Characteristics of Hyaluronic Acid and Its Use in Ocular Surface Diseases Including Dry Eye

Hyaluronic acid (HA) is a polysaccharide found in the extracellular matrix of the epithelial, nervous, and connective tissues of vertebrates. It is widely used in the treatment of ocular surface diseases (OSDs), including dry eye, due to its high water-retaining capacity, viscoelasticity, and role as a signaling molecule in inflammation and wound healing. This paper reviews the physicochemical and biological properties of HA related to the treatment of OSDs and the results of published preclinical studies, clinical trials, and meta-analyses on the effects of HA eye drops on the tear film, the mechanism of action of HA eye drops, and its clinical effects and adverse events in OSDs, such as corneal/conjunctival epithelial defects, dry eye, and postoperative dry eye. This review should help inform clinical judgments by providing clinical evidence and precautions on the use of HA eye drops in OSDs, including dry eye.

Evaluation of the Surgical Margin Threshold for Avoiding Recurrence after Partial Nephrectomy in Patients with Renal Cell Carcinoma

Purpose@#An adequate minimal surgical margin for partial nephrectomy (PN) has not yet been conclusively established. Therefore, we aimed to compare PN recurrence rates according to surgical margin status and to establish an adequate minimal surgical margin. @*Materials and Methods@#We retrospectively studied patients with clinically localized renal cell carcinoma who underwent PN between 2005 and 2014. Surgical margin width (SMW) was assessed for all surgical tissues and divided into three groups: SMW <1 mm, SMW ≥1 mm, and positive surgical margin (PSM). The data were analyzed using the Kaplan-Meier method with log-rank tests and multivariate Cox regression models. @*Results@#Of 748 patients (median age, 55 years; interquartile range, 46–64 years; 220 female), 704 (94.2%) and 44 (5.8%) patients had negative and PSMs, respectively. Recurrence-free survival was significantly lower in patients with PSMs (p<0.001) and was not significantly different between SMW ≥1 mm and <1 mm groups (p=0.604). PSM was a significant predictor of recurrence (hazard ratio: 8.03, 95% confidence interval: 2.74–23.56, p<0.001), in contrast to SMW <1 mm (p=0.680). @*Conclusion@#A PSM after PN significantly increases the risk of recurrence. We discovered that even a submillimeter safety surgical margin may be enough to prevent recurrence. To maximize normal renal parenchyma preservation and to avoid cancer recurrence in renal parenchymal tumor patients, PN may be a safe treatment, except for those with a PSM in the final pathology.

Ganglion Cell Analysis in an Optic Tract Syndrome Patient Previously Diagnosed with Glaucoma

PURPOSE: To report the results of ganglion cell analysis in a patient with optic tract syndrome who was previously diagnosed with glaucoma. CASE SUMMARY: A 32-year-old male, who had been diagnosed with glaucoma 12 years ago, but had not visited an ophthalmology clinic since then, came to our clinic for evaluation of his glaucoma. Both eyes showed an increased cup-to-disc ratio and temporal pallor of the disc. Retinal nerve fiber layer (RNFL) optical coherence tomography showed thinning of the superior, inferior, and temporal peripapillary RNFL in both eyes. On ganglion cell analysis (GCA), ganglion cell layer thinning in the nasal region of the right eye and in the temporal region of the left eye was observed. The visual field test showed right incongruous homonymous hemianopsia. After the atrophic change of the left optic tract was confirmed by orbit magnetic resonance imaging, he was diagnosed with left optic tract syndrome. CONCLUSIONS: We report the results of GCA in a case of optic tract syndrome, previously diagnosed as glaucoma. GCA can be useful when diagnosing optic tract syndrome.

Incidentally found cystic lymphangioma of the adrenal gland in an elderly male cadaver / 영남의대학술지

Adrenal cystic lymphangiomas are extremely rare entities that are often identified incidentally, with less than 60 cases reported to date. We found a protruding ovoid mass consisting of a multiloculated cystic lesion within right adrenal gland in the cadaver of a 75-year-old Korean man. The epithelial cells lining the adrenal cyst were diffusely positive for cluster of differentiation 31 and podoplanin, and negative for pan-cytokeratin. The histopathological diagnosis confirmed a cystic lymphangioma arising from the adrenal gland. Post-mortem findings of the present case are discussed based on the clinicopathological features of adrenal cystic lymphangiomas.

Incidentally found cystic lymphangioma of the adrenal gland in an elderly male cadaver / 영남의대학술지

Adrenal cystic lymphangiomas are extremely rare entities that are often identified incidentally, with less than 60 cases reported to date. We found a protruding ovoid mass consisting of a multiloculated cystic lesion within right adrenal gland in the cadaver of a 75-year-old Korean man. The epithelial cells lining the adrenal cyst were diffusely positive for cluster of differentiation 31 and podoplanin, and negative for pan-cytokeratin. The histopathological diagnosis confirmed a cystic lymphangioma arising from the adrenal gland. Post-mortem findings of the present case are discussed based on the clinicopathological features of adrenal cystic lymphangiomas.

Cyclosporin A aggravates hydrogen peroxide-induced cell death in kidney proximal tubule epithelial cells / 대한해부학회지

Cyclosporin A (CsA) does not only exert a toxic effect on kidney parenchymal cells, but also protects them against necrotic cell death by inhibiting opening of mitochondrial permeability transition pore. However, whether CsA plays a role in hydrogen peroxide-induced kidney proximal tubular cell death is currently unclear. In the present study, treatment with CsA further increased apoptosis and necrosis in HK-2 human kidney proximal tubule epithelial cells during exposure to hydrogen peroxide. In addition, hydrogen peroxide-induced p53 activation and BH3 interacting-domain death agonist (BID) expression were higher in CsA-treated cells than those in non-treated cells, whereas hydrogen peroxide-induced activation of mitogen-activated protein kinases including p38, c-Jun N-terminal kinase, and extracellular signal-regulated kinase and activation of protein kinase B were not significantly altered by treatment with CsA. In oxidant-antioxidant system, reactive oxygen species (ROS) production induced by hydrogen peroxide was further enhanced by treatment with CsA. However, expression levels of antioxidant enzymes including manganese superoxide dismutase, copper/zinc superoxide dismutase, and catalase were not altered by treatment with hydrogen peroxide or CsA. Treatment with CsA further enhanced mitochondrial membrane potential induced by exposure to hydrogen peroxide, although it did not alter endoplasmic reticulum stress based on expression of glucose-regulated protein 78 and 94. Taken together, these data suggest that CsA can aggravate hydrogen peroxide-induced cell death through p53 activation, BID expression, and ROS production.

Renal sympathetic nerve activation via α₂-adrenergic receptors in chronic kidney disease progression

Chronic kidney disease (CKD) is increasing worldwide without an effective therapeutic strategy. Sympathetic nerve activation is implicated in CKD progression, as well as cardiovascular dysfunction. Renal denervation is beneficial for controlling blood pressure (BP) and improving renal function through reduction of sympathetic nerve activity in patients with resistant hypertension and CKD. Sympathetic neurotransmitter norepinephrine (NE) via adrenergic receptor (AR) signaling has been implicated in tissue homeostasis and various disease progressions, including CKD. Increased plasma NE level is a predictor of survival and the incidence of cardiovascular events in patients with end-stage renal disease, as well as future renal injury in subjects with normal BP and renal function. Our recent data demonstrate that NE derived from renal nerves causes renal inflammation and fibrosis progression through alpha-2 adrenergic receptors (α₂-AR) in renal fibrosis models independent of BP. Sympathetic nerve activation-associated molecular mechanisms and signals seem to be critical for the development and progression of CKD, but the exact role of sympathetic nerve activation in CKD progression remains undefined. This review explores the current knowledge of NE-α₂-AR signaling in renal diseases and offers prospective views on developing therapeutic strategies targeting NE-AR signaling in CKD progression.

Killian-Jamieson diverticulum lined with two epithelia in a Korean cadaver / 대한해부학회지

Killian-Jamieson diverticulum is a permanent protrusion of anterolateral proximal esophagus through anatomically weak muscular gap, known as Killian-Jamieson area, into adjacent area. During a routine educational dissection, we found a well-defined lateral diverticulum just inferior to the transverse fibers of the cricopharyngeus muscle in a Korean male cadaver. It had a dimension of 1.8×1.4×1.0 cm with two types of epithelial cells, stratified squamous and simple cuboidal to low-columnar epithelium, and attenuated and haphazardly arranged muscle fibers. No epithelial dysplasia or malignant transformation was identified except ulcerative changes. Although Killian-Jamieson diverticulum is a very rare disease, clinicopathological aspects should be considered.

Exogenous spermidine ameliorates tubular necrosis during cisplatin nephrotoxicity / 대한해부학회지

The hallmark of cisplatin-induced acute kidney injury is the necrotic cell death in the kidney proximal tubules. However, an effective approach to limit cisplatin nephrotoxicity remains unknown. Spermidine is a polyamine that protects against oxidative stress and necrosis in aged yeasts, and the present study found that exogenous spermidine markedly attenuated tubular necrosis and kidney dysfunction, but not apoptosis, during cisplatin nephrotoxicity. In addition, exogenous spermidine potently inhibited oxidative/nitrative DNA damage, poly(ADP-ribose) polymerase 1 (PARP1) activation and ATP depletion after cisplatin injection. Conversely, inhibition of ornithine decarboxylase (ODC) via siRNA transfection in vivo significantly increased DNA damage, PARP1 activation and ATP depletion, resulting in acceleration of tubular necrosis and kidney dysfunction. Finally, exogenous spermidine removed severe cisplatin injury induced by ODC inhibition. In conclusion, these data suggest that spermidine protects kidneys against cisplatin injury through DNA damage and tubular necrosis, and this finding provides a novel target to prevent acute kidney injury including nephrotoxicity.

Features of the Lamina Cribrosa and the Autonomic Nervous System in Glaucoma Patients with Disc Hemorrhages

PURPOSE: To assess the effects of structural changes in the lamina cribrosa (LC) and the status of the autonomic nervous system on disc hemorrhages (DHs). METHODS: A retrospective study was performed on 68 eyes of 68 patients with primary open-angle glaucoma and optic DHs. We divided the patients into two groups using optical coherence tomography according to the presence of LC defects, and then compared both groups. We also analyzed autonomic nervous system function using the heart rate variability test, and compared the two groups. RESULTS: Eyes with LC defects had significantly longer axial lengths than those without defects (p = 0.029), and the DH was located more proximally (p < 0.001). A significantly larger proportion of eyes without LC defects had configurational optic disc changes such as optic disc rim notching, focal rim thinning, or generalized thinning (p = 0.001). On heart rate variability testing, the group without LC defects had a significantly higher “low frequency/high frequency ratio” than the group with defects (p = 0.008). CONCLUSIONS: There was a difference in the clinical features of DH between eyes with and without LC defects. Eyes with LC defects were more myopic and the proximal part of the DH tended to be on the disc cup or characterized by peripapillary atrophy. These results suggest that the DH developed due to a mechanical cause in eyes with LC defects. Patients without LC defects had a more dysregulated autonomic nervous system. The DH location was related to disc rim notching and neural rim losses, which implies ischemia as the pathogenic mechanism involved in the development of DH in eyes without LC defects. Therefore, more careful observations of the LC would facilitate a better understanding of the specific pathogenic mechanisms underlying DH.

Changes in Clinical Characteristics of Patients with an Initial Diagnosis of Prostate Cancer in Korea: 10-Year Trends Reported by a Tertiary Center

BACKGROUND: The Korea Central Cancer Registry reported that incidence rates of prostate cancer have not increased continuously. We used recent trends in the incidence of prostate cancer to generate a preliminary report of the Korean population with prostate cancer. METHODS: Patients initially diagnosed with prostate cancer by prostate biopsy from 2006 to 2015 at our tertiary center were selected. All patients were categorized according to age ( 75 years), time period (2006–2010 vs. 2011–2015), and risk classification. Patients with insufficient data were excluded from the analysis. RESULTS: Of 675 patients (median prostate-specific antigen [PSA], 9.09 ng/mL), those with a Gleason score (GS) of 6 (32.3%) comprised the largest proportion in our cohort. The proportion with a GS of 8 increased for those aged 65–75 years, despite the lack of increase in PSA. Treatment patterns changed for those with very low to low risk cancer. The overall survival (OS) rate and the cancer-specific survival (CSS) rate for all patients at 5 years were 87% and 90%, respectively. Patients with a low body mass index (BMI; ≤ 23 kg/m2) had worse median OS and CSS rates. CONCLUSION: Significant differences in risk classifications and initial treatments were found between 2006–2010 and 2011–2015. Although PSA did not change, the GS did change. Lower BMI (≤ 23 kg/m2) had worse effects on OS and CSS rates for Korean prostate cancer patients.

A Bilateral Double Sternalis Muscle in a Korean Cadaver / 체질인류학회지

Although the sternalis muscle has been well known to anatomists, it is quite unfamiliar to clinicians. During routine educational dissection, we came across a well-defined bilateral double sternalis muscle innervated by the intercostal nerve, respectively. The right sternalis muscle 1) became tendinous to insert into the sternum and 2) crossed midline and then intermingled with the left pectoralis major muscle, which could be classified into a double with single cross based on Snosek et al.'s criteria. The left sternalis muscle was composed of two bellies, which were combined at the midway, and became tendinous to insert into the contralateral manubrium, which could be classified into a bicipital diverging with double cross based on Snosek et al.'s criteria. The detailed knowledge on the sternalisis is important for clinicians as well as for anatomists, since the clinical importance of the sternalis muscle has been highlighted in recent years.

Spermidine is protective against kidney ischemia and reperfusion injury through inhibiting DNA nitration and PARP1 activation / 대한해부학회지

Kidney ischemia and reperfusion injury (IRI) is associated with a high mortality rate, which is attributed to tubular oxidative and nitrative stresses; however, an effective approach to limit IRI remains elusive. Spermidine, a naturally occurring polyamine, protects yeast cells against aging through the inhibition of oxidative stress and necrosis. In the present study, spermidine supplementation markedly attenuated histological damage and kidney dysfunction during IRI. In addition, exogenous spermidine potently inhibited poly(ADP-ribose) polymerase 1 (PARP1) activation and DNA nitrative/oxidative stress following IRI. Conversely, inhibition of ornithine decarboxylase (ODC) via siRNA transfection in vivo significantly enhanced DNA nitration, PARP1 activation, and functional damage during IRI. Finally, in ODC knockdown kidneys, PARP1 inhibition attenuated histological and functional damage induced by IRI, but not DNA nitrative stress. In conclusion, these data suggest that spermidine protects kidneys against IRI through blocking DNA nitration and PARP1 activation and this finding provides a novel target for prevention of acute kidney injury including IRI.

Poly(ADP-ribose) polymerase regulates glycolytic activity in kidney proximal tubule epithelial cells / 대한해부학회지

After renal injury, selective damage occurs in the proximal tubules as a result of inhibition of glycolysis. The molecular mechanism of damage is not known. Poly(ADP-ribose) polymerase (PARP) activation plays a critical role of proximal tubular cell death in several renal disorders. Here, we studied the role of PARP on glycolytic flux in pig kidney proximal tubule epithelial LLC-PK1 cells using XFp extracellular flux analysis. Poly(ADP-ribosyl)ation by PARP activation was increased approximately 2-fold by incubation of the cells in 10 mM glucose for 30 minutes, but treatment with the PARP inhibitor 3-aminobenzamide (3-AB) does-dependently prevented the glucose-induced PARP activation (approximately 14.4% decrease in 0.1 mM 3-AB-treated group and 36.7% decrease in 1 mM 3-AB-treated group). Treatment with 1 mM 3-AB significantly enhanced the glucose-mediated increase in the extracellular acidification rate (61.1±4.3 mpH/min vs. 126.8±6.2 mpH/min or approximately 2-fold) compared with treatment with vehicle, indicating that PARP inhibition increases only glycolytic activity during glycolytic flux including basal glycolysis, glycolytic activity, and glycolytic capacity in kidney proximal tubule epithelial cells. Glucose increased the activities of glycolytic enzymes including hexokinase, phosphoglucose isomerase, phosphofructokinase-1, glyceraldehyde-3-phosphate dehydrogenase, enolase, and pyruvate kinase in LLC-PK1 cells. Furthermore, PARP inhibition selectively augmented the activities of hexokinase (approximately 1.4-fold over vehicle group), phosphofructokinase-1 (approximately 1.6-fold over vehicle group), and glyceraldehyde-3-phosphate dehydrogenase (approximately 2.2-fold over vehicle group). In conclusion, these data suggest that PARP activation may regulate glycolytic activity via poly(ADP-ribosyl)ation of hexokinase, phosphofructokinase-1, and glyceraldehyde-3-phosphate dehydrogenase in kidney proximal tubule epithelial cells.

Poly(ADP-ribose) polymerase 1 contributes to oxidative stress through downregulation of sirtuin 3 during cisplatin nephrotoxicity / 대한해부학회지

Enhanced oxidative stress is a hallmark of cisplatin nephrotoxicity, and inhibition of poly(ADP-ribose) polymerase 1 (PARP1) attenuates oxidative stress during cisplatin nephrotoxicity; however, the precise mechanisms behind its action remain elusive. Here, using an in vitro model of cisplatin-induced injury to human kidney proximal tubular cells, we demonstrated that the protective effect of PARP1 inhibition on oxidative stress is associated with sirtuin 3 (SIRT3) activation. Exposure to 400 µM cisplatin for 8 hours in cells decreased activity and expression of manganese superoxide dismutase (MnSOD), catalase, glutathione peroxidase (GPX), and SIRT3, while it increased their lysine acetylation. However, treatment with 1 µM PJ34 hydrochloride, a potent PARP1 inhibitor, restored activity and/or expression in those antioxidant enzymes, decreased lysine acetylation of those enzymes, and improved SIRT3 expression and activity in the cisplatin-injured cells. Using transfection with SIRT3 double nickase plasmids, SIRT3-deficient cells given cisplatin did not show the ameliorable effect of PARP1 inhibition on lysine acetylation and activity of antioxidant enzymes, including MnSOD, catalase and GPX. Furthermore, SIRT3 deficiency in cisplatin-injured cells prevented PARP1 inhibition-induced increase in forkhead box O3a transcriptional activity, and upregulation of MnSOD and catalase. Finally, loss of SIRT3 in cisplatin-exposed cells removed the protective effect of PARP1 inhibition against oxidative stress, represented by the concentration of lipid hydroperoxide and 8-hydroxy-2'-deoxyguanosine; and necrotic cell death represented by a percentage of propidium iodide–positively stained cells. Taken together, these results indicate that PARP1 inhibition protects kidney proximal tubular cells against oxidative stress through SIRT3 activation during cisplatin nephrotoxicity.

Dual left anterior interventricular coronary artery with a rare course in a Korean / 대한해부학회지

Dual left anterior interventricular coronary artery (also called left anterior descending artery, hereafter referred as LAD) is a rare congenital coronary artery anomaly. Notably, type IV dual LAD has never been reported in Koreans. During a routine dissection, a new variant of type IV dual LAD was found in a 57-year-old Korean male cadaver, whose cause of death was unknown. One LAD originated from the right coronary artery, coursed through the anterior interventricular sulcus, but did not reach the apex cordis. The other LAD arose from the left coronary artery, never entered the anterior interventricular sulcus through its course, but reached the apex cordis, where it met the posterior interventricular branch of the right coronary artery. This is the first report on a new variant of type IV dual LAD in Koreans, which is of clinical importance during procedures containing the coronary artery.

Cisplatin induces primary necrosis through poly(ADP-ribose) polymerase 1 activation in kidney proximal tubular cells / 대한해부학회지

Treatment with cisplatin for cancer therapy has a major side effect such as nephrotoxicity; however, the role of poly (ADP-ribose) polymerase 1 (PARP1) in necrosis in response to cisplatin nephrotoxicity remains to be defined. Here we report that cisplatin induces primary necrosis through PARP1 activation in kidney proximal tubular cells derived from human, pig and mouse. Treatment with high dose of cisplatin for 4 and 8 hours induced primary necrosis, as represented by the percentage of propidium iodide-positive cells and lactate dehydrogenase release. The primary necrosis was correlated with PARP1 activation during cisplatin injury. Treatment with PJ34, a potent PARP1 inhibitor, at 2 hours after injury attenuated primary necrosis after 8 hours of cisplatin injury as well as PARP1 activation. PARP1 inhibition also reduced the release of lactate dehydrogenase and high mobility group box protein 1 from kidney proximal tubular cells at 8 hours after cisplatin injury. Oxidative stress was increased by treatment with cisplatin for 8 hours as shown by 8-hydroxy-2'-deoxyguanosine and lipid hydroperoxide assays, but PARP1 inhibition at 2 hours after injury reduced the oxidative damage. These data demonstrate that cisplatin-induced PARP1 activation contributes to primary necrosis through oxidative stress in kidney proximal tubular cells, resulting in the induction of cisplatin nephrotoxicity and inflammation.

Neck muscle atrophy and soft-tissue fibrosis after neck dissection and postoperative radiotherapy for oral cancer

Late complications of head and neck cancer survivors include neck muscle atrophy and soft-tissue fibrosis. We present an autopsy case of neck muscle atrophy and soft-tissue fibrosis (sternocleidomastoid, omohyoid, digastric, sternohyoid, sternothyroid, and platysma muscles) within the radiation field after modified radical neck dissection type I and postoperative radiotherapy for floor of mouth cancer. A 70-year-old man underwent primary tumor resection of the left floor of mouth, left marginal mandibulectomy, left modified radical neck dissection type I, and reconstruction with a radial forearm free flap. The patient received adjuvant radiotherapy. The dose to the primary tumor bed and involved neck nodes was 63 Gy in 35 fractions over 7 weeks. Areas of subclinical disease (left lower neck) received 50 Gy in 25 fractions over 5 weeks. Adjuvant chemotherapy was not administered.

Intra-renal slow cell-cycle cells contribute to the restoration of kidney tubules injured by ischemia/reperfusion / 대한해부학회지

Renal epithelial cells damaged by ischemia/reperfusion (I/R) can be restored by timely and appropriate treatment. Recent studies have reported that intra renal adult kidney stem cells contribute to the restoration of tubules damaged by I/R. Here, we determined the role of adult tubular cells in the restoration of damaged tubules. We labeled slow cell-cycle cells (SCCs) with 5-bromo-2'-deoxyuridine (BrdU) and investigated their location in the kidneys as well as their contribution to the restoration of tubular cells damaged by I/R injury in mice. Thirty minutes of bilateral ischemia resulted in severe disruption of tubular epithelial cells along with a decline in renal function. The post-ischemic disruption of tubular epithelial cells was most severe in the S3 segment of the outer stripe of the outer medulla. Damaged tubules demonstrated gradual recovery of renal function over time. BrdU-labeled SCCs were mainly observed in tubules located at the junction of cortex and outer medulla, as well as in the inner medulla. The tubular SCCs expressed functional tubule cell markers such as Na/K-ATPase, Na-K-Cl cotransporter-2, and aquaporin 1 and 2. BrdU-labeled SCCs survived I/R injury and proliferated. These results demonstrate that SCCs present in tubules contribute to the restoration of tubular epithelial cells injured by I/R.

Kidney Tubular Cell Regeneration Starts in the Deep Cortex after Ischemia / 대한신장학회지

PURPOSE: In kidneys exposed to ischemia/reperfusion (I/R), the periodic and regional changes of loss and restoration of tubular epithelial cells and the influence of these processes for renal function remain to be defined. We investigated the loss and regeneration of tubular cells in each nephron segment at various times after I/R. METHODS: Mice were subjected to 30 min of bilateral renal ischemia and were administered 5-bromo-2'-deoxyuridine (BrdU) 20 hours before harvest kidneys. The numbers of tubular cell nuclei, BrdUincorporating cells and proliferative cell nuclear antigen (PCNA)-positive cells were analyzed by PASstaining and immunohistochemistry. RESULTS: Thirty minutes of ischemia induced loss of tubular epithelial cells in the outer stripe of the outer medulla. The loss of tubular epithelial cells peaked 24 hours after ischemia. After the maximum decrease, recovery of number of tubular epithelial cells was observed from 3 days after I/R in the outer medulla and from 5 days in the cortex. The tubular cell numbers were inversely correlated with the changes in concentrations of plasma creatinine and BUN by Pearson correlation, indicating that the decrease and increase of tubular epithelial cell numbers reflect functional failure and recovery, respectively. Cell proliferation as determined by BrdU-incorporating appeared in the deep cortex from 3 days after ischemia. CONCLUSION: The recovery of renal function was found to significantly correlate with the restoration of tubular cells. Furthermore, the regeneration of tubular cells started in the tubules of the deep cortex, suggesting that it may be a great proliferative cell niche.