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BACKGROUND Pharmacogenetic studies have shown that slow and intermediate metabolizers of efavirenz (EFV) gained less weight compared with extensive metabolizers. It is hypothesized that increased EFV exposure suppresses weight gain. We investigated the effect of EFV mid-dose plasma concentration (C12) on long-term weight change among virologically suppressed people living with HIV (PLWH). METHODS Participants in a prospective EFV pharmacokinetic study were included if they had been taking EFV-containing combination antiretroviral therapy for more than 240 weeks and had 3 or more weight measurements. The weight changes and time to ≥5% of weight gain over 192 weeks were compared between PLWH with higher and those with lower EFV C12 (using mean population C12 as the cutoff). EFV C12 and CYP2B6 516G>T polymorphism were examined in generalized estimating equations and in a Cox proportional hazards model for associations with weight gain, after adjustments for age, sex, companion antiretroviral agent, CD4 lymphocyte count, and plasma HIV RNA. RESULTS One hundred eighteen PLWH were included. PLWH with higher EFV C12 had less mean weight gain compared with those with lower C12 after 192 weeks (-0.09 vs +1.58 kg, P = 0.033). PLWH with higher C12 were less likely to gain ≥5% weight in Kaplan-Meier analysis (P = 0.0003). In both generalized estimating equations and Cox proportional hazards models, a higher EFV C12 was associated with less weight gain, while CYP2B6 516G>T was not, after adjustments made for confounding factors. CONCLUSIONS Our findings support that increased EFV exposure was associated with less weight gain.

Background Diabetes mellitus is one of the risk factors for coronary artery disease and frequently associated with multivessels disease and poor clinical outcomes. Long term outcome of successful revascularization of chronic total occlusions (CTO) in diabetes patients remains controversial. Methods and results From January 2005 to December 2015, 739 patients who underwent revascularization for CTO in Taipei Veterans General Hospital were included in this study, of which 313 (42%) patients were diabetes patients. Overall successful rate of revascularization was 619 (84%) patients whereas that in diabetics and non-diabetics were 265 (84%) and 354 (83%) respectively. Median follow up was 1095 days (median: 5 years, interquartile range: 1–10 years). During 3 years follow-up period, 59 (10%) in successful group and 18 (15%) patients in failure group died. Although successful revascularization of CTO was non-significantly associated with better outcome in total cohort (hazard ratio (HR): 0.593, 95% confidence interval (CI) 0.349–0.008, P: 0.054), it might be associated with lower risk of all-cause mortality (HR: 0.307, 95% CI 0.156–0.604, P: 0.001) and CV mortality (HR: 0.266, 95% CI 0.095–0.748, P: 0.012) in diabetics (P: 0.512). In contrast, successful CTO revascularization didn’t improve outcomes in non-diabetics (all P > 0.05). In multivariate cox regression analysis, successful CTO revascularization remained an independent predictor for 3-years survival in diabetic subgroup (HR: 0.289, 95% CI 0.125–0.667, P: 0.004). The multivariate analysis result was similar after propensity score matching (all-cause mortality, HR: 0.348, 95% CI 0.142–0.851, P: 0.021). Conclusions Successful CTO revascularization in diabetes may be related to better long term survival benefit but not in non-diabetic population.

Background Obesity is associated with metabolic syndrome which increases further risk of coronary artery disease and adverse cardiovascular events. Impact of body mass index (BMI) on long-term outcome in patients with coronary chronic total occlusion (CTO) is less clear. Method and results From January 2005 to November 2020, a total of 1301 patients with coronary angiographic confirmed CTO were enrolled in our study. Patients were divided into two groups: low BMI group: 18-24.99 kg/m2 and high BMI group ≥25 kg/m2 . Clinical outcomes were 3-year all-cause mortality, 3-year cardiovascular mortality and 3-year non-fatal myocardial infarct. During the 3-year follow-up period, all-cause mortality was significantly higher in patients with low BMI group compared to those in high BMI groups (14% vs. 6%, p = .0001). Kaplan-Meier analysis showed patients with high BMI groups had significant better survival compared with those in low BMI group (p = .0001). In multivariate analysis, higher BMI was independently associated with decreased risk of 3-year all-cause mortality (Hazard ratio [HR]: 0.534; 95% confidence interval [CI]: 0.349-0.819, p = .004) after controlling for age, renal function, prior history of stroke, coronary artery bypass graft, co-morbidities with peripheral arterial disease, heart failure and revascularization status for CTO. In propensity-matched multivariate analysis, high BMI remained a significant predictor of 3-year all-cause mortality (HR, 0.525; 95% CI, 0.346-0.795, p = .002). Conclusion Higher BMI was associated with better long-term outcome in patients with coronary CTO.

BackgroundSuperior outcomes after surgical treatment over medical treatment for primary aldosteronism (PA) has been reported in small-scale clinical studies, but no solid conclusion has been drawn as results of large randomized trials are lacking.MethodsWe performed a search of PubMed, MEDLINE, Embase and Cochrane Library for randomized or observational studies that investigated cardiovascular outcomes in patients with PA undergoing medical versus surgical treatment. Meta-analyses of both composite and individual outcomes were conducted. Risks of bias of the included studies were assessed with Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) checklist. Trial sequential analysis (TSA) was performed to control the risk of random errors and assess whether the results in our meta-analysis were conclusive.ResultsA total of 12 studies, including a total of 6148 PA patients, were included in the meta-analysis. The results of meta-analyses demonstrated lower incidence of composite cardiovascular outcomes among PA patients who underwent surgical treatment over medical treatment (odds ratio (OR): 0.49). Surgical treatment also led to less incidence of persistence of hypertension (OR of non-cure hypertension: 0.31). Fewer major cardiovascular events and mortality events were observed (OR: 0.60) after surgical treatment. TSA result showed that the required information size was 2151 and the cumulative Z curve crossed the futility boundary and reached the required information size.ConclusionSuperior performance of surgical treatment over medical treatment is confirmed with meta-analyses in terms of lower incidences of composite cardiovascular outcomes and non-cure of hypertension. Hence, adrenalectomy could now be concluded as the treatment of choice for lateralized PA.

The aim of this study was to update the information on internationally acceptable standards and clinical practice recommendations for the management of patients with primary aldosteronism (PA). The Taiwan Society of Aldosteronism (TSA) Task Force acknowledged the novel issues of PA and reached a group consensus on PA in Taiwan by collecting the best available evidence and conducting one group meeting, several conference calls, and multiple e-mail communications. Unilateral adrenalectomy is the preferred treatment for patients with aldosterone-producing adenoma (APA). For medical treatment with mineralocorticoid receptor antagonists (MRAs), spironolactone is the first-line treatment, and eplerenone is a reasonable alternative in PA patients intolerant or contraindicated to spironolactone. The dose of MRAs can be titrated according to plasma renin activity (PRA). For screening PA-related comorbidities, we suggest albuminuria to predict a post-treatment decline in renal function, echocardiography as cardiac evaluation, bone mineral density scan for osteoporosis, and obstructive sleep apnea. In tissue and genetic surveys, we suggest immunohistochemical staining and somatic mutation screening for post-operative adrenal specimens in APA patients. With this consensus, we hope to update the information on PA for clinical physicians to facilitate better identification, management and treatment of patients with PA.

Background: In primary aldosteronism (PA), kidney function impairment could be concealed by relative hyperfiltration and emerge after adrenalectomy. We hypothesized transtubular gradient potassium gradient (TTKG), a kidney aldosterone bioactivity indicator, could correlate to end organ damage and forecast kidney function impairment after adrenalectomy. Methods: In the present prospective study, we enrolled lateralized PA patients who underwent adrenalectomy and were followed up 12 months after operation in the Taiwan Primary Aldosteronism Investigation (TAIPAI) registry from 2010 to 2018. The clinical outcome was kidney function impairment, defined as estimated glomerular filtration rate (eGFR) 2 at 12 months after adrenalectomy. End organ damage is determined by microalbuminuria and left ventricular mass. Results: In total, 323 patients [mean, 50.8 ± 10.9 years old; female 178 (55.1%)] were enrolled. Comparing pre-operation and post-operation data, systolic blood pressure, serum aldosterone, urinary albumin to creatinine ratio and eGFR decreased. TTKG ⩾ 4.9 correlated with pre-operative urinary albumin to creatinine ratio >50 mg/g [odds ratio (OR) = 2.42; p = 0.034] and left ventricular mass (B = 20.10; p = 0.018). Multivariate logistic regression analysis demonstrated that TTKG ⩾ 4.9 could predict concealed chronic kidney disease (OR = 5.42; p = 0.011) and clinical success (OR = 2.90, p = 0.017) at 12 months after adrenalectomy. Conclusions: TTKG could predict concealed kidney function impairment and cure of hypertension in PA patients after adrenalectomy. TTKG more than 4.9 as an adverse surrogate of aldosterone and hypokalaemia correlated with pre-operative end organ damage in terms of high proteinuria and cardiac hypertrophy.

Optimal therapy for each patient depends on their subtype, anatomic cancer stage, gene status, and preferences. Neoadjuvant chemotherapy-treated tumors have shown attenuated tumor growth, but the therapy cannot completely reduce tumor cell dissemination to blood stream and distant metastasis. Though it has been indicated that the protein of the collagen type IV alpha 1 (COL4A1) gene is induced by p53 to inhibit angiogenesis and tumorigenic activity in cancer cells, its prognostic significance in breast cancer (BC) patients has not yet been fully elucidated. We analysed 206 BC and fresh paired-match adjacent normal breast tissue from tissue microarrays (TMAs) and COL4A1-stained TMAs using immunohistochemistry. These were used to evaluate COL4A1 expression in BC and to analyse the relationship between this expression and clinicopathological factors and prognosis. The expression of the COL4A1 protein was significantly higher in normal adjacent tissue than in the tumor tissues of BC (P<0.0001). The low COL4A1 expression of the BC patients had decreased metastasis incidence ratio than those exhibiting high COL4A1 expression (P=0.034). Low COL4A1 expression in the tumor cells of BC patients was found to significantly reduce the overall survival (OS) and relapse-free survival (RFS) rates of neoadjuvant chemotherapy patients (P=0.047 and P=0.025, respectively). We also validated the results to ensure their consistency with a web server program for survival analysis from the Cancer Genome Atlas (TCGA) database (P=0.057). Additionally, COL4A1 expression was positively correlated with p53 expression (P=0.00076). Thus, we present clinical evidence that COL4A1 expression can be used as a biomarker of better prognosis of BC patients receiving neoadjuvant chemotherapy.

Background The successful recanalization rate of chronic total occlusion (CTO) lesions without retrograde collaterals available is always low. Intravascular ultrasound (IVUS) may be useful to guide the subintimal guidewire to re-enter the true lumen. We evaluated the clinical feasibility and efficacy of the IVUS-guided wiring re-entry technique for these complex CTO lesions. Methods Twenty consecutive patients (19 male, mean age: 65.3 ± 12.8 years) with both failed antegrade and retrograde approaches were enrolled. The IVUS catheter was introduced into the subintimal space to identify the entry point into the subintimal space, and guide another stiff wire to re-enter the true lumen with the adjacent side-branch or first wire as markers, or using IVUS-guided parallel wire technique. Results The entry point into the subintimal space was identified by IVUS in all cases, and the IVUS-guided wiring re-entry technique succeeded in 17 cases (85%). No procedure-related complication was noted except one case of delayed cardiac tamponade due to the wire perforation. During the mean follow-up period of 1.9 ± 1.3 years, there was no adverse cardiac event, except one patient died of the complication of cardiac transplantation. Conclusion The IVUS-guided wiringre-entry technique might be feasible and safe for the recanalization of complex CTO lesions.

Objectives To evaluate the short- and long-term clinical outcomes of RA in CTO coronary intervention. Background The application of rotational atherectomy (RA) may improve the success rate of percutaneous recanalization of chronic total occlusion (CTO) with heavy calcification. Methods From January 2011 to September 2014, we enrolled 285 patients with CTO who underwent successful percutaneous coronary intervention (PCI). Resistant CTO lesions were defined as those with heavy calcifications as well as those that no devices are able to pass after guide wire crossing. Results All patients with resistant CTO lesions (n = 26) were successfully treated by RA without major complications, except 1 patient complicated with coronary perforation and treated by surgery successfully (success rate: RA group vs non-RA group: 96.2%, vs 89.5%, P = 0.038). Compared to the non-RA group, the patients in the RA group were older (P = 0.028), had higher J-CTO scores (P = 0.001), and needed longer stents (P = 0.001). All patients were followed up for a mean period of 3.4 ± 2.3 years, and the 1-year and long-term clinical outcomes of the RA group were excellent and comparable with those not receiving RA in multivariate analysis adjusted for multiple variables. Conclusion The treatment of RA is safe and feasible for resistant CTO lesions with heavy calcification. The short- and long-term clinical outcomes of the treatment of RA were excellent and comparable with those not needing RA for CTO PCI.

Background Recently, an association between CYP2B6 516 G > T polymorphism and weight change was observed among African people living with HIV (PLWH) who were started on efavirenz(EFV)-based antiretroviral therapy (ART). We aimed to investigate the effect of EFV mid-dose plasma concentration on weight change among Taiwanese PLWH. Methods The medical records of adult PLWH who were taking EFV-containing ART and had been enrolled in a EFV therapeutic drug monitoring study between Oct 2009 and May 2014 were accessed. EFV mid-dose plasma concentration (C12) was determined in the previous study and those with serial weight measurements within 48 weeks around the time of EFV C12 measurement were included in the present study. The weight change in the 48 weeks and its associations with mid-dose EFV concentrations and CYP2B6 516 G > T polymorphism were examined by general estimating equations (GEE) after adjusting for age, baseline HIV viremia, baseline weight, and the companion backbone antiretroviral agents. Results One-hundred and fifteen predominantly male (94.8%) PLWH were included in this study (Table 1). The mean CD4 lymphocyte count was 542 cells/μL at the beginning of the observation and 94.8% achieved HIV viral suppression. Forty-four (38.3%) patients had non-wildtype CYP2B6 516 G > T polymorphism. On average, the included PLWH gained 0.8 kilogram at 48 weeks and the weight change did not differ among those with wildtype and non-wildtype CYP2B6 516 G > T(Figure 1). In the GEE models, CYP2B6 516 G > T polymorphism was not associated with weight change (p=0.81), instead, higher EFV C12 was found to be independently associated with less weight gain (p=0.045). Table 1. Baseline characteristics. Figure 1. The absolute weight (A) and weight change from baseline (B) among patients with wildtype and non-wildtype CYP2B6 516G>T polymorphism. Conclusion Our findings support that increased EFV exposure may have a negative effect on weight gain. Disclosures Chien-Ching Hung, MD,PHD, Abbvie (Advisor or Review Panel member, Speaker’s Bureau)Bristol-Myers Squibb (Speaker’s Bureau)Gilead Sciences (Advisor or Review Panel member, Speaker’s Bureau)Janssen (Grant/Research Support, Advisor or Review Panel member)Merck (Grant/Research Support)ViiV (Grant/Research Support, Advisor or Review Panel member, Speaker’s Bureau)

Summary: We report a case of an 84-year-old widow from Taiwan who meets a classic presentation of symptomatology from very late-onset schizophrenia-like psychosis (VLOSLP). After 2 decades of reference idea, she subsequently suffered from persecutory, partition delusion and multimodal hallucinations. Acute psychiatric hospitalization was arranged for diagnostic workup and antipsychotics treatment. No laboratory abnormalities were found. We gave olanzapine and gradually titrated to 20 mg/day, and her psychotic symptoms were relieved in a month, then discharged. This case report is aimed to discuss the clinical characteristics, nosology, and treatment of VLOSLP. Further exploration of VLOSLP should be considered because of its unique clinical feature and course. Keywords: Very late-onset schizophrenia-like psychosis, Partition delusion, Olanzapine

IntroductionPrimary aldosteronism (PA) is a common form of secondary hypertension that has significant cardiovascular events and increased prevalence of metabolic syndrome and diabetics. Although plasma aldosterone concentration is positively correlated with visceral fat area (VFA) in non-PA individuals, the role of visceral adiposity associated with clinical success after surgery is not known.Research design and methodsWe analyzed patients who underwent adrenalectomy for aldosterone-producing adenoma (APA) at the Taiwan PA Investigator group. VFA was calculated from the abdominal CT scan at APA diagnosis, and all patients received adrenalectomy.ResultsThe study involved 100 consecutive patients with APA (42 males; mean age 49.3 years) matched with 41 essential hypertension (EH) patients. Patients with APA had smaller VFA (p=0.010) than their EH counterparts. Multiple linear regression analysis revealed that the duration of hypertension (p=0.007), but not plasma aldosterone, was negatively correlated with VFA in patients with APA. Logistic regression analysis showed that log VFA (OR=0.065, p<0.001) and duration of hypertension before PA diagnosis (OR=0.919, p=0.011) can predict complete clinical success after adrenalectomy. Multifactor-adjusted generalized additive model demonstrated that log VFA ConclusionsPatients with APA had smaller VFA than their EH counterparts, and VFA increased after adrenalectomy. Clinical complete cure of hypertension after surgery was associated with smaller VFA and shorter duration of hypertension at PA diagnosis, suggesting a potential interplay of visceral adiposity and aldosterone of the patients with APA.

Background Previous studies show that patients with primary aldosteronism are associated with higher risk of congestive heart failure ( CHF ). However, the effect of target treatment to the incidental CHF has not been elucidated. We aimed to investigate the risk of new‐onset CHF in patients with aldosterone‐producing adenomas ( APAs ) and explore the effect of adrenalectomy on new onset of CHF . Methods and Results From 1997 to 2009, 688 APA were identified and matched with essential hypertension controls. The risks of developing incidental CHF (hazard ratio, 0.49; 95% CI , 0.31–0.75; P =0.001) and mortality (hazard ratio, 0.29; 95% CI , 0.20–0.44; P APA group after targeted treatment. A total of 605 patients with APAs who underwent adrenalectomy lowered the risks of CHF (subdistribution hazard ratio, 0.55; 95% CI , 0.34–0.90; P =0.017) and mortality (adjusted hazard ratio, 0.27; 95% CI , 0.16–0.44; P Conclusions In conclusion, for patients with APAs, adrenalectomy can be associated with lower risk of incidental CHF and all‐cause mortality in a long‐term follow‐up.

OBJECTIVE The association between hyperaldosteronism and autoimmune disorders has been postulated. However, long-term incidence of a variety of new-onset autoimmune diseases (NOAD) among patients with primary aldosteronism has not been well investigated. METHODS From Taiwan's National Health Insurance Research Database with a 23-million population insurance registry, the identification of primary aldosteronism, essential hypertension and NOAD as well as all-cause mortality were ascertained by a validated algorithm. RESULTS From 1997 to 2009, 2319 primary aldosteronism patients without previously autoimmune disease were identified and propensity score-matched with 9276 patients with essential hypertension. Among those primary aldosteronism patients, 806 patients with aldosterone-producing adenomas (APA) were identified and matched with 3224 essential hypertension controls. NOAD incidence is augmented in primary aldosteronism patients compared with its matched essential hypertension (hazard ratio 3.82, P

Objective Primary aldosteronism (PA) is a common cause of secondary hypertension, and the long-term effect of excess aldosterone on kidney function is unknown. Patients and Methods We used a longitudinal population database from the Taiwan National Health Insurance system and applied a validated algorithm to identify patients with PA diagnosed between 1997 and 2009. Results There were 2699 patients with PA recruited, of whom 761 patients with an aldosterone-producing adenoma (APA) were identified. The incidence rate of end-stage renal disease (ESRD) was 3% in patients with PA after targeted treatments and 5.2 years of follow-up, which was comparable to the rate in controls with essential hypertension (EH). However, after taking mortality as a competing risk, we found a significantly lower incidence of ESRD when comparing patients with PA vs EH [subdistribution hazard ratio (sHR), 0.38; P = 0.007] and patients with APA vs EH (sHR 0.55; P = 0.021) after adrenalectomy; however, we did not see similar results in groups with mineralocorticoid receptor antagonist (MRA)‒treated PA vs EH. There was also a significantly lower incidence of mortality in groups with PA and APA who underwent adrenalectomy than among EH controls (P < 0.001). Conclusion Regarding incident ESRD, patients with PA were comparable to their EH counterparts after treatment. After adrenalectomy, patients with APA had better long-term outcomes regarding progression to ESRD and mortality than hypertensive controls, but MRA treatments did not significantly affect outcome.

Background Superior performance of surgical treatment over medical treatment for primary aldosteronism (PA) has been reported in small-scale clinical studies with diverse clinical outcomes, but no solid conclusion has been drawn as results of large randomized trials are lacking. Methods: We performed a search of PubMed, MEDLINE, Embase and Cochrane Library for randomized or observational studies that investigated cardiovascular outcomes in patients with primary aldosteronism undergoing medical versus surgical treatment. - Composite outcomes including persistence of hypertension (HT) and incidence of significant clinical events (e.g. major adverse cardiovascular events [MACE] and all-cause mortality) after treatment was considered. Meta-analyses of both composite and individual outcomes were conducted. Risks of bias of the included studies were assessed with Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) checklist. Findings: A total of 368 related citations were reviewed and 11 studies that fulfilled the inclusion criteria, with altogether 5,994 PA patients, were included in the meta-analysis. Evaluation showed that there were low-moderate risks of bias in (63.64%) 7 of the included studies. The results of meta-analyses demonstrated lower incidence of composite outcomes among PA patients who underwent surgical treatment over medical treatment (Odds Ratio (OR): 0.49, 95% CI: 0.29-0.83 in random effects model). Surgical treatment also led to less incidence of persistence of HT (OR of non-cure of HT: 0.31, 95% CI: 0.11-0.85 in random effects model). Fewer major cardiovascular events and mortality events after surgical treatment were observed in the fixed effect model (OR: 0.47, 95% CI: 0.39-0.56), but failed to reach significant statistical levels in random effects model (OR: 0.71, 95% CI: 0.33-1.52) when compared to medical treatment. Interpretation: Superior performance of surgical treatment over medical treatment for PA patients is confirmed with meta-analyses in terms of lower incidences of composite outcomes and non-cure of HT. Hence, adrenalectomy could now be concluded as the treatment of choice for lateralized PA. Funding Statement: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Declaration of Interests: All authors declare no competing interests Ethics Approval Statement: The pre-defined review protocol was registered at the PROSPERO international prospective register of systematic reviews (PROSPERO registration number CRD42019119175). The protocol for this trial and supporting CONSORT checklist are available as supporting information.

Impaired bioavailability of endothelium-derived nitric oxide (NO) and endothelial dysfunction may play a pivotal role in the pathogenesis of in-stent restenosis (ISR) after coronary stenting. We aimed to investigate the relation between asymmetric dimethylarginine (ADMA), an endogenous NO synthase inhibitor, and the ISR lesions tissue characteristics assessed by optical coherence tomography (OCT).Forty-five patients with symptomatic ISR lesions (17 bare metal stents, 28 drug-eluting stents, medium implantation duration: 58.0 months) were evaluated by OCT for in-stent tissue characteristics and calcification. We defined neoatherosclerosis as the presence of lipid or calcified neointima in ISR lesions, and 12 (26.7%), 33 (73.3%) ISR lesions were classified as with homogenous neointima and neoatherosclerosis respectively. The patients with neoatherosclerosis have significantly higher plasma ADMA levels compared to those of patients with homogenous neointima (1.12 ± 0.21 μmol/l versus 0.83 ± 0.08 μmol/l, p 0.001). Furthermore, the plasma ADMA level of ISR lesions with intra-stent calcification (n = 24, 53.3%) was also significantly higher than those of ISR lesions without (n = 21, 46.7%; p 0.001). There was a highly significant association between plasma ADMA level and intra-stent relative calcium index (mean calcium arc × calcium length)/(360 × analyzed length) (p 0.001, r = 0.702). In multivariate analyses adjusted for age, sex, diabetes, eGFR, plasma ADMA level remained the only significant predictor for the presence of neoatherosclerosis (p = 0.008) and intra-stent calcification (p 0.001). In contrast, plasma ADMA level correlated with intra-stent relative lipid core index (mean lipid core arc × lipid core length)/(360 × analyzed length) only in subgroup without intra-stent calcification (p = 0.004, r = 0.596, multivariate-adjusted p = 0.022).Increased plasma ADMA levels were associated with the development of in-stent neoatherosclerosis and calcification.

Michael Chaglasian,1 Murray Fingeret,2 Pinakin Gunvant Davey,3 Wei-Chieh Huang,4 Danny Leung,4 Edmund Ng,5 Charles A Reisman4 1Illinois Eye Institute, Illinois College of Optometry, Chicago, IL, USA; 2Department of Veterans Affairs, New York Harbor Health Care System, Brooklyn, NY, USA; 3School of Optometry, Western University of Health Sciences, Pomona, CA, USA; 4Topcon Healthcare Solutions Research and Development, Oakland, NJ, USA; 5Edmund Ng Consulting, LLC, Seattle, WA, USA Importance: The paper presents the range for measurements taken with a new spectral domain optical coherence tomography (OCT) device to establish a reference database for discrimination purposes. Objective: To report the range of thickness values for the new Topcon Maestro 3D OCT device with 2 scan size settings: the 12×9 mm wide field and 6×6 mm scans. Design: Prospective, multicenter cohort study conducted at 7 clinical sites across the USA. Setting: Primary eyecare clinics within academic, hospital, and private practice locations. Participants: Healthy volunteers; all enrolled participants underwent a complete ophthalmological examination to confirm healthy ocular status prior to being enrolled in the study. Main outcome measure: Average and 1st, 5th, 95th, and 99th percentile ranges for OCT parameters Early Treatment Diabetic Retinopathy Study macula full retinal thickness, ganglion cell + inner plexiform layer thickness (GCL + IPL), ganglion cell complex (GCC) thickness, circumpapillary retinal nerve fiber layer (cpRNFL) thickness. Results: Three hundred and ninety-nine eyes of 399 subjects were included in the analysis. Mean (SD) age was 46.3 (16.3) years (range 18–88 years). Forty-three percent of the subjects were male. Mean (SD) measurements (in μm) for the 12×9 mm wide scan were as follows: foveal thickness=237.079 (20.899), GCL + IPL=71.363 (5.924), GCC=105.949 (8.533), cpRNFL=104.720 (11.829); measurements for the 6×6 mm scans were as follows: foveal thickness=234.000 (20.657), GCL + IPL=71.726 (5.880), GCC=106.698 (9.094), cpRNFL=104.036 (11.341). Conclusion: The overall normal thickness values reported with Topcon 3D OCT-1 Maestro were like those studies with OCT from different manufactures. The reference limits at the 1st, 5th, 95th, and 99th percentile points establish the thresholds for the quantitative comparison of the cpRNFL and the macula in the human retina to a database of known healthy subjects. Keywords: spectral domain optical coherence tomography, normal eyes, 3D OCT-1 Maestro, macular measurements, circumpapillary retinal nerve fiber layer, optic disc

The intra-pericardial paraganglioma is very rare and most of them present with hypertension or palpitations. Here we reported an extraordinarily rare case of intra-pericardial paraganglioma presenting as faint, pitting edema, abdominal fullness with ascites, and hemopericardium with impending tamponade, which was treated successfully by emergent pericardiocentesis and surgical resection.

Aim Some patients with refractory peritoneal dialysis-related peritonitis continue to develop intra-abdominal complications despite removal of the peritoneal catheter. Repeated percutaneous drainage or open laparotomy is often required, and mortality is not uncommon. The benefits of pelvic drainage placement during catheter removal in decreasing these complications and interventions remain unproven. Methods Forty-six patients with refractory peritonitis who underwent removal of a Tenckhoff catheter between 1991 and 2013 were reviewed retrospectively. Twelve patients had pelvic drainage using closed active suction devices during catheter removal (drainage group). The remaining 34 patients underwent catheter removal without drainage (non-drainage group). The outcomes measured were the development of intra-abdominal complications and the requirement for repeated percutaneous drainage or open laparotomy within 90 days after the catheter removal. Results Baseline characteristics were similar with the exception of a higher median number of previous peritonitis episodes in the drainage group compared with the non-drainage group (2 vs 0, P = 0.02). During the follow-up period, intra-abdominal complications occurred in 15 (44%) of 34 patients in the non-drainage group, compared with one (8%) of 12 patients in the drainage group (P = 0.03). Twelve (35%) patients in the non-drainage group required repeated percutaneous drainage or open laparotomy for management, compared with zero (0%) patients in the drainage group (P = 0.02). Drain tubes were removed at a median of 6 days (inter-quartile range: 5–10) without complications. Conclusions In the management of refractory peritonitis, pelvic drainage during removal of dialysis catheter decreases the risk of subsequent intra-abdominal complications and invasive interventions.

Background: Ultrafiltration is an adjunctive treatment for decompensated heart failure patients with cardiorenal syndrome. The efficacy and safety of ultrafiltration in the patient cohort are still unknown. Methods: We systematically reviewed and evaluated randomized controlled trials, comparing diuretics with ultrafiltration in adult patients with decompensated heart failure and cardiorenal syndrome through January 2014. The primary outcomes were body weight loss and total fluid removal. Results: We identified 8 trials including 608 patients. In a random-effects model, the pooled difference of body weight loss was 1.44 kg between patients receiving ultrafiltration and diuretics (95% CI, 0.29-2.59; p = 0.01). The difference of fluid removal was 1.28 l between groups (95% CI, 0.43-2.12; p = 0.003). The RR for mortality was 0.90 for ultrafiltration compared with diuretics (95% CI, 0.61-1.33; p = 0.60) and the RR for renal function deterioration was 1.29 (95% CI, 0.90-1.85; p = 0.17). There is a trend toward reducing readmission rate in ultrafiltration group. Conclusions: Ultrafiltration is a safe and effective strategy in the treatment of cardiorenal syndrome without increasing the risk of renal deterioration.

Background CD133 (prominin-1) is widely believed to be a cancer stem cell marker in various solid tumor types, and CD133 has been correlated with tumor-initiating capacity. Recently, the nuclear location of CD133 expression in tumors has been discussed, but hepatocellular carcinoma (HCC) has not been included in these discussions. The goal of this study was to investigate the location of CD133 expression in HCC and this location’s potential value as a prognostic indicator of survival in patients with HCC. Methods We enrolled 119 cancerous tissues and pair-matched adjacent normal liver tissue from HCC patients. These tissues were obtained immediately after operation, and tissue microarrays were subsequently constructed. The expression of CD133 was measured by immunohistochemistry (IHC), and the correlations between this expression and clinical characteristics and prognosis was estimated using statistical analysis. Results The results showed that the CD133 protein expression levels of HCC in both the cytoplasm and nucleus were significantly higher than adjacent normal liver tissue. Kaplan–Meier survival and Cox regression analyses revealed that high CD133 expression in the cytoplasm was an independent predictor of poor prognosis for the overall survival (OS) and relapse-free survival (RFS) rates of HCC patients (P = 0.028 and P = 0.046, respectively). Surprisingly, high nuclear CD133 expression of HCC was an independent predictor of the good prognosis of the OS and RFS rates of HCC patients (P = 0.023 and P = 0.012, respectively). Conclusions The clinical evidence that revealed cytoplasmic CD133 expression was correlated with poor prognosis, while nuclear CD133 expression was significantly correlated with favorable prognosis. Electronic supplementary material The online version of this article (doi:10.1186/s12885-017-3460-9) contains supplementary material, which is available to authorized users.

Background: Many diagnostic procedures are conducted in patients with syndrome of inappropriate antidiuresis (SIAD). However, the contribution in identification of the cause of SIAD remains unknown. Methods: The study was conducted at Kaohsiung Veterans General Hospital in southern Taiwan. From January 2000 to December 2009, medical records of 439 adult patients hospitalized for new-onset SIAD at a single center were retrospectively collected. All diagnostic procedures during hospitalization were divided into four groups: chest/lung, central nervous system, abdomen, and bone marrow to evaluate their positive rate leading to the cause of SIAD. Factors associated with “procedures leading to the cause” were also analyzed to improve efficacy of survey. Results: Cause of SIAD was identified in 267 (60.8%). Of them, 150 were pulmonary disorders, 44 were drugs, 37 were central nervous system disorders, 32 were malignancy and 4 were post-surgery. Survey for chest/lung, central nervous system, abdomen, and bone marrow were performed in 96.6%, 29.2%, 38.0% and 3.6% of patients, respectively; positive findings leading to the cause of SIAD were 39.6%, 12.5%, 5.3% and 6.3%, respectively. Among the diagnostic procedures, chest x-ray (424/439, 96.6%) was most frequently performed with the highest identification rate of 34.7% (147 cases). Major significant independent factors that associated with “procedure leading to a cause” were: absence of SIAD-associated drug history, presence of fever/chills, and presence of respiratory symptoms. Cause of SIAD became evident later during the follow-up period in 10 of 172 (5.8%) patients who were initially thought to be cause-unknown. Malignancy was the cause for 5 cases and pulmonary tuberculosis was for the other five. Eight of these causes became evident within one year after the diagnosis of SIAD. Conclusions: SIAD with unidentified causes were prevalent. Current diagnostic procedures remain not satisfying in determining the cause of SIAD, but chest radiograph did demonstrate higher diagnostic rate, especially in patients presented with fever, chills, respiratory symptoms, and without SIAD-associated drug history. Patients with unidentified cause should be followed for at least one year when most hidden causes (e.g. malignancy and tuberculosis) become obvious.

SummaryObjective Secondary hyperparathyroidism and its associated abnormalities in mineral metabolism and haemodynamic changes increase the cardiovascular risk in patients with end-stage renal disease (ESRD). Our objective was to determine the association of parathyroidectomy (PTX) with major cardiovascular events in nondiabetic dialysis patients with severe secondary hyperparathyroidism (SHPTH). Design and Patients We performed a cohort study with fifty-three nondiabetic ESRD patients who were treated with maintenance haemodialysis and who had intact parathyroid hormone (PTH) levels > 800 pg/ml. Participants received either only medical therapy or medical therapy and total PTX with autotransplantation for SHPTH. Measurements We evaluated the associations between PTX and major cardiovascular events including death, cerebrovascular accident and myocardial infarction. The biochemical and haemodynamic changes associated with PTX were measured. Results During the mean follow-up of 72 months, twenty-three patients received only medical treatment (medical group) while thirty patients underwent PTX in addition to medical treatment (PTX group). The two groups were comparable in respect of baseline characteristics. PTX group was found to be associated with a reduced incidence of major cardiovascular events (P = 0·021). A multiple Cox regression analysis showed that the variable significantly associated with major cardiovascular events was treatment modality (medical therapy vs medical therapy and parathyroidectomy, hazard ratio = 26·12, 95% CI = 1·30–526·27, P = 0·033). Blood pressure, haemoglobin, alkaline phosphatase, calcium, phosphate and calcium × phosphate product significantly improved after PTX. Conclusions PTX was associated with better cardiovascular outcome in nondiabetic dialysis patients with severe SHPTH.

Leber congenital amaurosis (LCA) patients of 10 known genotypes (n = 24; age range, 3–25 years) were studied clinically and by optical coherence tomography (OCT). Comparisons were made between OCT results across the horizontal meridian (central 60o) of the patients. Three patterns were identified. First, there were LCA genotypes with unusual and readily identifiable patterns, such as near normal outer nuclear layer (ONL) across the central retina or severely dysplastic retina. Second, there were genotypes with well-formed foveal architecture but only residual central islands of normal or reduced ONL thickness. Third, some genotypes showed central ONL losses or dysmorphology suggesting early macular disease or foveal maldevelopment. Objective in vivo morphological features could complement other phenotypic characteristics and help guide genetic testing of LCA patients or at least permit a differential diagnosis of genotypes to be made in the clinic.

Aim Hyperkalemia increases the risk of sudden cardiac death (SCD) in hemodialysis patients. Our objective was to determine the association between administering low potassium dialysate to hyperkalemic hemodialysis patients and SCD. Methods We conducted a retrospective cohort study with patients undergoing maintenance hemodialysis from May 1, 2006, through December 31, 2013. The dialysate composition was adjusted over time according to monthly laboratory results. A 1.0 mEq/L potassium dialysate was applied in patients with predialysis hyperkalemia (>5.5 mEq/L) and was included as a time-dependent confounding factor. The clinical characteristics of enrolled patients, the incidence and timing of SCD and risk factors for all-cause mortality and SCD were analyzed. Results There were 312 patients on maintenance hemodialysis during the study period. One hundred and fifty-seven patients had been dialyzed against a 1.0 mEq/L potassium dialysate at least once. The rates of all-cause mortality and SCD were 48.17 and 20.74 per 1000 patient-years, respectively. A 1.12-fold increase in the risk of SCD in the 24-hour period starting with the hemodialysis procedure and a 1.36-fold increase in the 24 hours preceding a weekly cycle were found (p = 0.017). Multivariate Cox proportional hazards models showed that age, diabetes mellitus and predialysis hyperkalemia (>5.0 mEq/L) were significant predictors of all-cause mortality and SCD. Exposure to 1.0 mEq/L potassium dialysate, Kt/V, and serum albumin were independent protective factors against all-cause mortality. Only exposure to 1.0 mEq/L potassium dialysate significantly prevented SCD (hazard ratio = 0.33, 95% CI = 0.13–0.85). Conclusions Using low potassium dialysate in hyperkalemic hemodialysis patients may prevent SCD.

Most recent studies reported that FoxO1 transcription factor was a negative regulator of myogenesis under serum withdrawal condition, a situation not actually found in vivo. Therefore, the role of FoxO1 in myogenesis should be re-examined under more physiologically relevant conditions. Here we found that FoxO1 was preferentially localized to nucleus in proliferating (PMB) and confluent myoblasts (CMB) and its nuclear exclusion was a prerequisite for formation of multinucleated myotubes (MT). The nuclear shuttling of FoxO1 in PMB could be prevented by leptomycin B and we further found that cytoplasmic accumulation of FoxO1 in myotubes was caused by the blockade of its nuclear import. Although over-expression of wildtype FoxO1 in C2C12 myoblasts significantly blocked their myogenic differentiation under serum withdrawal condition, application of insulin and LiCl, an activator of Wnt signaling pathway, to these cells successfully rescued their myogenic differentiation and generated myotubes with larger diameters. Interestingly, insulin treatment significantly reduced FoxO1 level and also delayed nuclear re-accumulation of FoxO1 triggered by mitogen deprivation. We further found that FoxO1 directly repressed the promoter activity of myogenic genes and this repression can be relieved by insulin and LiCl treatment. These results suggest that FoxO1 inhibits myogenesis in serum withdrawal condition but turns into a hypertrophy potentiator when other myogenic signals, such as Wnt and insulin, are available.

MicroRNAs offer tools to identify and treat invasive cancers. Using highly invasive isogenic oral squamous cell carcinoma (OSCC) cells, established using in vitro and in vivo selection protocols from poorly invasive parental cell populations, we used microarray expression analysis to identify a relative and specific decrease in miR-491-5p in invasive cells. Lower expression of miR-491-5p correlated with poor overall survival of patients with OSCCs. miR-491-5p overexpression in invasive OSCC cells suppressed their migratory behavior in vitro and lung metastatic behavior in vivo. We defined the G-protein—coupled receptor kinase-interacting protein 1 (GIT1)—as a direct target gene for miR-491-5p control. GIT1 overexpression was sufficient to rescue miR-491-5p–mediated inhibition of migration/invasion and lung metastasis. Conversely, GIT1 silencing phenocopied the ability of miR-491-5p to inhibit migration/invasion and metastasis of OSCC cells. Mechanistic investigations indicated that miR-491-5p overexpression or GIT1 attenuation reduced focal adhesions, with a concurrent decrease in steady-state levels of paxillin, phospho-paxillin, phospho-FAK, EGF/EGFR-mediated extracellular signal–regulated kinase (ERK1/2) activation, and MMP2/9 levels and activities. In clinical specimens of OSCCs, GIT1 levels were elevated relative to paired normal tissues and were correlated with lymph node metastasis, with expression levels of miR-491-5p and GIT1 correlated inversely in OSCCs, where they informed tumor grade. Together, our findings identify a functional axis for OSCC invasion that suggests miR-491-5p and GIT1 as biomarkers for prognosis in this cancer. Cancer Res; 74(3); 751–64. ©2013 AACR.

PURPOSE: We investigated the retinal disease due to mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene in human patients and in an Rpgr conditional knockout (cko) mouse model.METHODS: XLRP patients with RPGR-ORF15 mutations (n = 35, ages at first visit 5-72 years) had clinical examinations, and rod and cone perimetry. Rpgr-cko mice, in which the proximal promoter and first exon were deleted ubiquitously, were back-crossed onto a BALB/c background, and studied with optical coherence tomography and electroretinography (ERG). Retinal histopathology was performed on a subset.RESULTS: Different patterns of rod and cone dysfunction were present in patients. Frequently, there were midperipheral losses with residual rod and cone function in central and peripheral retina. Longitudinal data indicated that central rod loss preceded peripheral rod losses. Central cone-only vision with no peripheral function was a late stage. Less commonly, patients had central rod and cone dysfunction, but preserved, albeit abnormal, midperipheral rod and cone vision. Rpgr-cko mice had progressive retinal degeneration detectable in the first months of life. ERGs indicated relatively equal rod and cone disease. At late stages, there was greater inferior versus superior retinal degeneration. CONCLUSIONS: RPGR mutations lead to progressive loss of rod and cone vision, but show different patterns of residual photoreceptor disease expression. Knowledge of the patterns should guide treatment strategies. Rpgr-cko mice had onset of degeneration at relatively young ages and progressive photoreceptor disease. The natural history in this model will permit preclinical proof-of-concept studies to be designed and such studies should advance progress toward human therapy.

Autosomal recessive retinitis pigmentosa (RP), a heterogeneous group of degenerations of the retina, can be due to mutations in the MFRP (membrane-type frizzled-related protein) gene. A patient with RP with MFRP mutations, one of which is novel and the first splice site mutation reported, was characterized by noninvasive retinal and visual studies. The phenotype, albeit complex, suggested that this retinal degeneration may be a candidate for gene-based therapy. Proof-of-concept studies were performed in the rd6 Mfrp mutant mouse model. The fast-acting tyrosine-capsid mutant AAV8 (Y733F) vector containing the small chicken β-actin promoter driving the wild-type mouse Mfrp gene was used. Subretinal vector delivery on postnatal day 14 prevented retinal degeneration. Treatment rescued rod and cone photoreceptors, as assessed by electroretinography and retinal histology at 2 months of age. This AAV-mediated gene delivery also resulted in robust MFRP expression predominantly in its normal location within the retinal pigment epithelium apical membrane and its microvilli. The clinical features of MFRP-RP and our preliminary data indicating a response to gene therapy in the rd6 mouse suggest that this form of RP is a potential target for gene-based therapy.

Background: The objective of this study was to assess the impact of heparin concentration retained in temporary double-lumen catheters on bleeding risk. Methods: Activated partial thromboplastin time (aPTT) was measured in patients hemodialyzed via double-lumen catheters. Heparin solutions of 5,000 U/ml (group 1, n = 95) and 1,000 U/ml (group 2, n = 89) were randomly retained in catheters after placement and each hemodialysis (HD) session. Blood transfusion, bleeding episodes, and changes of hematocrit were recorded. Results: The aPTT at the beginning of HD or 10 min after heparin lock was significantly prolonged, which was more prominent in the 5,000 U/ml group, whereas the aPTT declined to baseline values at the end of HD or before the next dialysis session in both groups. Infection and occlusion rates were similar in both groups. More patients suffered from major bleeding and prominent decline of hematocrit in the 5,000 U/ml group. Conclusions: Low-dose heparin (1,000 U/ml) retention in double-lumen catheters for temporary HD maintains comparable catheter patency and might reduce the bleeding risk.

Purpose Tumor growth factor-β1 (TGF-β1) plays a pivotal role in processes like kidney epithelial–mesenchymal transition (EMT) and interstitial fibrosis, which correlate well with progression of renal disease. Little is known about underlying mechanisms that regulate EMT. Based on the anatomical relationship between erythropoietin (EPO)-producing interstitial fibroblasts and adjacent tubular cells, we investigated the role of EPO in TGF-β1-mediated EMT and fibrosis in kidney injury. Methods We examined apoptosis and EMT in TGF-β1-treated LLC-PK1 cells in the presence or absence of EPO. We examined the effect of EPO on TGF-β1-mediated Smad signaling. Apoptosis and cell proliferation were assessed with flow cytometry and hemocytometry. We used Western blotting and indirect immunofluorescence to evaluate expression levels of TGF-β1 signal pathway proteins and EMT markers. Results We demonstrated that ZVAD-FMK (a caspase inhibitor) inhibited TGF-β1-induced apoptosis but did not inhibit EMT. In contrast, EPO reversed TGF-β1-mediated apoptosis and also partially inhibited TGF-β1-mediated EMT. We showed that EPO treatment suppressed TGF-β1-mediated signaling by inhibiting the phosphorylation and nuclear translocation of Smad 3. Inhibition of mitogen-activated protein kinase kinase 1 (MEK 1) either directly with PD98059 or with MEK 1 siRNA resulted in inhibition of EPO-mediated suppression of EMT and Smad signal transduction in TGF-β1-treated cells. Conclusions EPO inhibited apoptosis and EMT in TGF-β1-treated LLC-PK1 cells. This effect of EPO was partially mediated by a mitogen-activated protein kinase-dependent inhibition of Smad signal transduction.

To characterize in detail the phenotype and genotype of patients with pericentral retinal degeneration (PRD).Patients were screened for an annular ring scotoma ranging from 3° to 40° (n = 28, ages 24-71) with kinetic perimetry. All patients had pigmentary retinopathy in the region of the dysfunction. Further studies included cross-sectional and en face imaging, static chromatic perimetry, and electroretinography. Molecular screening was performed.Genotypes of 14 of 28 PRD patients were identified: There were mutations in eight different genes previously associated with autosomal dominant or autosomal recessive RDs. Kinetic fields monitored in some patients over years to more than a decade could be stable or show increased extent of the scotoma. Electroretinograms were recordable but with different severities of dysfunction. Patterns of photoreceptor outer nuclear layer (ONL) loss corresponded to the distribution of visual dysfunction. Outer nuclear layer thickness topography and en face imaging indicated that the greatest disease expression was in the area of known highest rod photoreceptor density.Molecular heterogeneity was a feature of the PRD phenotype. Many of the molecular causes were also associated with other phenotypes, such as maculopathies, typical retinitis pigmentosa (RP) and cone-rod dystrophy. The pericentral pattern of retinal degeneration is thus confirmed to be an uncommon phenotype of many different genotypes rather than a distinct disease entity.

Background Mutations in the CEP290 (cilia-centrosomal protein 290 kDa) gene in Leber congenital amaurosis (LCA) cause early onset visual loss but retained cone photoreceptors in the fovea, which is the potential therapeutic target. A cone-only mouse model carrying a Cep290 gene mutation, rd16;Nrl−/−, was engineered to mimic the human disease. In the current study, we determined the natural history of retinal structure and function in this murine model to permit design of pre-clinical proof-of-concept studies and allow progress to be made toward human therapy. Analyses of retinal structure and visual function in CEP290-LCA patients were also performed for comparison with the results in the model. Methods Rd16;Nrl−/− mice were studied in the first 90 days of life with optical coherence tomography (OCT), electroretinography (ERG), retinal histopathology and immunocytochemistry. Structure and function data from a cohort of patients with CEP290-LCA (n = 15; ages 7–48) were compared with those of the model. Results CEP290-LCA patients retain a central island of photoreceptors with normal thickness at the fovea (despite severe visual loss); the extent of this island declined slowly with age. The rd16;Nrl−/− model also showed a relatively slow photoreceptor layer decline in thickness with ∼80% remaining at 3 months. The number of pseudorosettes also became reduced. By comparison to single mutant Nrl−/− mice, UV- and M-cone ERGs of rd16;Nrl−/− were at least 1 log unit reduced at 1 month of age and declined further over the 3 months of monitoring. Expression of GNAT2 and S-opsin also decreased with age. Conclusions The natural history of early loss of photoreceptor function with retained cone cell nuclei is common to both CEP290-LCA patients and the rd16;Nrl−/− murine model. Pre-clinical proof-of-concept studies for uniocular therapies would seem most appropriate to begin with intervention at P35–40 and re-study after one month by assaying interocular difference in the UV-cone ERG.

Purpose To investigate the relationship between photoreceptor layers overlying and adjacent to large drusen in intermediate nonneovascular AMD. Methods Patients with AMD (n = 41; aged 53-83 years) and elderly control subjects without eye disease (n = 10; aged 51-79 years) were studied with spectral-domain optical coherence tomography. Characteristics of large drusen (≥125 μm) were measured and the thickness of photoreceptor laminae overlying drusen and in retinal regions neighboring the drusen were quantified. Results There were 750 large drusen in 63 intermediate AMD eyes studied. The width of the drusen sampled averaged 352 μm (SD = 153) and the height averaged 78 μm (SD = 31). There was significant reduction of the photoreceptor outer nuclear layer (ONL) thickness overlying 92% of the drusen. The thickness of the layer corresponding to photoreceptor inner and outer segments above drusen was also reduced, and the reduction was proportional to ONL thickness. In a substantial fraction (~20%) of normally laminated paradrusen locations sampled within ~300 μm of peak drusen height, ONL thickness was significantly increased compared with age and retinal location-matched normal values. Topographical analyses of the macula showed ONL thickening occurring in paradrusen regions as well as retinal locations distant from drusen. Conclusions Reductions in the photoreceptor laminae overlying drusen were detectable and this is consistent with histological studies revealing neuronal degeneration in AMD. ONL thickening in some macular areas of AMD eyes has not been previously reported and may be an early phenotypic marker for photoreceptor stress, as it has been speculated to be in hereditary retinal degenerations.

There has been longstanding scientific interest in Crumbs proteins, originating from discoveries in Drosophila; in mammals, there are several homologues of Crumbs (reviewed in Ref. 1). CRB1 is thought to be expressed in Muller glial (MG) cells and localizes at a subapical region near intercellular adherens junctions between photoreceptors and MG cells at the outer limiting membrane (OLM). Mutations in the CRB1 gene cause an autosomal recessive early-onset retinal degeneration characterized by abnormal retinal organization and severe visual loss.2–7 Results to date in patients with CRB1-associated retinal degenerations (CRB1-RD), taken together with findings in experimental animals, support the conjecture that CRB1 mutations result in retinal maldevelopment and progressive degeneration.5,8 There is also experimental evidence supporting a role for CRB1 in the maintenance of photoreceptor integrity.8,9 Major progress was made recently when gene replacement therapy for another recessive early-onset retinal degeneration, the RPE65 form of Leber congenital amaurosis (LCA), was shown to be safe and efficacious in early-phase clinical trials (reviewed in Ref. 10). One of the important challenges facing the field of retinal degenerations is how to expand the recent gene therapy success in RPE65-LCA to dozens of other molecular forms of retinitis pigmentosa (RP) and LCA with different pathophysiological mechanisms. It remains unclear whether CRB1-RD patients are candidates for such emerging therapies. In this work we used psychophysics, retinal imaging, and cortical imaging to increase understanding of the disease effects associated with CRB1-RD, with the ultimate goal of assessing the relevance of treatment strategies to this group of patients. In addition, we made a side-by-side comparison of the human retinopathy with that of the retinal disease in the rd8 mouse, a naturally occurring Crb1 mutant. The results of this comparison are a key issue for proof-of-concept studies.

Patient initials or identifier number 33092147 ### Relevant clinical history and physical exam Progressive dyspnea has been noted since one week ago. The patient's general performance had been relatively fair prior to admission. Sudden onset of shortness of breath after going to bathroom

IntroductionPathophysiological changes associated with chronic kidney disease impair angiogenic processes and increase renal fibrosis. Progenitor-like cells derived from adult kidney have been previously used to promote regeneration in acute kidney injury, even though it remained unclear whether the cells could be beneficial in chronic kidney disease (CKD).MethodsIn this study, we established a CKD model by five-sixths nephrectomy and mouse kidney progenitor-like cells (MKPCs) were intravenously administered weekly for 5 weeks after establishing CKD. We examined the impact of MKPCs on the progression of renal fibrosis and the potential of MKPCs to preserve the angiogenic process and prevent endothelial mesenchymal transition in vivo and in vitro.ResultsOur results demonstrate that the MKPCs delayed interstitial fibrosis and the progression of glomerular sclerosis and ameliorated the decline of kidney function. At 17 weeks, the treated mice exhibited lower blood pressures, higher hematocrit levels, and larger kidney sizes than the control mice. In addition, the MKPC treatment prolonged the survival of the mice with chronic kidney injuries. We observed a decreased recruitment of macrophages and myofibroblasts in the interstitium and the increased tubular proliferation. Notably, MKPC both decreased the level of vascular rarefaction and prevented endothelial mesenchymal transition (EndoMT) in the remnant kidneys. Moreover, the conditioned medium from the MKPCs ameliorated endothelial cell death under hypoxic culture conditions and prevented TGF-β-induced EndoMT through downregulation of phosphorylated Smad 3 in vitro.ConclusionsMKPCs may be a beneficial treatment for kidney diseases characterized by progressive renal fibrosis. The enhanced preservation of angiogenic processes following MKPC injections may be associated with decreased fibrosis in the remnant kidney. These findings provide further understanding of the mechanisms involved in these processes and will help develop new cell-based therapeutic strategies for regenerative medicine in renal fibrosis.