Risk of Sudden Cardiac Death in Patients Undergoing Cancer Treatment.

The risk of sudden cardiac death (SCD) in patients with cancer receiving cancer therapies is not well defined. In this study we aimed to (1) evaluate the risk of SCD during the first 6 months of cancer treatment and (2) identify risk factors (RFs) for SCD in patients who underwent active cancer treatment. The study population comprised 8,356 patients who received any cancer treatment at the University of Rochester Medical Center from 2011 to 2020. The primary end point was the occurrence of SCD within 6 months of cancer treatment. SCD was defined by using the modified Hinkle-Thaler classification. The mean age at the time of cancer treatment was 64 ± 14 years and 49% were women. All-cause mortality occurred in 834 patients (10%), of whom 51 (6%) were identified as SCD. The cumulative probability of SCD at 6 months was 0.6%. Age <74 years (0.042), history of congestive heart failure (0.058) and lung cancer (0.004) were identified as independent RFs for SCD in the multivariate Cox regression models. The cumulative probability of SCD at 6 months from cancer treatment initiation was significantly higher in patients with ≥2 RFs (1.6%) than in patients with 0 or 1 RF (0.5%) (log-rank p <0.001). In conclusion, our findings suggest that active cancer treatment is associated with SCD risk that is more pronounced in younger patients (< 74 years), patients with cancer and a history of heart failure, and those who underwent treatment for lung cancer. Future studies should address appropriate modalities for prevention and protection in this high-risk population.

Electroretinography is a prognostic indicator for postoperative vision in dogs undergoing retinal reattachment surgery.

PURPOSE: To determine whether pre-operative electroretinography (ERG) predicts postoperative vision in dogs undergoing retinal reattachment surgery (RRS). METHODS: This 18-month prospective study recorded signalment, duration, cause, and extent of retinal detachment and pre-operative vision status. Rod and mixed rod-cone ERG responses were recorded prior to RRS. Referring veterinary ophthalmologists assessed vision 2 months postoperatively. RESULTS: Thirty dogs (40 affected eyes) aged 4 months to 12.1 years were included. The detachment extent was 150° -320° in 15 of 40 eyes, 360° in 24 of 40 eyes, and not recorded in one eye. Most dogs had a genetic predisposition for retinal detachment. Eight eyes of seven dogs had previous cataract surgery. Mean estimated duration of detachment prior to surgery was 24.5 ± 19.6 days. Pre-operatively, 34 of 40 eyes were blind, two of 40 eyes were sighted, and four of 40 eyes had severely diminished vision. Compared to normative ERG values in our clinics, pre-operative ERGs were classified as "normal" in five of 40 eyes, "attenuated" in seven of 40 eyes, and "flat" in 28 of 40 eyes. Following RRS, the retina was fully reattached in all operated eyes. Two-month postoperatively, 30 of 40 eyes had "normal" vision as defined by referring veterinary ophthalmologists, six of 40 eyes had "limited" or "diminished" vision and four of 40 eyes were blind. Normal vision was regained in 12 of 12 (100%) of eyes with normal or attenuated pre-operative ERG's, but only in 18 of 28 (64%) of eyes with flat pre-operative ERG 's (Linear-by-linear test, P = 0.029). CONCLUSIONS: A recordable pre-operative ERG, even if attenuated, is associated with return of vision in canine RRS patients, and is a favorable prognostic indicator.

Keratoconus and Other Corneal Diseases: Pharmacologic Cross-Linking and Future Therapy.

The ability to cross-link collagen fibers and use this technique to strengthen the cornea has become of great interest to ophthalmologists in the last decade. For progressive diseases such as keratoconus, collagen cross-linking confers the possibility of halting progression and stabilizing the cornea, a benefit that is not observed with any other current treatment. Collagen cross-linking uses riboflavin combined with ultraviolet A light to induce the formation of bonds between collagen fibrils that strengthen the cornea. This chapter will discuss the theory, technique, indications, and complications of corneal cross-linking. Much of what will be discussed is in areas of active research that will likely be further clarified as more experience is gained with this procedure.

Indications for Keratoplasty at 3 Academic Centers from 2002 to 2012.

OBJECTIVES: To determine whether indications for keratoplasty differ between academic centers and the Eye Bank Association of America (EBAA) annual statistics from 2002 to 2012. METHODS: A retrospective review was performed for the indications for keratoplasty from 2002 to 2012 based on surgical specimens originating from three different academic centers. Data were compared with statistical reports obtained from the EBAA for the corresponding years. RESULTS: From 2002 to 2007, at Washington University in St Louis (WU), the most common indication for keratoplasty was graft failure at 31.6%. At St Louis University, the most common indications for keratoplasty were pseudophakic and aphakic bullous keratopathy (PBK/ABK) at 34.6% followed closely by graft failure at 32.7%. Combining the 2002 to 2007 EBAA data, the most common indication for keratoplasty was PBK/ABK at 19.5%, whereas regrafts accounted for only 13.0% of keratoplasties. From 2008 to 2012, regrafts accounted for 41.9% of keratoplasties at WU and 33.1% of keratoplasties at University of California, Davis. In contrast, the EBAA data showed that only 11.4% of keratoplasties were regrafts. CONCLUSIONS: Graft failure accounted for approximately 30% to 40% of indications for keratoplasties at three academic centers from 2002 to 2012, which was more than double and in some cases triple that of the EBAA data during this period. These higher frequencies of regrafting may represent a referral bias of patients with complicated cases to academic centers who then require multiple keratoplasties.

Systemic absorption and adverse ocular and systemic effects after topical ophthalmic administration of 0.1% diclofenac to healthy cats.

OBJECTIVE: To quantify plasma concentrations and determine adverse ocular, renal, or hepatic effects associated with repeated topical ophthalmic application of 0.1% diclofenac to healthy cats. ANIMALS: 8 healthy sexually intact male cats. PROCEDURES: A randomized, placebo-controlled crossover study was conducted. A topical formulation of 0.1% diclofenac was administered 4 times/d for 7 days to 4 cats, and artificial tear (control) solution was administered to the other 4 cats. After a 12-day washout period, cats received the other treatment. Ophthalmic examinations were performed daily. Plasma samples were obtained on days 1 and 7 for pharmacokinetic analysis. A CBC, serum biochemical analysis, urinalysis, determination of urine protein-to-creatinine ratio, and determination of glomerular filtration rate were performed before the start of the study and after each 7-day treatment period. RESULTS: Mild conjunctival hyperemia was the only adverse ocular effect detected. Maximal drug concentration and area under the curve were significantly higher on day 7 than on day 1. Diclofenac-treated cats had a significantly lower glomerular filtration rate than did control-treated cats after the second but not after the first treatment period, presumably associated with iatrogenic hypovolemia. CONCLUSIONS AND CLINICAL RELEVANCE: Topical ophthalmic administration of 0.1% diclofenac was well tolerated in healthy cats, with only mild signs of ocular irritation. Detectable systemic concentrations of diclofenac were achieved with accumulation over 7 days. Systemic absorption of diclofenac may be associated with reduced glomerular filtration rate, particularly in volume-contracted animals. Topical ophthalmic 0.1% diclofenac should be used with caution in volume-contracted or systemically ill cats.

Iatrogenic hyperadrenocorticism, calcinosis cutis, and myocardial infarction in a dog treated for IMT.

An 8 yr old male English bulldog receiving treatment for immune-mediated thrombocytopenia was diagnosed with calcinosis cutis 90 days after initiation of corticosteroid therapy. Twenty-four days later, the patient presented in a comatose state after collapsing and was euthanized. Postmortem examination revealed coronary arteriosclerosis and myocardial infarction leading to congestive heart failure. Calcinosis cutis and myocardial necrosis were most likely complications associated with administration of corticosteroids in this dog. Important implications regarding the classification of calcinosis cutis and the use of immunosuppressive doses of corticosteroids are discussed.

Lack of functional P-selectin ligand exacerbates Salmonella serovar typhimurium infection.

The selectin family of adhesion molecules mediates the recruitment of immune cells to the site of inflammation, which is critical for host survival of infection. To characterize the role of selectins in host defense against Salmonella Typhimurium infection, wild-type (WT) mice and mice lacking P-selectin glycoprotein ligand-1 (PSGL-1), P-, E-, or L-selectin, or the glycosyltransferase C2GlcNAcT-I (core 2) were infected using a Salmonella acute gastroenteritis model. Mice were monitored for survival and assessed for intestinal inflammation at 1 and 4 days postinfection. Infected mice lacking core 2, PSGL-1, or P-selectin showed a more pronounced morbidity and a significantly higher mortality rate associated with higher bacterial load and proinflammatory cytokine production, including that of TNF-alpha, MCP-1, and IL-6, from the colons at 4 days postinfection as compared with WT control. Surprisingly, at 1 day postinfection, more severe inflammation and higher neutrophil infiltration were observed in the ceca of mice lacking core 2, PSGL-1, or P-selectin compared with WT control. Enhanced levels of alpha(4)beta(7)(+) and MAdCAM-1(+) cells were observed in the ceca of infected mice lacking core 2, PSGL-1, or P-selectin. Neutrophil recruitment, cecal inflammation, and mortality rates were dramatically reduced in infected P-selectin knockout mice receiving blocking mAb to alpha(4)beta(7) integrin, indicating that this alternative adhesion molecule may attempt to compensate for the loss of selectins in neutrophil recruitment. These results demonstrate a definitive phenotypic abnormality in mice lacking core 2, PSGL-1, or P-selectin, suggesting that the interaction of functional PSGL-1 with P-selectin is an important process in host defense against Salmonella infection.

Murine cytomegalovirus displays selective infection of cells within hours after systemic administration.

A distinctive feature of the cytomegaloviruses is their wide tissue tropism, demonstrated by the infection of many organs and cell types in an active infection. However, in experimental models of systemic infection, the earliest stages of infection are not well characterized, and it is unclear whether only certain cells are initially infected. Using a recombinant murine cytomegalovirus (MCMV) expressing green fluorescent protein (GFP), we tracked viral infection after systemic administration via intraperitoneal injection and showed that specific cells are infected within the first hours. We provide evidence that MCMV traffics as free virus from the peritoneal cavity into the mediastinal lymphatics, providing access to the bloodstream. We demonstrate that MCMV productively infected CD169(+) subcapsular sinus macrophages in the mediastinal lymph nodes, ER-TR7(+) CD29(+) reticular fibroblasts in the spleen and hepatocytes. Infection in the spleen followed a distinctive pattern, beginning in the marginal zone at 6 h and spreading into the red pulp by 17 h. By 48 h after infection, there was widespread infection in the spleen and liver with degeneration of infected cells. In addition, infected dendritic cells appeared in the white pulp of the spleen at 48 h post-infection. On the other hand, cowpox virus showed a different pattern of infectivity in the spleen and liver. Thus, early MCMV infection produces a distinct pattern of infection of selective cells.

Enhanced detergent extraction for analysis of membrane proteomes by two-dimensional gel electrophoresis.

BACKGROUND: The analysis of hydrophobic membrane proteins by two-dimensional gel electrophoresis has long been hampered by the concept of inherent difficulty due to solubility issues. We have optimized extraction protocols by varying the detergent composition of the solubilization buffer with a variety of commercially available non-ionic and zwitterionic detergents and detergent-like phospholipids. RESULTS: After initial analyses by one-dimensional SDS-PAGE, quantitative two-dimensional analyses of human erythrocyte membranes, mouse liver membranes, and mouse brain membranes, extracted with buffers that included the zwitterionic detergent MEGA 10 (decanoyl-N-methylglucamide) and the zwitterionic lipid LPC (1-lauroyl lysophosphatidylcholine), showed selective improvement over extraction with the common 2-DE detergent CHAPS (3 [(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate). Mixtures of the three detergents showed additive improvements in spot number, density, and resolution. Substantial improvements in the analysis of a brain membrane proteome were observed. CONCLUSION: This study demonstrates that an optimized detergent mix, coupled with rigorous sample handling and electrophoretic protocols, enables simple and effective analysis of membrane proteomes using two-dimensional electrophoresis.