Abstract Purpose To report the clinical features, causative organisms, and visual acuity (VA) outcomes associated with acute-onset endophthalmitis after clear corneal cataract surgery over the past ...two decades. Design Retrospective case series. Methods Clinical and microbiology records were reviewed for 63 eyes of 63 patients who presented to a tertiary referral center between 2006 and 2015 with culture-positive endophthalmitis occurring within 6 weeks of clear corneal cataract surgery. Results The mean time between surgery and diagnosis of endophthalmitis was 8 days (median 6 days). The initial treatment included intravitreal vancomycin and ceftazidime in 59 of 63 (94%) eyes and intravitreal vancomycin and amikacin in 4 of 63 (6%) eyes. Intravitreal dexamethasone was used in 50 of 63 (79%) eyes. A vitreous tap and injection with antibiotics was performed as the initial treatment in 57 of 63 (90%) eyes and pars plana vitrectomy in 6 of 63 (10%) eyes. Coagulase-negative Staphylococcus was isolated in 39 of 63 (62%) eyes, Staphylococcus aureus in 7 of 63 (11%) eyes, and Streptococcus species in 7 of 63 (11%) eyes. A VA of ≥20/40 was achieved in 24 of 63 (38%) eyes. None of the gram-positive isolates were vancomycin resistant. Twenty-four of 49 isolates (49%) were sensitive to cephalothin, cefazolin, and cefuroxime. Sensitivity to fluoroquinolones included 22/52 (42%) to levofloxacin, 20/54 (37%) to ciprofloxacin, 16/47 (34%) to moxifloxacin, and 3/13 (23%) to gatifloxacin. Conclusion Causative organisms and visual outcomes are similar to those reported in the prior decade. In the current study, a number of isolates were resistant to cephalosporins and fluoroquinolones.
Carcinogenic polycyclic aromatic hydrocarbons (PAHs) were disposed directly into the Saguenay River of the St. Lawrence Estuary (SLE) by local aluminum smelters (Quebec, Canada) for 50 years ...(1926–1976). PAHs in the river sediments are likely etiologically related to gastrointestinal epithelial cancers observed in 7% of 156 mature (>19‐year old) adult beluga found dead along the shorelines. Because DNA adduct formation provides a critical link between exposure and cancer induction, and because PAH–DNA adducts are chemically stable, we hypothesized that SLE beluga intestine would contain PAH–DNA adducts. Using an antiserum specific for DNA modified with several carcinogenic PAHs, we stained sections of paraffin‐embedded intestine from 51 SLE beluga (0–63 years), 4 Cook Inlet (CI) Alaska beluga (0–26 years), and 20 beluga (0–46 years) living in Arctic areas (Eastern Beaufort Sea, Eastern Chukchi Sea, Point Lay Alaska) and aquaria, all with low PAH contamination. Stained sections showed nuclear light‐to‐dark pink color indicating the presence of PAH–DNA adducts concentrated in intestinal crypt epithelial lining cells. Scoring of whole tissue sections revealed higher values for the 51 SLE beluga, compared with the 20 Arctic and aquarium beluga (P = 0.003). The H‐scoring system, applied to coded individual photomicrographs, confirmed that SLE beluga and CI beluga had levels of intestinal PAH–DNA adducts significantly higher than Arctic and aquarium beluga (P = 0.003 and 0.02, respectively). Furthermore, high levels of intestinal PAH–DNA adducts in four SLE beluga with gastrointestinal cancers, considered as a group, support a link of causality between PAH exposure and intestinal cancer in SLE beluga. Environ. Mol. Mutagen. 60:29–41, 2019. Published 2018. This article is a U.S. Government work and is in the public domain in the USA.
To report the clinical features organisms and treatment outcomes in patients with endophthalmitis after penetrating keratoplasty (PK).
Retrospective noncomparative case series.
Eleven eyes of 11 ...patients with culture positive endophthalmitis after PK were included. The time to diagnosis of endophthalmitis from last PK was less than 1 week in 3/11 (27%), between 1 and 4 weeks in 3/11 (27%), and greater than one month in 5/11 (46%) (range 2-924 days). The distribution of isolates included gram positive (GP) 9/11 (82%), gram negative (GN) 1/11 (9%), and fungal 1/11 (9%) species, respectively. Of GP bacteria tested, 9/9 (100%) were sensitive to Vancomycin. Of fungal isolates tested, none (0/1) were sensitive to Amphoteracin, Fluconazole, and/or Voriconazole. Among patients with rim culture data available, 1/7 (14%) donor rims were culture positive for
and 6/7 (86%) were culture negative. Patients were treated with primary tap and inject in 10/11 (91%) and primary vitrectomy in 1/11 (9%). VA of ≥5/200 was present in 2/11 (18%) at time of endophthalmitis diagnosis, and was recorded in 6/11 (55%) at last follow-up.
Patients with endophthalmitis after PK presented at variable time points after surgery. Gram positive organisms were the most common isolate. VA outcomes after treatment were generally poor.
Abstract
The northern Gulf of Mexico has a long history of polycyclic aromatic hydrocarbon (PAH) contamination from anthropogenic activities, natural oil seepages, and the 2010 Deepwater Horizon ...explosion and oil spill. The continental shelf of the same area is a known breeding ground for sperm whales (Physeter macrocephalus). To evaluate PAH-DNA damage, a biomarker for potential cancer risk, we compared skin biopsies collected from Gulf of Mexico sperm whales in 2012 with skin biopsies collected from sperm whales in areas of the Pacific Ocean in 1999–2001. All samples were obtained by crossbow and comprised both epidermis and subcutaneous blubber. To evaluate exposure, 7 carcinogenic PAHs were analyzed in lipids extracted from Pacific Ocean sperm whale blubber, pooled by sex, and location. To evaluate PAH-DNA damage, portions of all tissue samples were formalin-fixed, paraffin-embedded, sectioned, and examined for PAH-DNA adducts by immunohistochemistry (IHC) using an antiserum elicited against benzoapyrene-modified DNA, which crossreacts with several high molecular weight carcinogenic PAHs bound to DNA. The IHC showed widespread epidermal nuclear localization of PAH-DNA adducts in the Gulf of Mexico whales (n = 15) but not in the Pacific Ocean whales (n = 4). A standard semiquantitative scoring system revealed significantly higher PAH-DNA adducts in the Gulf of Mexico whales compared to the whales from the Pacific Ocean study (p = .0002).
To report the incidence rates, causative organisms, and visual acuity (VA) outcomes in patients with endophthalmitis associated with intravitreal injection of anti-vascular endothelial growth factor ...inhibitors.
Retrospective case series between 2005 and 2017.
The study included 39 eyes of 39 patients, including 27 (69%) referred and 12 (31%) institutional patients. The use of topical antibiotics after an injection was gradually phased out at the authors' institution, where the preinjection rate of all clinically suspected endophthalmitis was 0.013% (24 of 183,898). The most common isolates were coagulase-negative Staphylococcus and Streptococcus. A VA of 5/200 or better was achieved in 21 of 39 eyes (54%) overall and in two of 15 eyes (13%) infected with Streptococcus.
The rate of post-intravitreal injection endophthalmitis is low. Outcomes were generally poor, and the worst were associated with Streptococcus. Ophthalmic Surg Lasers Imaging Retina. 2018;49:313-319..
We're All on This Spaceship Earth Si, Nancy
HCA healthcare journal of medicine (Print),
2020, Letnik:
1, Številka:
6
Journal Article
Odprti dostop
Description The photo features the geodesic sphere at Epcot, Disney World in Orlando, FL. Inside the dome, there was an iconic ride called "Spaceship Earth", which has since been shut down for ...refurbishment. This photo was taken November 2019, approximately 6 months before it was shut down. Much like how the ride emphasized the progress that human civilization has made in the last several hundred years and hopes to make in years to come, the current pandemic has shown us how far we have come in the medicine and other STEM fields. We hope only to do better and be better for everyone on our little Spaceship Earth.
Abstract
Tamoxifen (TAM) is a selective estrogen receptor modulator used worldwide for adjuvant therapy and chemoprevention of breast cancer. However, women receiving TAM therapy have an increased ...risk of endometrial and myometrial cancer, which may be due to genotoxicity and/or estrogen receptor-related mechanisms. It is now accepted that cancer can be both a genetic and an epigenetic disease, with these components participating at all stages of cancer development. DNA methylation at the 5-position of cytosine silences gene expression. Aberrant global DNA 5-methylcytosine (5-mC) levels may produce critical changes in the expression of genes that regulate cell growth and invasiveness. In order to study the effect of TAM exposure on uterine 5-mC levels, we examined uterine tissues taken from aging Erythrocebus patas (patas) and Macaca fascicularis (macaque) monkeys given oral TAM dosing for 3-4 months. In addition, we evaluated endometrial and myometrial samples from breast cancer survivors, who typically receive adjuvant TAM therapy for 5 years. The percentage of 5-mC in DNA was determined by an ELISA that employed a highly-specific 5-mC antibody. Of 5 female patas, 2 were unexposed and 3 were given oral dosing with 1.7 mg TAM/kg bw/day for 3 months. Of 12 female macaques, 6 were unexposed and 6 were given 1.3 mg TAM/kg bw/day for 4 months. Also, uterine tissue was taken at surgery or autopsy from normal-appearing areas and malignant-appearing areas, from women who received 20 mg TAM/day (n=9) and unexposed women (n=6). The patas monkeys given TAM had significantly increased levels of uterine 5-mC compared to the controls (2.9±0.13% vs. 1.9±0.26%, mean ± SE, respectively, p=0.03). However, the macaques showed no significant differences in uterine 5-mC between unexposed and TAM-exposed animals (0.93%±0.1 vs. 1.07%±0.05, mean ± SE, respectively). In human patients, TAM treatment did not alter the global 5-mC levels in either normal-appearing or malignant-appearing endometrium. However, global 5-mC levels in normal-appearing endometrium from the combined TAM-treated and untreated women (n=6) were significantly lower than those found in malignant-appearing uterine tissue from the combined TAM-treated and untreated (n=9) group (0.33%±0.01 vs. 0.70%±0.09, mean ± SE, respectively, p=0.006). Therefore, changes in uterine global DNA 5-mC are not altered consistently within primate species as a result of long-term TAM exposure, suggesting that 5-mC alterations are not major contributors to TAM-induced endometrial cancer. Continuing studies will evaluate 5-mC levels in the promoter regions of specific genes that are modulated in expression level during TAM therapy.
Citation Format: Elena E. Hernandez Ramon, Nancy Si, Mark J. Cline, Charles E. Wood, Ruth Woodward, Miriam C. Poirier. Comparison of global DNA methylation in uterine tissue from different species of monkeys and humans exposed to tamoxifen. abstract. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5367. doi:10.1158/1538-7445.AM2013-5367
Type I interferon (IFN) is the primary antiviral cytokine establishing a broad and potent antiviral response to protect mammalian cells from virus infection. The functional repertoire of IFN extends ...to innate and adaptive immunity, neoplastic transformation, resistance and cancer immunotherapy. IFN functions are primarily mediated through the Janus kinase (JAK) and signal transducers and activators of transcription (STAT) signaling pathway. Stimulation of the IFN-JAK-STAT signaling cascade drives the expression of hundreds of diverse IFN-stimulated gene (ISG) effectors underlying IFN functions. Similar to other mammalian genes, ISGs are encoded within a chromatin structure in the human genome. ISG expression is activated primarily by the trimeric transcription factor complex, ISG factor 3 (ISGF3), consisting of STAT1, STAT2, and IRF9 proteins. ISGF3 engages target gene promoters and recruits coactivators, Mediator, and RNA polymerase II machinery. To access the native gene template and induce transcription, ISGF3 must engage with chromatinized ISG promoters. ISGF3-associated coactivators with chromatin modifying functions support the notion of a dynamic chromatin regulation in ISG activation; thus, necessitating recruitment of specialized factors to modulate gene accessibility during the IFN response. However, our characterization of the dynamic ISG chromatin environment is insufficient to understand the interplay between ISGF3 and ISG chromatin. In particular, the chromatin architecture at ISG promoters and dynamic alterations following IFN stimulation remain relatively unexplored. To advance our understanding of the dynamic ISG chromatin architecture in relation to ISGF3, I generated genome-wide maps of ISGF3 occupancy to accompany high-resolution nucleosome maps for 20 representative ISGs during steady state and following IFN stimulation. Characterization of the relationship between ISGF3 and ISG promoter nucleosomes led to uncovering a previously unknown role for the histone variant, H2A.Z, in ISG transcription. H2A.Z is present at ISG promoters, but rapidly removed following IFN. H2A.Z eviction from ISG promoter nucleosomes was inversely correlated with ISGF3 recruitment and was found to require the activity of the histone acetyltransferase, GCN5, and the bromodomain protein, BRD2. Reduction of H2A.Z led to enhanced ISGF3 recruitment, increased ISG expression and potentiated antiviral protection, implicating a suppressive role for H2A.Z nucleosomes in the IFN response. Proper gene accessibility is essential to the homeostasis of the IFN response in establishing a protective environment during infection, while preventing adverse effects of a prolonged IFN response. Coordinately controlled H2A.Z removal and incorporation at ISG promoter nucleosomes is an essential component for the activation and repression of ISG effectors for cellular protection and homeostatic integrity.
Background
Distraction-induced enterogenesis, whereby the intestine lengthens with application of linear forces, is an emerging area which may provide a unique treatment for short bowel syndrome. ...With an increase in overall tissue mass, there is an increase in oxygen and nutrient demand. We hypothesized that a neovascularization within the mesentery is necessary to support the growing small bowel.
Methods
A curvilinear hydraulic device was used to induce growth within the small bowel of Yorkshire pigs, and the intestine was harvested after 14 days. High-resolution gross pictures were recorded of the mesentery at implantation and at harvest, and CT imaging of the bowel and mesentery was performed at harvest after dye injection.
Results
After 2 weeks of distraction, an average of 72.5 % (8.7 cm) bowel lengthening was achieved. Gross images of the mesentery between major vessels showed a blossoming of the microvasculature and this was confirmed by CT imaging with 3D reconstruction. Mesenteric sample taken from the distracted segment had a fourfold increase in the volume of microvasculature versus controls.
Conclusion
Enterogenesis results not only in increased bowel length, but also significant increase in the mesenteric microvascularity. Presumably, this sustains the lengthened segment after application of longitudinal forces.
Presently, substantially more children diagnosed with cancer survive than ever before. However, powerful cancer chemotherapy is associated with serious drug-induced organ damage, adversely affecting ...the health and the quality of life of these pediatric cancer survivors. This thesis focuses on a chemotherapeutic agent called ifosfamide, which is commonly used to treat pediatric solid tumours such as rhabdomyosarcoma, neuroblastoma, Wilm's tumour and soft tissue sarcoma. It has been shown to cause serious renal damage substantially more in younger children (less than 3 years of age) than among older children or adults. This often leads to devastating consequences on the long-term health of children. Previous work from our lab has demonstrated that this age-dependent nephrotoxicity is caused by a toxic ifosfamide metabolite produced in the kidney by CYP3A. We found that glutathione depletion enhances renal damage caused by ifosfamide in tubular cells. We sought to develop a therapeutic intervention to protect the kidney from ifosfamide-induced damage. We have selected N-acetylcysteine (NAC) as it has been used extensively and safely to treat acetaminophen overdose in children. Investigating its efficacy, we found that NAC prevents ifosfamide-induced nephrotoxicity in porcine renal proximal tubular cells and in a rat model. The use of NAC in children will be feasible only if it does not interfere with the antitumour effect of ifosfamide. To that end we demonstrated that in relevant cancer cell lines (rhabdomyosarcoma and neuroblastoma), NAC does not affect the cytotoxicity of ifosfamide mustard, the pharmacological active metabolite of ifosfamide. In parallel, we measured the plasma concentrations of NAC in children treated for acetaminophen overdose. The systemic exposure of NAC in these pediatric patients produced significantly higher levels as compared to our successful rat model. This indicates that the regular safe dosing schedule of NAC in these young patients may be used to prevent ifosfamide nephrotoxicity. In summary, NAC improves the risk-benefit ratio of ifosfamide, suggesting a novel therapeutic role in preventing nephrotoxicity in children treated with ifosfamide. Keywords. N-acetylcysteine, ifosfamide, nephrotoxicity, cancer chemotherapy, children, glutathione depletion, systemic exposure.
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