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.
CONCLUSIONS AND RELEVANCE
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.
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.
calcitriol; saline hydration; toxicity
Lichen simplex chronicus; psychogenic excoriation; conjunctival metaplasia
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.
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.
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.
anaerobic methane oxidation; Guaymas Basin; hydrothermal vents; thermophiles
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.
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.
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.
Resveratrol; Neuroblastoma; Calcium Signaling; Bioaviailability
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.
Systemic lupus erythematosus; Registry; Repository; Autoimmune diseases; Genetics; Heritability; Genome-wide association studies; Linkage analysis; Minorities; Women
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.
hyperuricemia; coronary heart disease; meta-analysis
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.
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.
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.
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.
Calcitriol; Cisplatin; Retinoblastoma; Xenograft model
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.
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.
hyperuricemia; stroke; systematic review; meta-analysis
Subsurface fluids from deep-sea hydrocarbon seeps undergo methane- and sulfur-cycling microbial transformations near the sediment surface. Hydrocarbon seep habitats are naturally patchy, with a mosaic of active seep sediments and non-seep sediments. Microbial community shifts and changing activity patterns on small spatial scales from seep to non-seep sediment remain to be examined in a comprehensive habitat study.
We conducted a transect of biogeochemical measurements and gene expression related to methane- and sulfur-cycling at different sediment depths across a broad Beggiatoa spp. mat at Mississippi Canyon 118 (MC118) in the Gulf of Mexico. High process rates within the mat (∼400 cm and ∼10 cm from the mat's edge) contrasted with sharply diminished activity at ∼50 cm outside the mat, as shown by sulfate and methane concentration profiles, radiotracer rates of sulfate reduction and methane oxidation, and stable carbon isotopes. Likewise, 16S ribosomal rRNA, dsrAB (dissimilatory sulfite reductase) and mcrA (methyl coenzyme M reductase) mRNA transcripts of sulfate-reducing bacteria (Desulfobacteraceae and Desulfobulbaceae) and methane-cycling archaea (ANME-1 and ANME-2) were prevalent at the sediment surface under the mat and at its edge. Outside the mat at the surface, 16S rRNA sequences indicated mostly aerobes commonly found in seawater. The seep-related communities persisted at 12–20 cm depth inside and outside the mat. 16S rRNA transcripts and V6-tags reveal that bacterial and archaeal diversity underneath the mat are similar to each other, in contrast to oxic or microoxic habitats that have higher bacterial diversity.
The visual patchiness of microbial mats reflects sharp discontinuities in microbial community structure and activity over sub-meter spatial scales; these discontinuities have to be taken into account in geochemical and microbiological inventories of seep environments. In contrast, 12–20 cm deep in the sediments microbial communities performing methane-cycling and sulfate reduction persist at lower metabolic rates regardless of mat cover, and may increase activity rapidly when subsurface flow changes.
Tyrosine Kinase Inhibitors (TKI) have significantly changed the landscape of current cancer therapy. Understanding of mechanisms of aberrant TK signaling and strategies to inhibit TKs in cancer, further promote the development of novel agents.
ABT-869, a novel ATP-competitive receptor tyrosine kinase inhibitor is a potent inhibitor of members of the vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) receptor families. ABT-869 showed potent antiproliferative and apoptotic properties in vitro and in animal cancer xenograft models using tumor cell lines that were "addicted" to signaling of kinases targeted by ABT-869. When given together with chemotherapy or mTOR inhibitors, ABT-869 showed at least additive therapeutic effects. The phase I trial for ABT-869 was recently completed and it demonstrated respectable efficacy in solid tumors including lung and hepatocellular carcinoma with manageable side effects. Tumor cavitation and reduction of contrast enhancement after ABT-869 treatment supported the antiangiogenic activity. The correlative laboratory studies conducted with the trial also highlight potential biomarkers for future patient selection and treatment outcome.
Parallel to the clinical development, in vitro studies on ABT-869 resistance phenotype identified novel resistance mechanism that may be applicable to other TKIs. The future therapeutic roles of ABT-869 are currently been tested in phase II trials.
To test the efficacy of resveratrol, a nontoxic plant product, in the treatment of uveal melanoma.
The effect of oral administration and peritumor injection of resveratrol was tested on tumor growth in two animal models of uveal melanoma. The mechanism of resveratrol action on uveal melanoma cells was studied in vitro in a cell-viability assay: with JC-1 dye, to measure mitochondrial membrane potential; by Western blot analysis, to analyze the cellular redistribution of cytochrome c and Smac/diablo; and in a fluorescence assay with specific substrates, to measure activation of different caspases.
Resveratrol treatment inhibited tumor growth in animal models of uveal melanoma. Since oral administration resulted in relatively low bioavailability of resveratrol, the effect of increased local levels was tested by peritumor injection of the drug. This method resulted in tumor cell death and tumor regression. In vitro experiments with multiple uveal melanoma cell lines demonstrate that resveratrol causes a decrease in cell viability, resulting at least in part from an increase in apoptosis through a mitochondrial pathway. An early event in drug action is the direct targeting of mitochondria by resveratrol, which leads to a decrease in mitochondrial membrane potential and the eventual activation of caspase-3.
These data suggest that resveratrol can inhibit tumor growth and can induce apoptosis via the intrinsic mitochondrial pathway and that by further increasing bioavailability of resveratrol the potency of the drug can be increased, leading to tumor regression. The nontoxic nature of the drug at levels needed for therapy make resveratrol an attractive candidate for the treatment of uveal melanoma.