Therapeutic targeting of adipose tissue macrophages ameliorates liver fibrosis in non-alcoholic fatty liver disease.

Background & Aims: : The accumulation of adipose tissue macrophages (ATMs) in obesity has been associated with hepatic injury. However, the contribution of ATMs to hepatic fibrosis in non-alcoholic fatty liver disease (NAFLD) remains to be elucidated. Herein, we investigate the relationship between ATMs and liver fibrosis in patients with patients with NAFLD and evaluate the impact of modulation of ATMs over hepatic fibrosis in an experimental non-alcoholic steatohepatitis (NASH) model. Methods: Adipose tissue and liver biopsies from 42 patients with NAFLD with different fibrosis stages were collected. ATMs were characterised by immunohistochemistry and flow cytometry and the correlation between ATMs and liver fibrosis stages was assessed. Selective modulation of the ATM phenotype was achieved by i.p. administration of dextran coupled with dexamethasone in diet-induced obesity and NASH murine models. Chronic administration effects were evaluated by histology and gene expression analysis in adipose tissue and liver samples. In vitro crosstalk between human ATMs and hepatic stellate cells (HSCs) and liver spheroids was performed. Results: Patients with NAFLD presented an increased accumulation of pro-inflammatory ATMs that correlated with hepatic fibrosis. Long-term modulation of ATMs significantly reduced pro-inflammatory phenotype and ameliorated adipose tissue inflammation. Moreover, ATMs modulation was associated with an improvement in steatosis and hepatic inflammation and significantly reduced fibrosis progression in an experimental NASH model. In vitro, the reduction of the pro-inflammatory phenotype of human ATMs with dextran-dexamethasone treatment reduced the secretion of inflammatory chemokines and directly attenuated the pro-fibrogenic response in HSCs and liver spheroids. Conclusions: Pro-inflammatory ATMs increase in parallel with fibrosis degree in patients with NAFLD and their modulation in an experimental NASH model improves liver fibrosis, uncovering the potential of ATMs as a therapeutic target to mitigate liver fibrosis in NAFLD. Impact and implications: We report that human adipose tissue pro-inflammatory macrophages correlate with hepatic fibrosis in non-alcoholic fatty liver disease (NAFLD). Furthermore, the modulation of adipose tissue macrophages (ATMs) by dextran-nanocarrier conjugated with dexamethasone shifts the pro-inflammatory phenotype of ATMs to an anti-inflammatory phenotype in an experimental murine model of non-alcoholic steatohepatitis. This shift ameliorates adipose tissue inflammation, hepatic inflammation, and fibrosis. Our results highlight the relevance of adipose tissue in NAFLD pathophysiology and unveil ATMs as a potential target for NAFLD.

Evaluating the Incidence and Neuro-Ophthalmic Manifestations of Carotid-Cavernous Fistulas.

BACKGROUND: To determine the incidence of carotid-cavernous fistula (CCF) and describe the neuro-ophthalmic manifestations and eventual clinical outcomes. METHODS: This was a population-based, retrospective cohort study using the Rochester Epidemiology Project to identify patients aged 18 years or older residing in Olmsted County, MN, diagnosed with CCF from 1997 to 2019. The medical records were reviewed for ophthalmic signs and symptoms, including conjunctival chemosis, proptosis, orbital bruit, diplopia, ophthalmoplegia, orbital pain, ocular hypertension, and blurred vision. Also determined was the number of patients with CCF found incidentally on neuroimaging, without clinical manifestations. RESULTS: Ten patients were diagnosed with a CCF between 1997 and 2019 with an overall incidence rate of 0.37 per 100,000 per year (95% CI 0.20-0.68). The median age was 50.5 years (range 23-74 years), 6 (60%) were female, and 9 were White and 1 patient was Korean. Three patients (30%) were asymptomatic and found incidentally on imaging that was obtained for unrelated reasons, and one patient's ocular details were unavailable because she passed away from severe head trauma. The following neuro-ophthalmologic or ocular manifestations were identified in the remaining 6 patients: chemosis/conjunctival injection (n = 6), cranial nerve (CN) VI palsy (n = 6), CN III palsy (n = 2), proptosis (n = 4), ocular/orbital pain (n = 3), audible orbital bruit (n = 2), ocular hypertension (n = 1), and blurred vision (n = 1). Of those patients with symptomatic CCFs, all underwent treatment except for one that spontaneously resolved. None of the patients suffered a stroke or cerebral hemorrhage. The 3 patients with incidentally discovered CCFs were asymptomatic and did not require treatment. CONCLUSIONS: This is the first population-based study to show a low incidence rate of CCFs, supporting the notion that it is an uncommon condition. Neuro-ophthalmic manifestations are common, especially chemosis/conjunctival injection and CN VI palsy. Up to a third of patients with CCF can be asymptomatic and may be found incidentally on neuroimaging during the evaluation for unrelated symptoms.

Transient Bilateral Central Scotoma on Awakening: A Distinct Phenomenon.

BACKGROUND: Transient vision loss can be an alarming symptom owing to potentially serious etiologies such as thromboembolism or giant cell arteritis. Transient monocular vision loss (TVML) on awakening has been recently described as a benign phenomenon (Bouffard et al, 2017). Our objective was to describe the unique phenomenon of transient binocular vision loss (TBVL) on awakening. METHODS: Retrospective observational case series of 5 patients who experienced TBVL on awakening seen in the neuro-ophthalmology clinic at the Mayo Clinic between 2016 and 2020. Patients who described generalized blurred vision and those with monocular transient vision loss were excluded. RESULTS: The median age was 81.4 years (range, 68-92 years), and all were male. Every patient described a stereotyped transient bilateral central scotoma on awakening with slightly irregular borders and mild asymmetry between the 2 eyes lasting between 15 and 90 minutes. Frequency ranged from 3 to 7 times per week, and there was a median of 319 episodes (range, 126-728 episodes) before evaluation in the neuro-ophthalmology clinic. All patients had normal optic nerves, and no plaques were noted in the retinal vessels. All 5 had macular drusen, which were predominantly extrafoveal and mild. Two patients underwent electrophysiology testing, which were both normal on full-field electroretinogram (ERG), but there was blunted central wave forms on multifocal ERG. Two patients underwent dark adaptation testing, which showed both prolong and diminished dark adaptation. Neuroimaging and thromboembolic workup were unrevealing. CONCLUSIONS: TBVL is a distinct phenomenon from TMVL on awakening, which has a different demographic and symptomology. The etiology is unclear but seems to be a focal macular process in conjunction with an autoregulatory failure resulting in a supply-demand mismatch during low-light conditions.

Proceedings of the 42nd Annual and First Virtual Upper Midwest Neuro-Ophthalmology Group Meeting, 24 July 2020.

The 42nd meeting of the Upper Midwest Neuro-Ophthalmology Group (UMNOG) took place on 24 July 2020 in an inaugural virtual format due to COVID-19 precautions. Eighty-seven people attended virtually, including 25 trainees, which marked the highest UMNOG meeting attendance on record. We present a synopsis of the meeting presentations.

Next generation sequencing-based molecular diagnosis in familial congenital cataract expands the mutational spectrum in known congenital cataract genes.

Congenital cataract (CC) is a significant cause of childhood blindness worldwide. CC is a genetically heterogeneous disease because mutations in over 40 genes have been demonstrated to cause the disorder and up to 40% of cases arise from single-gene mutations. Hence, next generation sequencing (NGS) of deoxyribonucleic acid is a suitable approach for CC molecular diagnosis. In this study, we used commercially available inherited disease NGS panels including 50 CC genes for the genetic diagnosis of 11 probands with hereditary CC. Causal variants were recognized in six families. A novel CRYGC variant, p.(Phe6Ser), was identified in two apparently unrelated families. Two additional novel variants in the crystallin genes CRYBB2 (p.[Gly149Asp]) and CRYGA (p.[Arg48Cys]) were also identified. One family carried the novel p.[Gly8_Leu11del] variant in GJA8, while another family exhibited the previously reported c.2826-9G>A pathogenic change in EPHA2. Our results illustrate the utility of NGS for diagnosing CC in our population, and our results contribute to expand the mutational spectrum with four novel pathogenic variants in known CC genes.

El sistema nacional de salud en el Perú / The national health system in Peru

Un grupo de profesionales en el Perú, conocedores de sistemas nacionales de salud, conformado desde 1975, comenzó un proceso que llevó al país a ser el primero en América del Sur en iniciar la organización moderna de este sistema. El avance pionero que significó la creación del Sistema Nacional de Servicios de Salud en 1978 ocurrió antes de las reformas de los sistemas de salud en Chile (1980), Brasil (1990), Colombia (1993) y Ecuador (2008). El alentador inicio tuvo vaivenes reformistas permanentes desde entonces, con evolución negativa por falta de una política de Estado. Las características actuales del sistema peruano son el desempeño ineficiente y la discontinuidad, sin evaluación alguna, lo que determina un gran atraso con relación a los sistemas de salud de América. En el siglo XXI se han desaprovechado importantes esfuerzos técnicos para modernizar el sistema y sus funciones. El futuro es preocupante y el papel de las nuevas generaciones será decisivo.

In 1975, a group of professionals in Peru who were experts on national health systems began a process that led the country to be the first in South America to initiate a modern organization of the health system. This pioneering development meant that the creation of the National Health Services System [in Peru] in 1978 occurred before the health system reforms in Chile (1980), Brazil (1990), Colombia (1993), and Ecuador (2008). This encouraging start has had permanent reformist fluctuations since then, with negative development because of the lack of a State policy. Current features of the Peruvian system are inefficient performance, discontinuity, and lack of assessment, which creates a major setback in comparison with other health systems in America. In the 21st century, significant technical efforts have been missed to modernize the system and its functions. The future is worrying and the role of new generations will be decisive.

[The national health system in Peru]. / El sistema nacional de salud en el Perú

In 1975, a group of professionals in Peru who were experts on national health systems began a process that led the country to be the first in South America to initiate a modern organization of the health system. This pioneering development meant that the creation of the National Health Services System [in Peru] in 1978 occurred before the health system reforms in Chile (1980), Brazil (1990), Colombia (1993), and Ecuador (2008). This encouraging start has had permanent reformist fluctuations since then, with negative development because of the lack of a State policy. Current features of the Peruvian system are inefficient performance, discontinuity, and lack of assessment, which creates a major setback in comparison with other health systems in America. In the 21st century, significant technical efforts have been missed to modernize the system and its functions. The future is worrying and the role of new generations will be decisive.

La inequidad en salud afecta el desarrollo en el Perú / Inequity in health affects the development in Peru

Las diferencias injustas y evitables en el ejercicio del derecho a la salud coexisten con la Declaración Universal de Derechos Humanos desde 1948. Algunas causas de la persistente inequidad se infieren después de Alma-Ata, tales como financiación insuficiente, desarrollo de los sistemas nacionales de salud sin adecuada priorización, y desde la década de 1980 concertación económica para introducir el modelo de mercado en salud. En la actualidad en Perú, la salud sigue siendo un ámbito de escasos avances, ostensible inequidad y participación limitada en el desarrollo. Continúan las insuficientes políticas del siglo XX y es recurrente la pérdida de oportunidades, incluyendo la que brinda el incremento del valor de las exportaciones desde hace más de una década. Para una reforma de salud exitosa hacia la equidad y el desarrollo, se requiere concertar una política de Estado, establecer financiación moderna y equitativa del aseguramiento social y terminar con los vaivenes del sistema nacional de salud.

Unfair and avoidable differences in exercising the right to health coexist with the Universal Declaration of Human Rights since 1948. Some causes of the persistent inequality inferred after Alma-Ata are insufficient funding, development of national health systems without adequate prioritization, and since the 80s with economic consensus to introduce the health market model. Health in Peru is still an area of little progress, ostensible inequality and limited participation in development. Policies in the 20th century are still insufficient; and missing opportunities like increasing the value of exports overa decade ago is a recurring issue. For a health reform to be successful in terms of equality and development, it is necessary to agree on a state policy, establish a modern and equitable social security funding system and eradicate the inconsistencies in the national health system.

[Inequity in health affects the development in Peru]. / La inequidad en salud afecta el desarrollo en el Perú

Unfair and avoidable differences in exercising the right to health coexist with the Universal Declaration of Human Rights since 1948. Some causes of the persistent inequality inferred after Alma-Ata are insufficient funding, development of national health systems without adequate prioritization, and since the 80s with economic consensus to introduce the health market model. Health in Peru is still an area of little progress, ostensible inequality and limited participation in development. Policies in the 20th century are still insufficient; and missing opportunities like increasing the value of exports over a decade ago is a recurring issue. For a health reform to be successful in terms of equality and development, it is necessary to agree on a state policy, establish a modern and equitable social security funding system and eradicate the inconsistencies in the national health system.

Enfoques de la reforma de la salud en el Perú de 1998: Ecos de un debate / Approaches to the peruvian health care reform of 1998: about a discussion

La Mesa Redonda organizada por el Departamento de Medicina Preventiva y Salud Pública de la Facultad de Medicina de San Fernando, contó con la participación de connotados representantes del Estado y la sociedad peruanos ligados a la Salud Pública: el Dr. Oscar Bueno del Ministerio de Salud, el Dr. Julio Castro del Colegio Médico del Perú, y el Dr. Francisco Sánchez Moreno de la Academia Peruana de Salud. Ellos debatieron sobre la Reforma de la Salud en el Perú de hoy. Mientras para el representante del Ministerio de Salud la Reforma es una realidad que va transformando al sector y particularmente la antigua estructura sanitaria, de exclusiva responsabilidad estatal; para el representante de la Academia Peruana de Salud, ésta es la segunda reforma puesta en marcha por el mismo gobierno (1990-98) y ambas han fracasado, proponiendo los principios de una auténtica Reforma. Por último, el representante del Colegio Médico igualmente criticó los fundamentos de la Reforma, remarcando su carácter no democrático y centralista. Todos coincidieron en la necesaria participación de la Universidad para una adecuada Reforma de la Salud en el Perú. Finalmente, concuerdan en la necesidad de construir un consenso nacional para la Reforma de la Salud a mediano y largo plazo.