examination showed bilateral blepharitis. Moreover, mobile insects and eggs attached to the eyelashes were observed. A microbiological study was performed with a Phthirus pubis result. The patient was treated with mechanical dislodging. Results: The resolution of the infection was carried out removing every insect and egg. A vaseline application twice daily for 7 days was necessary to stifle any nits that could remain. Conclusions: The eyelashes pediculosis is frequently caused by Phthirus pubis. Only a minor percentage of the cases are due to Phthirus capitis, but the differential diagnosis is essential: there are Phthirus pubis pediculosis cases due to sexual abuse. A sexual history and screening for other sexually transmitted diseases is warranted.
No disponible
Humans , Female , Middle Aged , Intravitreal Injections/adverse effects , Vascular Endothelial Growth Factors/administration & dosage , Vascular Endothelial Growth Factors/adverse effects , Scleritis/etiology , Scleritis/microbiology , Mycobacterium chelonae , Mycobacterium Infections, Nontuberculous/etiology , Mycobacterium Infections, Nontuberculous/microbiology , Pain , Severity of Illness Index
No disponible
Humans , Female , Aged , Corynebacterium Infections , Corynebacterium/isolation & purification , Endophthalmitis/microbiology , Visual Acuity , Anti-Bacterial Agents/administration & dosage , Ceftazidime/administration & dosage , Endophthalmitis/drug therapy , Intravitreal Injections , Time Factors , Trabeculectomy/adverse effects , Vancomycin/administration & dosage
Paciente de 14 años remitida para valorar fondo de ojo por cefalea. Presenta agudeza visual de 8/10 en ambos ojos y en fundoscopia se visualizan papilas de contornos escasamente definidos. Se solicita Autofluorescencia identificando lesiones autofluorescentes compatibles con drusas (Figura 1A,B). La OCT de fibras revela afectación sectorial bilateral sin papiledema (Figura 1C,D) y el campo visual mostró una afectación del hemicampo nasal bilateral (Figura 1E,F). Las drusas en el nervio óptico representan habitualmente un hallazgo casual. Pueden progresar paulatinamente generando gran deterioro campimétrico. No existe un tratamiento eficaz. Solo en casos donde aparezca neovascularización asociada, puede estar indicado el tratamiento con fármacos antiangiogénicos.
Optic Disk Drusen , Optic Nerve , Scotoma , Eye Diseases , Visual Field Tests , Optical Imaging
El uso indebido de los punteros láser, especialmente el recreativo en los niños, puede causar lesiones retinianas que amenazan la visión. El daño retiniano que producen no está bien caracterizado, debido a que la mayoría de las publicaciones son casos aislados o series pequeñas. El tratamiento y el pronóstico visual es variable según la morfología del daño macular que presenten. En algunos casos, no existe tratamiento, y pueden evolucionar a la curación espontánea; sin embargo, otros precisan cirugía. En una serie de 13 casos, uno requirió cirugía, mientras que el resto necesitó solo observación. De estos 13 casos, 3 pacientes se curaron en forma espontánea, con agudeza visual de 10/10.Se describen dos pacientes de 16 y 12 años con disminución de agudeza visual tras el uso indebido de punteros láser. En el fondo de ojo, presentaron alteraciones maculares. La agudeza visual de ambos se recuperó completamente sin tratamiento.
The improper use of laser pointers, especially for recreational use in children, may cause sight-threatening retinal injuries. The retinal damage it is not well characterized because most publications are isolated cases or small series.The treatment and visual prognosis are variable according to the morphology of the macular damage. In some cases, there is no treatment, and spontaneous healing can be developed; however, others require surgery. In a series of 13 cases, 1 required surgery and the rest observation; 3 patients obtained a spontaneous healing with visual acuity of 10/10.We describe two patients aged 16 and 12 years with decreased visual acuity. Macular alterations appear in the fundus of the eye. The visual acuity of both recovered completely without treatment
Humans , Male , Child , Adolescent , Retinal Diseases , Lasers/adverse effects , Macula Lutea/radiation effects , Macula Lutea/injuries
The improper use of laser pointers, especially for recreational use in children, may cause sight-threatening retinal injuries. The retinal damage it is not well characterized because most publications are isolated cases or small series. The treatment and visual prognosis are variable according to the morphology of the macular damage. In some cases, there is no treatment, and spontaneous healing can be developed; however, others require surgery. In a series of 13 cases, 1 required surgery and the rest observation; 3 patients obtained a spontaneous healing with visual acuity of 10/10. We describe two patients aged 16 and 12 years with decreased visual acuity. Macular alterations appear in the fundus of the eye. The visual acuity of both recovered completely without treatment.
El uso indebido de los punteros láser, especialmente el recreativo en los niños, puede causar lesiones retinianas que amenazan la visión. El daño retiniano que producen no está bien caracterizado, debido a que la mayoría de las publicaciones son casos aislados o series pequeñas. El tratamiento y el pronóstico visual es variable según la morfología del daño macular que presenten. En algunos casos, no existe tratamiento, y pueden evolucionar a la curación espontánea; sin embargo, otros precisan cirugía. En una serie de 13 casos, uno requirió cirugía, mientras que el resto necesitó solo observación. De estos 13 casos, 3 pacientes se curaron en forma espontánea, con agudeza visual de 10/10. Se describen dos pacientes de 16 y 12 años con disminución de agudeza visual tras el uso indebido de punteros láser. En el fondo de ojo, presentaron alteraciones maculares. La agudeza visual de ambos se recuperó completamente sin tratamiento.
Eye Injuries/etiology , Lasers/adverse effects , Retinal Diseases/etiology , Adolescent , Child , Eye Injuries/pathology , Humans , Male , Retinal Diseases/pathology , Vision Disorders/etiology , Visual Acuity
Malaria, the disease caused by Plasmodium spp. infection, remains a major global cause of morbidity and mortality. Host protection from malaria relies on immune-driven resistance mechanisms that kill Plasmodium However, these mechanisms are not sufficient per se to avoid the development of severe forms of disease. This is accomplished instead via the establishment of disease tolerance to malaria, a defense strategy that does not target Plasmodium directly. Here we demonstrate that the establishment of disease tolerance to malaria relies on a tissue damage-control mechanism that operates specifically in renal proximal tubule epithelial cells (RPTEC). This protective response relies on the induction of heme oxygenase-1 (HMOX1; HO-1) and ferritin H chain (FTH) via a mechanism that involves the transcription-factor nuclear-factor E2-related factor-2 (NRF2). As it accumulates in plasma and urine during the blood stage of Plasmodium infection, labile heme is detoxified in RPTEC by HO-1 and FTH, preventing the development of acute kidney injury, a clinical hallmark of severe malaria.
Heme/metabolism , Kidney/metabolism , Malaria/physiopathology , Animals , Apoferritins/metabolism , Cell Line , Disease Progression , Epithelial Cells/metabolism , Ferritins/metabolism , Ferritins/physiology , Heme Oxygenase-1/metabolism , Heme Oxygenase-1/physiology , Humans , Immune Tolerance/physiology , Mice , Mice, Inbred C57BL , NF-E2-Related Factor 2/metabolism , NF-E2-Related Factor 2/physiology , Oxidoreductases , Plasmodium berghei/metabolism , Plasmodium berghei/parasitology , Up-Regulation
Sepsis is an often lethal syndrome resulting from maladaptive immune and metabolic responses to infection, compromising host homeostasis. Disease tolerance is a defense strategy against infection that preserves host homeostasis without exerting a direct negative impact on pathogens. Here, we demonstrate that induction of the iron-sequestering ferritin H chain (FTH) in response to polymicrobial infections is critical to establish disease tolerance to sepsis. The protective effect of FTH is exerted via a mechanism that counters iron-driven oxidative inhibition of the liver glucose-6-phosphatase (G6Pase), and in doing so, sustains endogenous glucose production via liver gluconeogenesis. This is required to prevent the development of hypoglycemia that otherwise compromises disease tolerance to sepsis. FTH overexpression or ferritin administration establish disease tolerance therapeutically. In conclusion, disease tolerance to sepsis relies on a crosstalk between adaptive responses controlling iron and glucose metabolism, required to maintain blood glucose within a physiologic range compatible with host survival.
Glucose/metabolism , Iron/metabolism , Sepsis/metabolism , Animals , Apoferritins/genetics , Apoferritins/metabolism , Ceruloplasmin/metabolism , Gluconeogenesis , Glucose-6-Phosphatase/metabolism , Mice , Mice, Inbred C57BL
Alzheimer's disease (AD) is the most prevalent among the aging diseases known as neurodegenerative disorders. Drug design programs over the last two decades were mainly based on the cholinergic, the amyloid or the tau hypothesis. However, none of the new drugs have a real impact on the outcome of the disease. The complex nature of AD has led to new approaches for drug development programs, the multitarget drug design hypothesis. Based on this hypothesis, the generation of multitarget hybrid compounds from previously known active molecules has been one of the most widely used to obtain new candidates for the future treatment of AD. Here, we summarize recent developments based on the hybridization hypothesis to obtain a potential clinical candidate for AD.
Acetylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Cholinesterase Inhibitors/therapeutic use , Neuroprotective Agents/therapeutic use , Alzheimer Disease/metabolism , Animals , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Humans , Molecular Structure , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry
