Lipofuscin Deposition Research Articles

Colonic Bluish–Black Patches in a 57-Year-Old Woman with Crohn’s Disease

Question: A 57-year-old woman with a past history of aplastic anemia was diagnosed with Crohn’s disease, Montreal A3, L3, B1, in September 2015. The initial endoscopic examination revealed multiple ulcers over the terminal ileum, ileocecal valve, and proximal ascending colon. She received oral mesalazine 4 g/d and prednisolone 2.5–15.0 mg/d during the first year after diagnosis, but did not respond to the treatment; she continued to experience right lower quadrate abdominal pain and intermittent bloody diarrhea. A follow-up colonoscopy showed progressive ulcers over the terminal ileum and ileocecal valve in July 2016. Given her history of aplastic anemia and sepsis, she hesitated to take azathioprine, methotrexate, or tumor necrosis factor inhibitors. Instead, she started taking indigo naturalis (Qing-Dai) 4.5 g/d in December 2016. She achieved steroid-free clinical remission under the treatment with mesalazine and indigo naturalis. However, a follow-up colonoscopy still revealed a 1.5-cm ulcer over the ileocecal valve in November 2018. In addition, we observed multiple discrete or coalescing irregularly shaped, bluish–black patches from the ileocecal valve to the rectum with a haphazard distribution, reminiscent of the skin markings of Holstein Friesian cattle (Figure A). A colonic biopsy was obtained, and a representative hematoxylin and eosin stain is shown (Figure B). What is the diagnosis? See the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI. Histology of the discolored colonic lesion revealed scattered pigment-laden histiocytes in the lamina propria and submucosa. Higher magnification disclosed bluish, needle-like crystals in the cytoplasm of these histiocytes. In light of the presence of pigment-laden histiocytes, we called the lesions indigo naturalis-related pseudomelanosis. Unlike melanosis coli, which typically shows continuous homogeneous brown or black discoloration of colon mucosa (snake-skin appearance or starry sky appearance), indigo naturalis-related pseudomelanosis exhibits a haphazard distribution of black discoloration reminiscent of the skin markings of Holstein Friesian cattle.1Freeman H.J. “Melanosis” in the small and large intestine.World J Gastroenterol. 2008; 14: 4296-4299Crossref PubMed Scopus (43) Google Scholar Microscopically, melanosis coli is characterized by the deposition of lipofuscin in histiocytes, and deposition of bluish needle-like crystals is noted in indigo naturalis-related pseudomelanosis.2Kimber R.D. Roberts-Thomson I.C. Gastrointestinal: melanosis coli.J Gastroenterol Hepatol. 1999; 14: 1047Crossref PubMed Scopus (6) Google Scholar The distribution of discolored mucosa did not correlate with inflammatory activity, which was most severe over the terminal ileum and ileocecal valve. This finding implies that the absorption of indigo naturalis occurred not only at the inflammatory sites, but also over normal colon mucosa. It remains to be seen whether deposition of indigo naturalis has any long-term adverse effect, although histologically the mucosa with indigo deposition was not accompanied by significant inflammatory activity.

Epithelial-Mesenchymal Transition and Senescence in the Retinal Pigment Epithelium of NFE2L2/PGC-1α Double Knock-Out Mice.

Age-related macular degeneration (AMD) is the most prevalent form of irreversible blindness worldwide in the elderly population. In our previous studies, we found that deficiencies in the nuclear factor, erythroid 2 like 2 (NFE2L2) and peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) genes caused AMD-like pathological phenotypes in mice. In the present work, we show hijacked epithelial-mesenchymal transition (EMT) due to the common loss of PGC-1α and NFE2L2 (double knock-out, dKO) genes in aged animals. The implanted area was assessed by histology, immunohistochemistry and transmission electron microscopy. Confocal microscopy revealed altered regions in the filamentous actin ring. This contrasted with hexagonal RPE morphology in wild-type mice. The ultrastructural RPE features here illustrated loss of apical microvilli, alteration of cell-cell contact, loss of basal in-folding with deposits on Bruch’s membrane, and excessive lipofuscin deposition in dKO samples. We also found the expression of epithelial-mesenchymal transition transcription factors, such as Snail, Slug, collagen 1, vimentin and OB-cadherin, to be significantly different in dKO RPEs. An increased immunoreactivity of senescence markers p16, DEC1 and HMGB1 was also noted. These findings suggest that EMT and senescence pathways may intersect in the retinas of dKO mice. Both processes can be activated by damage to the RPE, which may be caused by increased oxidative stress resulting from the absence of NFE2L2 and PGC-1α genes, important for antioxidant defense. This dKO model may provide useful tools for studying AMD pathogenesis and evaluating novel therapies for this disease.

V1a Vasopressin Receptor Deficient Mice as a Model for Accelerated Aging

Deposition of age-related fluorescent pigment in tissues was initially discovered by A. Hanover in 1842 and the pigments were subsequently called lipofuscin by W. Hueck in 1912 and M. Borst in 1922. It has been known for decades that the lipofuscin is found in several aged organs such as the eyes, brain and adrenal cortex of humans and rodents. However, how these normal aging processes proceed is not known. In a preliminary study, we found that in the adrenal gland of V1a vasopressin receptor-deficient mice (V1aKO), more lipofuscin deposits were accumulated with age compared with wild-type (WT) mice. To quantitatively examine lipofuscin deposits, we have collected 60 adrenal glands from V1aKO and WT mice of both sexes at 2, 6 and 12 months of age. The sections were stained to visualize nucleus and plasma membrane and examined by using confocal microscope. We found lipofuscin fluorescent signals in the adrenal gland of both V1aKO and WT mice. However, the amount of lipofuscin in V1a-deficient adrenal gland was significantly increased compared with the adrenal gland of WT mice in both sexes at all ages. In particular, at 6 month of age, lipofuscin deposition in WT and V1aKO males occupied 3.9 and 5.6 % of entire adrenal cortex areas. Also, we found that lipofuscin accumulation started in the cytoplasm. The mechanism of an increase in this deposit formation, especially its relationship to the V1a receptor, needs to be further examined.

Dystrophie des cônes

We report a case of a 30-year-old woman, who complains of a progressive loss of visual acuity since 20 years old. Visual acuity was 1/10 which cannot be improved in both of eyes. The examination of the anterior segment of both of eyes was normal. The fundus examination revealed the existence of a rounded yellowish macular lesion with major macular atrophy in both of eyes (A, B). The vitreous is transparent, the examination of the retinal periphery was normal. The auto fluorescence pictures describe a granular appearance of macula with alternating hypo-autofluorescent (alteration of the pigment epithelium) and hyper-autofluorescent (lipofuscin deposits) points (C, D). Fluorescein angiography shows the presence of macular atrophy accompanied by an alteration in the pigment epithelium. There is also a window effect that achieves the appearance of a bull´s eye at the macula (E, F). An electroretinography was performed confirming the diagnosis of cone dystrophy. Histologically, progressive cone dystrophy corresponds to a selective cone attack and there has long been debate on the origin of the degenerative process, between a primary attack of pigment epithelium and a primary cone attack, which is more likely. Progressive cone dystrophy most often concerns young adults who consult for a decrease in bilateral central visual acuity and which is frequently asymmetrical. The affection quickly evolves towards an acuity between 3/10 and 1/20, then towards a central scotoma.

Novel BEST1 mutation in autosomal recessive bestrophinopathy in Japanese siblings.

PURPOSE:Autosomal recessive bestrophinopathy (ARB) is a disease that results from the mutations in the BEST1 gene. It is characterized by multifocal yellowish lipofuscin deposits, cystoid macular edema, and subretinal fluid. Among approximately 270 BEST1 mutations, only 40 that include both heterozygous and homozygous mutations are associated with ARB. However, very few ARB-related mutations have been reported in the Japanese population. Therefore, in this study, we aimed to identify BEST1 mutations and describe the genotype–phenotype relationship in Japanese dizygotic twins presenting with ARB.MATERIALS AND METHODS:We performed clinical examinations in Japanese dizygotic twin patients (male: 29 years) with ARB as well as whole-exome sequencing in seven family members of these twins.RESULTS:In this study, we have reported on a novel BEST1 mutation, the p. Phe151Cys mutation, associated with ARB in Japanese dizygotic twins who had bi-allelic p. Ala160Pro mutations in BEST1. The clinical features observed were binocular abnormalities of the fundus, such as multifocal yellowish subretinal deposits, cystoid macular edema, and subretinal fluid. The full-field electroretinography results were subnormal.CONCLUSION:It was indicated that the novel BEST1 mutations identified may be strongly correlated with binocular ARB. This study provides significant information of the genotype–phenotype association in Japanese ARB patients. Further, the genetic analysis that we performed was very useful for the differential diagnosis and might have implications in the development of future treatment modalities.

S2804 Brown Bowel Syndrome as a Result of Chronic Bowel Obstruction

INTRODUCTION: Brown bowel syndrome (BBS) is a rare condition characterized by deposition of lipofuscin in the smooth muscle cells of the muscularis propria and muscularis mucosa. This condition has been attributed to various chronic malabsorptive conditions that result in deficiency in vitamin E. Vitamin E normally acts as an antioxidant which helps stabilize the mitochondrial membranes. Lack of vitamin E leads to mitochondrial degeneration with release of lipofuscin that accumulates in the smooth muscle cells. This results in a form of myopathy with uncoordinated bowel function. There have been case reports of BBS attributed to celiac disease, IBD, chronic pancreatitis, Whipple's disease and malignancy. We present an interested case of BBS attributed to chronic bowel obstruction. CASE DESCRIPTION/METHODS: 56 yo Caucasian female who had been having chronic abdominal pain associated with a 20lb weight loss. CT scan showed a markedly dilated RLQ small bowel with air-fluid levels concerning for ileus vs partial small bowel obstruction (SBO). She subsequently under a small bowel follow through which showed a relatively high-grade partial SBO. She had an EGD and colonoscopy, both of which were unremarkable. Her medical history is notable for a congenital SBO that was repaired at birth as well as a history of ectopic pregnancy requiring removal. She eventually underwent ex-lap with extensive lysis of adhesions. There was one majorly dilated area of the small intestine measuring over 12 cm in diameter. This area was resected and histology was notable for extensive deposition of light brown granular, lipofuscin-like pigment within the smooth muscle cells of the muscularis propria. These pigments were highlighted by special stains for PAS and PAS-D. This was consistent with ceroidosis (BBS). Review of the bowel histology was unremarkable for celiac disease or Whipple’s disease. The patient also had no findings concerning for chronic pancreatitis. DISCUSSION: We describe a case of BBS that was attributed to malabsorption from a chronic partial SBO. Her bowel obstruction was believed to be caused by adhesions related to prior surgeries. While bowel dilation and atresia can occur from the myopathy associated with BBS, this patient's pathologic findings were actually attributed to a series of events that originated from her having chronic SBO. This case illustrates the impact of bowel obstructions on adequate absorption of nutrients as well as the consequences of chronic malabsorption, including the development of BBS.Figure 1.: Gross Pathology.Figure 2.: HE Stain.Figure 3.: PAS-D Stain showing lipofuscin deposition.

Cerium oxide nanoparticles reduce the accumulation of autofluorescent deposits in light-induced retinal degeneration: Insights for age-related macular degeneration

Accumulation of lipofuscin deposits in the retinal pigment epithelium (RPE) is one of the main events involved in age-related macular degeneration and its increase together with RPE dysfunction, blood retinal barrier disruption and photoreceptors death progressively leads to blindness. Lipofuscin is the main autofluorescent (AF) component of the retina and therapies to counteract its deposition are a main goal to be achieved, since effective treatments have not yet been identified. Here, we first investigated the spatio-temporal pattern of AF deposits accumulation in the light-damage model of age-related macular degeneration. Afterward, we tested the ability of cerium oxide nanoparticles, a well known anti-oxidant agent, to counteract AF granules accumulation. The treatment was performed both before and after the induction of the degeneration. AF granules were quantified by confocal microscopy on whole mounted retinas. We demonstrated that the acute light-damage increases the accumulation of AF deposits in the hot spot retina in terms of number of granules and percentage of occupied area, with a peak 7 days after the exposure. Remarkably, cerium oxide nanoparticles showed a strong efficacy in preventing the formation of AF deposits when they were injected 3 days before light exposure. Moreover, when the treatment was performed 7 days after light exposure, nanoceria activity was found to be effective also in reducing the amount of the AF granules still deposited up to 60 days. These important results represent the very first evidence about the ability of cerium oxide nanoparticles to counteract AF deposits accumulation in retinal degeneration, laying the foundations for the development of a new therapy possibly targeting lipofuscin in AMD.

Posterior uveal melanoma in 321 Asian Indian patients: analysis based on the 8th edition of American Joint Committee Cancer classification.

To evaluate the presenting features, treatment, and outcomes of posterior uveal melanoma (PUM) in Asian Indians based on the 8th edition of American Joint Committee on Cancer (AJCC) classification. Retrospective interventional case series of 321 Asian Indian patients with PUM. Based on AJCC, PUM was classified into categories T1 (n = 36; 11%), T2 (n = 74; 23%), T3 (n = 126; 39%), and T4 (n = 85; 27%). Regarding tumor features, T4 was more likely to have pre-equatorial epicenter (vs T1 and T2; p ≤ 0.011), iris abnormalities (vs T2 and T3; p ≤ 0.002), and extraocular tumor extension (vs T3; p = 0.001), whereas T1 was more likely to have macular epicenter (vs T2, T3, T4; p ≤ 0.013), lipofuscin deposits (vs T3 and T4; p ≤ 0.008), and amelanotic tumors (vs. T4; p = 0.003). On multivariate analysis, factors predictive of systemic metastasis were increasing tumor thickness (p = 0.002) and extraocular tumor extension (p = 0.009). The 5-, 10-, and 15-year melanoma-related metastases rates were 0%, 0%, and 0% in T1, 0%, 60%, and 60% in T2, 7%, 40%, and 70% in T3 and 13%, 36%, and 76% in T4, respectively. Risk for metastasis was 1.23 times more for every 1-mm increase in tumor thickness and 9 times more with extraocular tumor extension. The AJCC 8th edition provides prognostic classification for PUM in Asian Indian patients. The significant risk factors for metastasis were increasing tumor thickness and extraocular tumor extension.

Tiao Geng decoction for treating menopausal syndrome exhibits anti-aging effects likely via suppressing ASK1/MKK7/JNK mediated apoptosis in ovariectomized rats

Ethnopharmacological relevanceTG-decoction (Tiao Geng decoction) is the extract of a Chinese herb mixture that has been used for treating menopausal symptoms for over 30 years. We have previously reported anti-aging and anti-oxidative effects of the TG-decoction on hypothalamic neurons in ovariectomized (OVX) rats.Aim of the study: The present study further investigates the effects of TG-decoction on the prevention of aging-related ultrastructural changes in menopausal hypothalamic neurons and the likely molecular mechanism. Materials and methodsA total of 120 four-month-old female SPF Sprague Dawley rats were divided into six groups. Five groups were ovariectomized (OVX) and one group served as a sham control. Three OVX groups received TG-decoction at three different doses. The remaining two OVX groups served as positive and negative controls by receiving estradiol valerate and saline solution. The sham group received saline. After one month, aging-related ultrastructural alterations in hypothalamic neurons were evaluated using transmission electron microscopy. Nissl staining was used to assess the pathomorphological changes of the hypothalamic neurons. Cell apoptosis was evaluated by TUNEL. Expression of Bcl-2 family genes was studied using qRT-PCR. Expression of the apoptosis-related proteins ASK1, MKK7, JNK, c-Jun, Bax, Casp3 and Bcl-2 was studied using western blotting. ResultsOvariectomy of female rats led to visible damage and aging-like alterations in the mitochondria and endoplasmic reticulum as well as large deposits of lipofuscin in hypothalamic tissue. TG-decoction treatment prevented this visible damage and lipofuscin deposition, increased the number of nerve cells and normally-shaped Nissl bodies, and reduced the number of TUNEL-positive cells. Expression of Bcl-2 gene was increased, while Bax gene reduced. Expression of the proteins ASK1, MKK7, JNK, c-Jun, Bax and Casp3 was reduced, while that of Bcl-2 was increased. ConclusionTG-decoction reduces aging-related ultrastructural changes in hypothalamic neurons, likely by suppressing ASK1/MKK7/JNK-mediated apoptosis in neuronal mitochondria or nuclei.

Amelioration of age-related alterations in rat liver: Effects of curcumin C3 complex, Astragalus membranaceus and blueberry.

Ageing is an unavoidable, universal, biological phenomenon affecting all organisms, which involves variable declines of individuals motor and memory capabilities. This study aimed to investigate the potential ameliorating effects of curcumin C3 complex, Astragalus membranaceus and blueberry on certain age-related biochemical alterations in rat liver. Four groups of rats, aged 12months-old, were used. The first group; aged control group in which rats were left without any treatment until the age of 17months. The other three groups received daily by oral gavage for 5months the following supplements; curcumin C3 complex (110 mg/kg), Astragalus membranaceus (100 mg/kg) and blueberry (100 mg/kg) respectively. Additionally, a fifth group of rats, aged 5months-old, was used as an adult control group. Our supplements alleviated ageing-induced redox state imbalance and inflammation as evidenced by reduction of hepatic thiobarbituric acid reactive substances and 8-hydroxydeoxyguanosine levels, restoration of total antioxidant capacity and nitric oxide contents, and lessening of lipofuscin deposition. All supplements decreased hepatic interlukin-6 gene expression and serum levels. Notably, Astragalus membranaceus and blueberry upregulated hepatic telomerase reverse transcriptase gene expression and increased telomere length. Our findings recommend the use of these natural hepatoprotective supplements for the elderly to promote healthy ageing and minimize the risk of age-related liver diseases.

CDK5RAP2 primary microcephaly is associated with hypothalamic, retinal and cochlear developmental defects

BackgroundPrimary hereditary microcephaly (MCPH) comprises a large group of autosomal recessive disorders mainly affecting cortical development and resulting in a congenital impairment of brain growth. Despite the identification of >25...

Sesame lignans suppress age-related disorders of the kidney in mice.

Sesamin is a functional ingredient in sesame (Sesamum indicum) seeds and has many physiological effects. This study investigated whether sesame lignans, sesamin and episesamin (1:1), can suppress age-related disorders of the kidney. Twenty-month-old mice were divided into three groups, and each group received a regular diet (O-C), diet containing sesame lignans (O-SE), and diet containing sesame lignans and α-tocopherol (VE; O-SE+VE), respectively, for 5 months. Six-month-old young mice (Y-C) were compared to the older mice. Renal lipofuscin deposition was increased in the O-C group compared to that in the Y-C group and its deposition with aging was significantly decreased in both O-SE and O-SE+VE groups. Plasma blood urea nitrogen levels in the O-C group increased compared to those in the Y-C group; however, those in both O-SE and O-SE+VE groups did not differ from those in the Y-C group. The number of podocytes in the O-C group decreased compared to that in the Y-C group and this effect was attenuated in the O-SE and O-SE+VE groups. The effect was strongest in the O-SE+VE group. Histological examinations showed that glomerular hypertrophy accompanied by mesangial hyperplasia and renal tubular degeneration was less severe in the O-SE and O-SE+VE groups than in the O-C group. Moreover, age-related increases in the mRNA expression of NADPH oxidase- and inflammation-related genes, including p67phox, p40phox, TNFα, and IL-6, in the kidney were suppressed in the O-SE and O-SE+VE groups. Sesame lignans might be useful to suppress age-related kidney disorders, and these effects could be enhanced with VE.

Cardiac Adverse Events in EGFR-Mutated Non-Small Cell Lung Cancer Treated With Osimertinib

ObjectivesThe purpose of this study was to assess osimertinib-associated cardiac adverse events (AEs) in a real-world setting, using a retrospective single-center cohort study in Japan. BackgroundCases of osimertinib-associated cardiac AEs have been reported but remain poorly understood. MethodsA total of 123 cases of advanced non–small cell lung cancer (NSCLC) with confirmed EGFR mutations who received osimertinib monotherapy from 2014 to 2019 at the Osaka International Cancer Institute (Osaka, Japan) were evaluated. Cardiac AEs were defined according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Changes in left ventricular ejection fraction (LVEF) and rates of cancer therapeutics-related cardiac dysfunction (CTRCD), defined as a ≥10 % absolute decline in LVEF from baseline to a value of <53%, were further assessed in 36 patients in whom serial measurements of LVEF were obtained before and during osimertinib treatment. ResultsSevere cardiac AEs (CTCAE grade 3 or higher) occurred in 6 patients (4.9%) after osimertinib administration. These AEs included acute myocardial infarction (n = 1), heart failure with reduced LVEF (n = 3), and valvular heart disease (n = 2). Five of the 6 patients had a history of cardiovascular risk factors or disease. Myocardial biopsies in 2 of the patients showed cardiomyocyte hypertrophy and lipofuscin deposition. In 36 patients assessed with serial LVEF, LVEF declined from 69.4 ± 4.2% to 63.4 ± 10.5% with osimertinib therapy (p < 0.001). CTRCD occurred in 4 patients with a nadir LVEF of 40.3 ± 9.1% with osimertinib. ConclusionsIn this retrospective cohort analysis, the incidence of cardiac AEs in patients treated with osimertinib was 4.9%. Additional prospective data collected from patients with NSCLC treated with osimertinib will be important in understanding the incidence, pathophysiology, and management of cardiac AEs with osimertinib.

Brown Bowel Syndrome: A Multi-institutional Case Series.

Brown bowel syndrome (BBS) is a rare condition associated with vitamin E deficiency and defined by prominent lipofuscin deposition in the muscularis propria. Eight unique cases of BBS were identified: 5 men and 3 women (mean age=58.6 y). Pertinent comorbidities included bariatric surgery=2, malnourishment=2, Crohn=2, cystic fibrosis=1, alcohol and cocaine abuse=1, and prior small bowel resections=1. Presenting symptoms included abdominal pain=3, bleeding=1, nausea and vomiting=1, and nonresponsiveness=1. Imaging studies were often abnormal: thickened bowel wall=3 (1 with a mass), small bowel obstruction=2, and edematous and dilated bowel wall=2. Most specimens were surgical resections (n=7, autopsy=1): extended right colectomy=2, small bowel only=5 (terminal ileum=3, jejunum=2). Two specimens were grossly described as mahogany, and 1 case contained a perforation. Histologic sections of all cases showed finely granular, brown cytoplasmic pigment in smooth muscle cells on hematoxylin and eosin. This pigment was most conspicuous in the muscularis propria (small bowel>colon), and it was not identified in the mucosa. The pigment was reactive with Fontana-Masson, carbol lipofuscin, Periodic acid-Schiff, and Periodic acid-Schiff with diastase, and electron microscopy was compatible with lipofuscin. The mean clinical follow-up was 208 weeks: 1 patient died of complications of encephalitis, the others were alive and well. BBS is important to recognize because it is linked with malnutrition, specifically vitamin E deficiency, and it can (rarely) clinically simulate malignancy. The diagnosis is based on the identification of the lipofuscin pigment in the cytoplasm of smooth muscle cells, which is most easily seen in the muscularis propria of the small bowel.

Apocynin Dietary Supplementation Delays Mouse Ovarian Ageing.

Advanced maternal age is associated with higher infertility rates, pregnancy-associated complications, and progeny health issues. The ovary is considered the main responsible for these consequences due to a continuous decay in follicle number and oocyte quality. Intracellular imbalance between oxidant molecules and antioxidant mechanisms, in favour of the former, results in oxidative stress (OS) that is believed to contribute to ovarian ageing. This work is aimed at evaluating whether an age-related increase in ovarian OS, inflammation, and fibrosis may contribute to tissue dysfunction and whether specific antioxidant supplementation with a NADPH oxidase inhibitor (apocynin) could ameliorate them. Mice aged 8–12 weeks (reproductively young) or 38-42 weeks (reproductively aged) were employed. Aged mice were divided into two groups, with one receiving apocynin (5 mM) in the drinking water, for 7 weeks, upon which animals were sacrificed and their ovaries collected. Ovarian structure was similar at both ages, but the ovaries from reproductively aged mice exhibited lipofuscin deposition, enhanced fibrosis, and a significant age-related reduction in primordial and primary follicle number when compared to younger animals. Protein carbonylation and nitration, and markers of OS were significantly increased with age. Moreover, mRNA levels of inflammation markers, collagens, metalloproteinases (MMPs), and tissue inhibitor MMPs (TIMPs) were upregulated. Expression of the antifibrotic miRNA29c-3p was significantly reduced. Apocynin supplementation ameliorated most of the age-related observed changes, sometimes to values similar to those observed in young females. These findings indicate that there is an age-related increase in OS that plays an important role in enhancing inflammation and collagen deposition, contributing to a decline in female fertility. Apocynin supplementation suggests that the imbalance can be ameliorated and thus delay ovarian ageing harmful effects.

A case report on lipofuscin deposition in a graft biopsy two years after kidney transplantation: an insignificant bystander or a pathogenic benefactor?

BackgroundLipofuscin deposition is a characteristic manifestation of aging. There is very limited literature in humans and in animals describing these deposits in native kidneys. Overall, it is thought to be non-pathogenic and successful transplants from a donor with lipofuscin deposits have been reported. We present the case of a patient who underwent a kidney transplant and a for-cause biopsy post-transplantation incidentally revealed lipofuscin deposition.Case presentationA 48-year old gentleman with a past medical history of diabetes, hypertension, coronary artery disease, and ischemic and then hemorrhagic cardiovascular accident underwent a successful kidney transplant. His donor was an expanded criteria donor with no major past medical history. Post-transplant course was complicated by delayed graft function requiring one dialysis treatment for hyperkalemia. After that he had an uneventful course and achieved a baseline creatinine of 1.2 mg/dL, with no proteinuria. On a routine 19-month follow-up he was noted to have proteinuria and an antibody against the major-histocompatibility-complex class I-related chain A. A graft biopsy revealed acute antibody-mediated rejection and impressive lipofuscin deposition. He was subsequently treated with an antibody-mediated rejection protocol that included high dose steroids, Rituximab, plasmapheresis, and intravenous immunoglobulin, but responded poorly to this regimen. A 6-month follow up biopsy continued to show lipofuscin deposition, with similar microvascular injury scores and 12-months later his creatinine remained stable but his proteinuria worsened. Patient was struggling with recurrent infectious episodes requiring hospitalizations and thus no further diagnostic or therapeutic treatments were pursued.ConclusionsLipofuscin deposition has been reported in solid organ transplants but the significance and cause are not well understood. Several physiologic and some pathologic causes to these deposits have been reported including age, diabetes, medications and a genetic syndrome. We propose that immunologic causes such as rejection in the presence of other risk factors could potentiate the oxidative stress leading to excessive lipofuscin deposition in kidney transplants. In the case of our patient, we conclude that these deposits were likely recipient-derived, and postulate that the cumulative burden of inflammation from rejection, and underlying medical conditions led to increased lipofuscin deposition. We speculate them to be an innocent bystander.

3215 Duodenal Blackout: A Rare, Benign Endoscopic Finding

INTRODUCTION: First described in 1976, psuedomelanosis is a rare, benign, incidental endoscopic finding most commonly seen in the duodenum. PD has been associated with chronic renal disease and the ingestion of various medications including hydralazine and iron supplements. Here we describe a classic presentation of an uncommon endoscopic abnormality. CASE DESCRIPTION/METHODS: A 66-year-old woman with decompensated cirrhosis, end stage renal disease, and hypertension presented to the hospital with hepatic encephalopathy and failure to thrive. Her medications included hydralazine and a history of iron supplementation. An esophagogastroduodenoscopy (EGD) performed for early satiety, weight loss and to initiate a liver transplant evaluation demonstrated diffuse mucosal hyperpigmentation in a striped pattern, predominantly in the second portion of the duodenum (Figure 1). Mucosal biopsy revealed an abundance of brown pigment deposition in the lamina propria (Figure 2) which was negative on Prussian blue stain and immunohistochemistry—consistent with a diagnosis of pseudomelanosis duodeni (PD). DISCUSSION: Despite its striking endoscopic appearance, there is no evidence that pseudomelanosis duodeni is associated with any progressive pathology. Though PD has been described anecdotally in case report and case series, little is known about the pathophysiology. Some have posited PD is related to iron or lipofuscin deposition in the lamina propria. PD has been associated with end-stage renal disease, hydralazine, thiazide diuretics, and iron supplementation. This case describes a classic presentation of PD with the archetypal imaging and histopathology to support the diagnosis of this uncommon condition.

Nove mogućnosti liječenja „suhe” senilne makularne degeneracije

Senilna makularna degeneracija (engl. age-related macular degeneration; AMD) jedan je od najvažnijih uzroka gubitka centralnog vida kod starije populacije. Dijelimo je na „vlažnu” i „suhu” formu, ovisno o prisutnosti koroidne neovaskularizacije (engl. choroidal neovascularization; CNV). Do sada nijedna terapija nije potvrđena i odobrena za liječenje geografske atrofije (engl. geographic atrophy; GA), najtežeg oblika „suhog” AMD-a, jer nije bilo moguće popraviti oštećenja retinalnog pigmentnog epitela (engl. retinal pigment epithelium; RPE) i fotoreceptora. Liječenje se svodilo na pokušaje zaustavljanja progresije oboljenja i širenja geografske atrofije. Namjera ovog članka je prikazati podatke novijih dovršenih i tekućih kliničkih ispitivanja s naglaskom na mjesto djelovanja potencijalnih lijekova. Danas su nam dostupne brojne nove dijagnostičke metode koje nam omogućavaju bolje praćenje morfoloških promjena mrežnice, RPE-a i žilnice, kao i širenja područja atrofije. Oksidativni stres, kronična upala, insuficijentni koroidalni protok krvi te depoziti lipofuscina za koje se pretpostavlja da bi imali važniju ulogu u razvoju bolesti predstavljaju potencijalne mete za djelovanje lijekova. Velik je broj tekućih studija koje istražuju moguća rješenja, kao što su protuupalni i neuroprotektivni lijekovi te matične stanice, dok će samo neki od lijekova biti dostupni na tržištu i pružiti nadu pacijentima za očuvanje centralnog vida, pa ih je potrebno dugoročno pratiti. Uključiti treba i tretman ispodpražnim i mikropulsnim laserom koji je kod nekih oboljenja mrežnice pokazao određene rezultate u revitalizaciji tkiva, a koji koristimo i na našoj Klinici, te su prvi kratkoročni rezultati skromni ali ohrabrujući i zahtijevaju daljnje tretmane i praćenje.

Can Lipofuscin Deposition on Renal Allograft Tubular Epithelium Be a Surrogate Marker for Kidney Allograft Aging?

BackgroundLipofuscin is an indicator of aging. We examined the clinicopathologic significance of lipofuscin deposition in the renal tubules of renal allografts. MethodWe analyzed allograft biopsy specimens from living kidney transplantations from January to December 2015. For controls, we analyzed native kidney biopsy specimens obtained from January 2015 to December 2016. We identified granules with a yellow-to-tan shade in renal tubules as lipofuscin. ResultsThe donor age at transplantation was significantly older in lipofuscin deposition biopsy specimens than in those without, whereas the time after transplantation age was not different between the 2 groups with renal allografts. In native kidney biopsies, age at biopsy was significantly older in lipofuscin deposition biopsy specimens than in those without. We compared “massive lipofuscin deposition,” defined as lipofuscin deposition on both sides of 3 or more renal tubules, and donor-age matched control allograft biopsies without lipofuscin deposition. Comparing these 2 groups, recipient age at transplantation was significantly older in the massive lipofuscin deposition group. ConclusionLipofuscin deposition on tubular epithelium is not a surrogate marker of aging of kidneys allografts, although lipofuscin deposition was significantly greater in older tissues from native kidneys. The older age of recipients may be associated with massive lipofuscin deposition in renal allografts.

Quantitative fundus autofluorescence in smokers compared to non-smokers

Increased fundus autofluorescence is directly related to increased RPE lipofuscin deposition in the retina and has been observed in eyes with age-related macular degeneration (AMD). Smoking is the most significant modifiable risk factor for the development and progression of AMD, in which one of the main mechanisms is oxidative damage from smoking leading to RPE cell toxicity. The relationship between smoking and autofluorescence is not established and could provide insight into pathogenic mechanism of AMD. Therefore, our objective was to compare quantitative fundus autofluorescence (qAF) in the retinae of healthy non-smokers to smokers. We conducted a cross-sectional study at the 2016 Minnesota State Fair. Participants self-reported past medical and ocular history and underwent eye examination as well as qAF imaging with Spectralis confocal scanning laser ophthalmoscope (cSLO) equipped with an internal fluorescent reference. Two sets of images were obtained per eye. Stepwise multiple mixed effects regression model was used to examine the relationship between mean qAF values and smoking status. We enrolled 105 individuals (54 smokers, 61 females, mean age 41 years with range 18–78 years old). Fundus autofluorescence images were analyzable for 85 of 105 individuals contributing 161 eyes (80 right, 81 left). The repeatability coefficients between the first set and second set of images were ±21% of their mean qAF values. Older age and female gender were independently associated with higher qAF. Positive smoking history tended to result in higher qAF values after adjusting for age and gender but was not statistically significant (0.118, 95%CI -0.003, 0.240, P = 0.056). Among smokers, the number of pack-years smoked was not significantly associated with higher qAF. Our study's results are consistent with existing literature in which older age is predictive of intensified autofluorescence, while smoking history does not have as important of an impact on autofluorescence as hypothesized. Several large epidemiological studies have shown that smoking is significantly associated with AMD, and qAF is likely not the appropriate modality to clinically assess smoking's impact on retinae.