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1.  Randomized Trial of Automated, Electronic Monitoring to Facilitate Early Detection of Sepsis in the Intensive Care Unit 
Critical care medicine  2012;40(7):2096-2101.
To determine whether automated identification with physician notification of the systemic inflammatory response syndrome in medical intensive care unit (MICU) patients expedites early administration of new antibiotics or improvement of other patient outcomes in patients with sepsis.
A prospective, randomized, controlled, single-center study.
MICU of an academic, tertiary-care medical center.
442 consecutive patients admitted over a 4 month period who met modified SIRS criteria in a MICU.
Patients were randomized to monitoring by an electronic “Listening Application” to detect modified (SIRS) criteria vs. usual care. The Listening Application notified physicians in real-time when modified SIRS criteria were detected, but did not provide management recommendations.
Measurements and Main Results
The median time to new antibiotics was similar between the intervention and usual care groups whether comparing among all patients (6.0h vs 6.1h, p=0.95), patients with sepsis (5.3h vs. 5.1h; p=0.90), patients on antibiotics at enrollment (5.2h vs. 7.0h, p= 0.27), or patients not on antibiotics at enrollment (5.2h vs. 5.1h, p= 0.85). The amount of fluid administered following detection of modified SIRS criteria was similar between groups whether comparing all patients or only patients hypotensive at enrollment. Other clinical outcomes including ICU length of stay, hospital length of stay, and mortality were not shown to be different between patients in the intervention and control groups.
Real-time alerts of modified SIRS criteria to physicians in one tertiary care MICU were feasible and safe but did not influence measured therapeutic interventions for sepsis or significantly alter clinical outcomes.
PMCID: PMC4451061  PMID: 22584763
systemic inflammatory response syndrome; sepsis; physiologic monitoring; patient monitoring; infection
2.  Angiolymphoid Hyperplasia with Eosinophilia of the Orbit and Ocular Adnexa: Report of Five Cases 
JAMA ophthalmology  2014;132(5):633-636.
To report the clinical and histopathologic findings of ocular adnexal angiolymphoid hyperplasia with eosinophilia (ALHE), an unusual but often misdiagnosed benign disorder.
The ophthalmologic findings of ALHE with ocular adnexal involvement are variable and include eyelid swelling, ptosis, proptosis, and loss of vision. Imaging studies typically demonstrate a well-circumscribed mass in the orbit. The condition may resemble other diseases involving the orbit and ocular adnexal tissue such as lymphoma, hemangioma, sarcoidosis, and dermoid cyst. The histopathology reveals marked vascular proliferation with an accompanying inflammation composed of numerous eosinophils, lymphocytes, and plasma cells.
ALHE is a rare disease that can affect the ocular adnexal tissue. The clinical presentation is often nonspecific; therefore, histopathologic studies are essential for diagnosis and subsequent management of this benign condition.
PMCID: PMC4431616  PMID: 24676051
4.  Localization of Burkholderia cepacia Complex Bacteria in Cystic Fibrosis Lungs and Interactions with Pseudomonas aeruginosa in Hypoxic Mucus 
Infection and Immunity  2014;82(11):4729-4745.
The localization of Burkholderia cepacia complex (Bcc) bacteria in cystic fibrosis (CF) lungs, alone or during coinfection with Pseudomonas aeruginosa, is poorly understood. We performed immunohistochemistry for Bcc and P. aeruginosa bacteria on 21 coinfected or singly infected CF lungs obtained at transplantation or autopsy. Parallel in vitro experiments examined the growth of two Bcc species, Burkholderia cenocepacia and Burkholderia multivorans, in environments similar to those occupied by P. aeruginosa in the CF lung. Bcc bacteria were predominantly identified in the CF lung as single cells or small clusters within phagocytes and mucus but not as “biofilm-like structures.” In contrast, P. aeruginosa was identified in biofilm-like masses, but densities appeared to be reduced during coinfection with Bcc bacteria. Based on chemical analyses of CF and non-CF respiratory secretions, a test medium was defined to study Bcc growth and interactions with P. aeruginosa in an environment mimicking the CF lung. When test medium was supplemented with alternative electron acceptors under anaerobic conditions, B. cenocepacia and B. multivorans used fermentation rather than anaerobic respiration to gain energy, consistent with the identification of fermentation products by high-performance liquid chromatography (HPLC). Both Bcc species also expressed mucinases that produced carbon sources from mucins for growth. In the presence of P. aeruginosa in vitro, both Bcc species grew anaerobically but not aerobically. We propose that Bcc bacteria (i) invade a P. aeruginosa-infected CF lung when the airway lumen is anaerobic, (ii) inhibit P. aeruginosa biofilm-like growth, and (iii) expand the host bacterial niche from mucus to also include macrophages.
PMCID: PMC4249344  PMID: 25156735
5.  The Occurrence and Proposed Significance of Schnabel Cavernous Degeneration in Uveal Melanoma 
JAMA ophthalmology  2014;132(5):600-604.
Schnabel cavernous degeneration (SCD) has been observed in eyes with uveal melanoma (UM), but, to our knowledge, a definitive study establishing the association between SCD and UM has not been conducted.
To explore an association between SCD and UM.
A historical cohort analysis was performed using histologic slides and related clinical records of cases from the Collaborative Ocular Melanoma Study and Eye Pathology Laboratory at the University of Wisconsin, including 1985 UM eyes, 517 eye bank eyes, and 155 enucleated glaucomatous eyes.
The prevalence of SCD was calculated and compared between each group; subgroup analysis was also conducted of eyes with and without SCD for the prevalence of glaucoma.
Schnabel cavernous degeneration was seen in 17 (0.9%) UM eyes, 9 (1.7%) eye bank eyes, and 2 (1.3%) enucleated glaucomatous eyes. No difference was detected between the prevalence of SCD in UM eyes and eye bank eyes (odds ratio [OR], 0.49; 95% CI, 0.22–1.10) or enucleated glaucomatous eyes (OR, 0.66; 95% CI, 0.15–2.89). Subgroup analysis, performed on 421 UM eyes, provided sufficient clinical information to definitively establish the presence or absence of glaucoma. Of the 95 (22.6%) eyes with glaucoma, 11 (11.6%) revealed histopathologic evidence of SCD. Compared with enucleated end-stage glaucoma eyes, this represents a 10-fold increase in SCD in UM eyes with glaucoma (OR, 10.10; 95% CI, 2.17–46.26). The prevalence of glaucoma in UM eyes with SCD, however, was respectively 7-and 15-fold higher than the prevalence of glaucoma in SCD-negative UM eyes (OR, 6.98; 95% CI, 2.51–19.43) and SCD-positive eye bank eyes (OR, 14.67; 95% CI, 1.46–146.97).
Although an association between SCD and UM was not confirmed, subgroup analysis did reveal an increased incidence of SCD in eyes with both UM and glaucoma. This suggests that the occurrence of glaucoma may increase the risk of SCD in eyes with UM.
PMCID: PMC4273558  PMID: 24652500
6.  Multiple pigmented basal cell carcinomas of the eyelids 
JAMA ophthalmology  2013;131(11):1412.
PMCID: PMC4017670  PMID: 24232081
7.  Shaken Adult Syndrome 
JAMA ophthalmology  2013;131(11):1468-1470.
To establish that the intracranial and ophthalmologic findings present in victims of abusive head trauma can also be seen in shaken adults.
We report 2 cases of shaken adults with intracranial and ophthalmologic findings that resulted from repetitive acceleration-deceleration injury. These findings included intracranial hemorrhages, hemorrhages involving the optic nerve sheath, intraretinal and subretinal hemorrhages, and macular folds.
The intracranial and ophthalmologic findings that are characteristic of abusive head trauma—subdural hemorrhages, optic nerve sheath hemorrhages, and retinal hemorrhages—are generally thought to be limited to young children and infants. Adults may also be victims of shaking abuse, and an ophthalmic examination may be beneficial when shaking is suspected.
PMCID: PMC4049539  PMID: 24077385
8.  Leiomyoma of the Lower Eyelid 
JAMA ophthalmology  2013;131(8):1085.
PMCID: PMC4017663  PMID: 23929515
9.  Hydration with Saline Decreases Toxicity of Mice Injected With Calcitriol in Preclinical Studies 
The effectiveness of saline injection in reducing the toxicity profile of calcitriol when coadministered in mice was evaluated. Mortality was used as an end point to study the toxic effects of calcitriol; the relative risk of mortality in mice injected with saline was evaluated from our previously published animal experiments. We discovered that coadministration with 0.25 mL normal saline solution injected intraperitoneally is associated with a lower mortality rate than calcitriol given alone. The estimated relative risk of mortality was 0.0789 (95% confidence interval, 0.0051–1.22; z = 1.82; P = 0.070) when saline is administered with calcitriol compared to calcitriol alone. There was a reduction in serum calcium levels in mice that received saline (11.4 ± 0.15 mg/dL) compared to mice that did not receive saline (12.42 ± 1.61 mg/dL). Hydration with saline seems to reduce mortality and toxicity in mice receiving calcitriol. Given the decrease in mortality rates, intraperitoneal injections of saline should be considered in studies involving mice receiving injections of calcitriol.
PMCID: PMC4016973  PMID: 24266410
calcitriol; saline hydration; toxicity
10.  Lichen Simplex Chronicus of the Conjunctiva 
JAMA ophthalmology  2013;131(6):816-818.
PMCID: PMC3943845  PMID: 23559160
Lichen simplex chronicus; psychogenic excoriation; conjunctival metaplasia
11.  The Postoperative Visual Acuity in Fuchs’ Dystrophy Patients Undergoing DSAEK Does Not Correlate With the Severity of Histologic Changes 
Archives of ophthalmology  2012;130(1):33-38.
To investigate a correlation between the severity of histologic changes of Descemet’s membrane in patients with Fuchs’ endothelial dystrophy and the postoperative best-corrected visual acuity following Descemet’s membrane stripping endothelial keratoplasty (DSAEK).
In a retrospective study design, a histologic grading system was created based on common characteristics observed histologically among 92 DSAEK specimens sent to the UW Eye Pathology Laboratory with a clinical diagnosis of Fuchs’ dystrophy from three separate corneal surgeons. Cases were graded as mild, moderate, or severe based on four characteristics including guttae dispersion, presence of a laminated Descemet’s membrane, presence of embedded guttae, and density of guttae. Regression models were built to study the relationship between preoperative visual acuity, histological findings and best corrected visual acuity six months, 1 year, and 2 years after DSAEK surgery.
No correlation was found between the severity of histologic changes of Descemet’s membrane and preoperative visual acuity. A correlation exists, however, between the preoperative visual acuity and final visual acuity. Cases with a laminated Descemet’s membrane but no embedded guttae (n=8) appear less responsive to DSAEK surgery. Otherwise, the severity of histologic changes of Descemet’s membrane observed in patients with Fuchs’ corneal dystrophy following DSAEK did not show a statistically significant correlation with final visual acuity.
Our analysis fails to show an inverse relationship between the severity of histologic changes of Descemet’s membrane and the best-corrected visual acuity of ≥ 20/40 following DSAEK for Fuchs’ endothelial dystrophy. However, in a subset of Fuchs’ dystrophy patients, those who develop a laminated Descemet’s membrane without embedded guttae, the visual recovery following DSAEK is less than expected. The laminated architecture of Descemet’s membrane without embedded guttae may facilitate the separation between the layers of Descemet’s and, thus, incomplete removal of the recipient’s Descemet’s membrane during DSAEK, which may then limit the postoperative visual outcome.
PMCID: PMC3660984  PMID: 22232473
12.  Ensuring Appropriate Expert Testimony for Cases Involving the “Shaken Baby” 
For the past 50 years, the “shaken baby” syndrome (SBS) has been one of the many terms used to describe a form of abusive head trauma in children. The term now preferred is pediatric abusive head trauma (AHT), which is defined as “an injury to the skull or intracranial contents of an infant or young child (less than five years of age) due to inflicted blunt impact and/or violent shaking.”1, 2 This new term reflects the fundamental construct that certain forms of head trauma are intentionally inflicted. The incidence is estimated to be 20 to 30 cases per 100,000 children under one year of age with a case fatality rate exceeding 20% and significant disability for about two-thirds of the survivors. 1 In addition, AHT results in major healthcare costs for the survivors. (see Libby AM, Sills MR, Thurston NK, Orton HD. Costs of childhood physical abuse: comparing inflicted and unintentional traumatic brain injuries.
PMCID: PMC3660987  PMID: 22760288
13.  Anaerobic oxidation of methane at different temperature regimes in Guaymas Basin hydrothermal sediments 
The ISME Journal  2011;6(5):1018-1031.
Anaerobic oxidation of methane (AOM) was investigated in hydrothermal sediments of Guaymas Basin based on δ13C signatures of CH4, dissolved inorganic carbon and porewater concentration profiles of CH4 and sulfate. Cool, warm and hot in-situ temperature regimes (15–20 °C, 30–35 °C and 70–95 °C) were selected from hydrothermal locations in Guaymas Basin to compare AOM geochemistry and 16S ribosomal RNA (rRNA), mcrA and dsrAB genes of the microbial communities. 16S rRNA gene clone libraries from the cool and hot AOM cores yielded similar archaeal types such as Miscellaneous Crenarchaeotal Group, Thermoproteales and anaerobic methane-oxidizing archaea (ANME)-1; some of the ANME-1 archaea formed a separate 16S rRNA lineage that at present seems to be limited to Guaymas Basin. Congruent results were obtained by mcrA gene analysis. The warm AOM core, chemically distinct by lower porewater sulfide concentrations, hosted a different archaeal community dominated by the two deep subsurface archaeal lineages Marine Benthic Group D and Marine Benthic Group B, and by members of the Methanosarcinales including ANME-2 archaea. This distinct composition of the methane-cycling archaeal community in the warm AOM core was confirmed by mcrA gene analysis. Functional genes of sulfate-reducing bacteria and archaea, dsrAB, showed more overlap between all cores, regardless of the core temperature. 16S rRNA gene clone libraries with Euryarchaeota-specific primers detected members of the Archaeoglobus clade in the cool and hot cores. A V6-tag high-throughput sequencing survey generally supported the clone library results while providing high-resolution detail on archaeal and bacterial community structure. These results indicate that AOM and the responsible archaeal communities persist over a wide temperature range.
PMCID: PMC3329104  PMID: 22094346
anaerobic methane oxidation; Guaymas Basin; hydrothermal vents; thermophiles
14.  A Synergetic Screening Approach with Companion Effector for Combination Therapy: Application to Retinoblastoma 
PLoS ONE  2013;8(3):e59156.
For many cancers, the lack of potency and the toxicity of current drugs limits the dose achievable in patients and the efficacy of treatment. Among them, retinoblastoma is a rare cancer of the eye for which better chemotherapeutic options are needed. Combination therapy is a compelling approach to enhance the efficacy of current treatment, however clinical trials to test rationally designed combinations of approved drugs are slow and expensive, and limited by our lack of in-depth knowledge of drug specificity. Since many patients already turn to nutraceuticals in hopes of improving their condition, we hypothesized that certain approved drugs could potentially synergize with widely consumed supplements. Following this hypothesis, we devised an alternative screening strategy aimed at taking advantage of a bait compound such as a nutraceutical with potential therapeutic benefits but low potency, by screening chemical libraries for approved drugs that synergize with this companion effector. As a proof of concept, we sought to identify approved drugs with synergetic therapeutic effects toward retinoblastoma cells in combination with the antioxidant resveratrol, popular as a supplement. We systematically tested FDA-approved drugs and known bioactives seeking to identify such pairs, which led to uncovering only a few additive combinations; but to our surprise, we identified a class of anticancer drugs widely used in the clinic whose therapeutic effect is antagonized with resveratrol. Our observations could explain in part why some patients do not respond well to treatment. Our results validate this alternative approach, and we expect that our companion effector strategy could significantly impact both drug discovery and the nutraceutical industry.
PMCID: PMC3602587  PMID: 23527118
15.  Suppression of Thrombospondin-1 Expression during Uveal Melanoma Progression and its Utilization as Potential Therapeutic 
Archives of Ophthalmology  2012;130(3):336-341.
To determine whether expression of thrombospondin-1 (TSP1), an endogenous inhibitor of angiogenesis, is down-regulated during progression of uveal melanoma and if administration of TSP1 and/or its antiangiogenic peptides attenuate tumor growth.
Tyr-tag transgenic mice were used for evaluation of TSP1 expression during tumor progression using immunohistological methods. The therapeutic potential of TSP1 on tumor progression was evaluated by either crossing Tyr-tag mice to a line of transgenic mice over expressing TSP1 in the eye (Tyr-tag;TSP1), or by administration of TSP1 mimetic peptide with known antiangiogenic, antitumor activity. Tumor areas were measured in histological sections using Optima software.
Tyr-tag tumors from 3-week-old mice showed significant TSP1 expression which was dramatically down-regulated in tumors from 12-week-old mice. Furthermore, the development and progression of tumor was significantly delayed in Tyr-tag;TSP1 transgenic mice or Tyr-tag mice receiving TSP1 mimetic peptides (100 mg/Kg/day).
Conclusions and Clinical relevance
TSP1 expression was decreased with the angiogenic switch during progression of uveal melanoma. TSP1 and/or its antiangiogenic peptides were effective in attenuation of tumor growth. Therefore, modulation of TSP1 expression and/or activity may be beneficial in treatment of uveal melanoma.
PMCID: PMC3381901  PMID: 22411663
16.  Resveratrol Metabolites Do Not Elicit Early Pro-apoptotic Mechanisms in Neuroblastoma Cells 
Resveratrol, a non-toxic polyphenol, has been shown to inhibit tumor growth in a xenograft mouse model of neuroblasoma. However, resveratrol is rapidly metabolized, mainly to its glucuronidated and sulfated derivatives. In this study we demonstrate that resveratrol alone, and not the glucuronidated or sulfated metabolites, is taken up into tumor cells, induces a rise in [Ca2+]i, and ultimately leads to a decrease in tumor cell viability. A new water-soluble resveratrol formulation was delivered directly at the site of the tumor in a neuroblastoma mouse model. The amount of unmodified resveratrol associated with the tumor increased more than 1000-fold. The increase of unmodified resveratrol associated with the tumor resulted in tumor regression. The number of residual tumor cells that remained viable also decreased as the ratio of the metabolites relative to unmodified resveratrol declined.
PMCID: PMC3099401  PMID: 21401048
Resveratrol; Neuroblastoma; Calcium Signaling; Bioaviailability
17.  The Lupus Family Registry and Repository 
Rheumatology (Oxford, England)  2010;50(1):47-59.
The Lupus Family Registry and Repository (LFRR) was established with the goal of assembling and distributing materials and data from families with one or more living members diagnosed with SLE, in order to address SLE genetics. In the present article, we describe the problems and solutions of the registry design and biometric data gathering; the protocols implemented to guarantee data quality and protection of participant privacy and consent; and the establishment of a local and international network of collaborators. At the same time, we illustrate how the LFRR has enabled progress in lupus genetics research, answering old scientific questions while laying out new challenges in the elucidation of the biologic mechanisms that underlie disease pathogenesis. Trained staff ascertain SLE cases, unaffected family members and population-based controls, proceeding in compliance with the relevant laws and standards; participant consent and privacy are central to the LFRR’s effort. Data, DNA, serum, plasma, peripheral blood and transformed B-cell lines are collected and stored, and subject to strict quality control and safety measures. Coded data and materials derived from the registry are available for approved scientific users. The LFRR has contributed to the discovery of most of the 37 genetic associations now known to contribute to lupus through 104 publications. The LFRR contains 2618 lupus cases from 1954 pedigrees that are being studied by 76 approved users and their collaborators. The registry includes difficult to obtain populations, such as multiplex pedigrees, minority patients and affected males, and constitutes the largest collection of lupus pedigrees in the world. The LFRR is a useful resource for the discovery and characterization of genetic associations in SLE.
PMCID: PMC3307518  PMID: 20864496
Systemic lupus erythematosus; Registry; Repository; Autoimmune diseases; Genetics; Heritability; Genome-wide association studies; Linkage analysis; Minorities; Women
18.  Hyperuricemia and Coronary Heart Disease: A Systematic Review and Meta-Analysis 
Arthritis care & research  2010;62(2):170-180.
The role of serum uric acid as an independent risk factor for cardiovascular disease remains unclear although hyperuricemia is associated with cardiovascular disease such as coronary heart disease (CHD), stroke and hypertension.
A systematic review and meta-analysis using a random-effects model was conducted to determine the risk of CHD associated with hyperuricemia in adults. Studies of hyperuricemia and CHD were identified by searching major electronic databases using the Medical Subject Headings and keywords without language restriction (through February 2009). Only prospective cohort studies were included if they had data on CHD incidences or mortalities related to serum uric acid levels in adults.
26 eligible studies of 402,997 adults were identified. Hyperuricemia was associated with an increased risk of CHD incidence (unadjusted risk ratio (RR) 1.34; 95% confidence interval (CI) 1.19-1.49) and mortality (unadjusted RR 1.46; 95% CI 1.20-1.73). When adjusted for potential confounding, the pooled RR was 1.09 (95% CI: 1.03-1.16) for CHD incidence and 1.16 (95% CI: 1.01-1.30) for mortality. For each increase of 1 mg/dl in uric acid level, the pooled multivariate RR for CHD mortality was 1.12 (95% CI: 1.05-1.19). Subgroup analyses showed no significant association between hyperuricemia and CHD incidence/mortality in men, but an increased risk for CHD mortality in women (RR 1.67; 95% CI: 1.30-2.04).
Hyperuricemia may marginally increase the risk of CHD events, independently of traditional CHD risk factors. A more pronounced increased risk for CHD mortality in women should be investigated in future research.
PMCID: PMC3156692  PMID: 20191515
hyperuricemia; coronary heart disease; meta-analysis
19.  PRL-3, a Metastasis Associated Tyrosine Phosphatase, Is Involved in FLT3-ITD Signaling and Implicated in Anti-AML Therapy 
PLoS ONE  2011;6(5):e19798.
Combination with other small molecule drugs represents a promising strategy to improve therapeutic efficacy of FLT3 inhibitors in the clinic. We demonstrated that combining ABT-869, a FLT3 inhibitor, with SAHA, a HDAC inhibitor, led to synergistic killing of the AML cells with FLT3 mutations and suppression of colony formation. We identified a core gene signature that is uniquely induced by the combination treatment in 2 different leukemia cell lines. Among these, we showed that downregulation of PTP4A3 (PRL-3) played a role in this synergism. PRL-3 is downstream of FLT3 signaling and ectopic expression of PRL-3 conferred therapeutic resistance through upregulation of STAT (signal transducers and activators of transcription) pathway activity and anti-apoptotic Mcl-1 protein. PRL-3 interacts with HDAC4 and SAHA downregulates PRL-3 via a proteasome dependent pathway. In addition, PRL-3 protein was identified in 47% of AML cases, but was absent in myeloid cells in normal bone marrows. Our results suggest such combination therapies may significantly improve the therapeutic efficacy of FLT3 inhibitors. PRL-3 plays a potential pathological role in AML and it might be a useful therapeutic target in AML, and warrant clinical investigation.
PMCID: PMC3093398  PMID: 21589872
21.  Development of Choroidal Neovascularization in rats with Advanced Intense Cyclic Light-induced Retinal Degeneration 
Archives of ophthalmology  2010;128(2):212.
To study the progressive changes of intense cyclic light-induced retinal degeneration and determine whether it results in choroidal neovascularization (CNV).
Albino rats were exposed to 12 h of 3000 lux cyclic light for 1, 3, or 6 months. Prior to euthanization, fundus examination, fundus photographs, fluorescein and indocyanine green angiography, and Optical Coherence Tomography (OCT) evaluations were performed. Light exposed animals were euthanized after 1, 3, or 6 months for histopathological evaluation. Retinas were examined for the presence of 4-hydroxy-2-nonenal (HNE) and nitrotyrosine modified proteins by immunofluorescence staining.
Chronic intense cyclic light exposure resulted in retinal degeneration with loss of the outer segments of photoreceptors and approximately two-thirds of the outer nuclear layer (ONL) and development of sub-retinal pigment epithelium (RPE) neovascularization after 1 month. Almost the entire ONL was absent with the presence of CNV, which penetrated Bruch’s membrane and extended into the outer retina after 3 months. Absence of the ONL, multiple foci of CNV, RPE fibrous metaplasia, and connective tissue bands containing blood vessels extending into the retina were observed after 6 months. All intense light exposed animals showed an increased presence of HNE and nitrotyrosine staining. OCT and angiographic studies confirmed retinal thinning and leakiness of the newly fromed blood vessels.
Our results suggest albino rats develop progressive stages of retinal degeneration and CNV after chronic intense cyclic light exposure allowing the detailed study of the pathogenesis and treatment of age-related macular degeneration.
PMCID: PMC2820133  PMID: 20142545
22.  Sebaceous Cell Carcinoma of the Eyelid: A Rapidly Enlarging Lesion with Massive Xanthogranulomatous Inflammation 
A 76-year-old man presented atypically with 4 week history of a rapidly enlarging ulcerated nodular lesion of the left upper eyelid that was found to be sebaceous cell carcinoma. Further investigation showed no metastasic disease, and Mohs surgery was performed to resect the tumor. Histopathologic analysis showed features diagnostic of sebaceous cell carcinoma. However, most of the mass consisted of xanthomatous granulomatous inflammatory reaction vastly out of proportion with the tumor burden. The patient was spared from orbital exenteration, and no evidence of recurrence was present 6 months after resection.
PMCID: PMC2994249  PMID: 20489549
23.  Use of Combination Therapy with Cisplatin and Calcitriol in the Treatment of Y-79 Human Retinoblastoma Xenograft Model 
The British journal of ophthalmology  2009;93(8):1105-1108.
Retinoblastoma is the most common primary malignant intraocular neoplasm of childhood. The poor outcomes of patients with metastatic retinoblastoma have encouraged the search for new therapies. In the current study, the efficacy of combination therapy with calcitriol and cisplatin in athymic mice with subcutaneous Y-79 human retinoblastoma tumors was assessed.
60 athymic mice were subcutaneously injected with human Y79 retinoblastoma cells. Animals were randomized into four groups: group 1 - 50 μg of cisplatin; group 2 - 0.05 μg of calcitriol; group 3 - 0.05μg of calcitriol and 50 μg of cisplatin; group 4 - control. The cisplatin was administered once a week, and the calcitriol was given 5 times a week.
There was a significant inhibition of tumor growth in animals treated with the combination therapy of calcitriol and cisplatin as compared to controls and cisplatin alone (p=0.0001 and p=0.0041 respectively). In terms of toxicity, serum calcium levels were increased, but there was no mortality and minimal nephrotoxicity in any of the groups.
The present study shows that cisplatin given in combination with calcitriol may be a viable multidrug therapy option in the treatment of high risk retinoblastoma.
PMCID: PMC2991058  PMID: 19336429
Calcitriol; Cisplatin; Retinoblastoma; Xenograft model
24.  A Study of Histopathological Features of Latanoprost-Treated Irides With or Without Darkening Compared With Non–Latanoprost-Treated Irides 
Archives of ophthalmology  2008;126(5):626-631.
To study the histopathological features of latanoprost-treated irides with or without darkening, compared with non–latanoprost-treated irides.
Iridectomy specimens and patient history forms were independently examined by 3 ophthalmic pathologists in a masked fashion. Specimens were evaluated for premalignant changes and for differences in level of pigmentation and degrees of cellularity, inflammation, and vascular abnormalities.
The specimens consisted of 22 latanoprost-treated darkened irides, 35 latanoprost-treated irides without darkening, and 35 non–latanoprost-treated irides. There was a statistically significant decrease in the number of nuclear invaginations and prominent nucleoli in latanoprost-treated darkened irides compared with the other 2 groups (P=.004 and P=.005, respectively). The average thickness and pigmentation of the anterior border layer was greater in the latanoprost-treated darkened irides than in the other 2 groups (P=.03 and P=.02, respectively). The latanoprost-treated darkened irides had increased pigmentation of the stroma (P<.001), stromal fibroblasts (P<.001), melanocytes (P=.005), vascular endothelium (P=.02), and adventitia (P<.001) relative to the other 2 groups.
There is no histopathological evidence of premalignant changes in latanoprost-treated darkened irides. The latanoprost-induced iris color changes are due to a thickening of the anterior border layer and an increased amount of melanin in the anterior border layer and within the stromal melanocytes.
PMCID: PMC2988227  PMID: 18474771
25.  Hyperuricemia and Risk of Stroke: A Systematic Review and Meta-analysis 
Arthritis and rheumatism  2009;61(7):885-892.
Hyperuricemia is hypothesized to be a risk factor for stroke and other cardiovascular disease, but to date results from observational studies are conflicting.
We conducted a systematic review and meta-analysis to assess the association between hyperuricemia and risk of stroke incidence and mortality. Studies were identified by searching major electronic databases using the Medical Subject Headings and keywords without restriction in languages. Only prospective cohort studies were included if they had data on stroke incidences or mortalities related to serum uric acid levels in adults. Pooled risk ratios (RRs) for the association of stroke incidence and mortality with serum uric acid levels were calculated.
A total of 16 studies including 238,449 adults were eligible and abstracted. Hyperuricemia was associated with a significantly higher risk of both stroke incidence [N=6 studies, RR 1.41, 95% confidence interval (CI): 1.05–1.76] and mortality [N=6 studies, RR 1.36, 95% CI: 1.03–1.69] in our meta-analyses of unadjusted study estimates. Subgroup analyses of studies adjusting for known risk factors such as age, hypertension, diabetes, and cholesterol still showed that hyperuricemia was significantly associated with both stroke incidence [N=4 studies, RR 1.47, 95% CI: 1.19–1.76] and mortality [N=6 studies, RR 1.26, 95% CI: 1.12–1.39]. The pooled estimate of multivariate RRs did not differ much by gender.
Our study suggests that hyperuricemia may modestly increase the risks of both stroke incidence and mortality. Future research is needed to determine whether lowering uric acid level has any beneficial effects on stroke.
PMCID: PMC2714267  PMID: 19565556
hyperuricemia; stroke; systematic review; meta-analysis

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