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The computed tomographic and angiographic findings of an isolated external iliac artery aneurysm secondary to cystic medial necrosis in a patient without Marfan's disease are demonstrated. A review of the differential diagnosis and surgical treatment of iliac artery aneurysms is presented. The dramatic surgical sequelae in this patient underscore the importance of preoperative consideration of this rare diagnosis. [ABSTRACT FROM AUTHOR] more...

Background: Sentinel lymphadenectomy is the standard of care for evaluation of the axilla in breast cancer. Not infrequently, despite a clinically negative axilla, axillary nodes are found and removed that are only palpable intraoperatively at the time of sentinel lymph node biopsy. There is limited data suggesting that their resection is beneficial, and there is some controversy over whether these non-hot, non-blue nodes should also be called "sentinel nodes" (SNs). Methods: A retrospective chart review was conducted of breast cancer patients who underwent sentinel lymph node biopsy from 2007 to 2011 at a single institution. Patients were only included if they had SNs removed (defined as blue and/or radioactive nodes), as well as additional non-sentinel nodes that were only palpable intraoperatively (pNSNs) and not part of an axillary dissection (ALND). Pathology of both SNs and pNSNs were reviewed. Histologic nodal evaluation was performed by H&E alone. Results: From 2007 to 2011, a total of 59 patients had both SNs and pNSNs removed. Fifty-five patients (93.2%) were female and the average age was 55 years old. Fifty-two patients (88.1 %) had invasive ductal carcinoma while 7 had lobular carcinoma (11.9%). Average tumor size was 2.0 cm. Among the 59 patients, a total of 109 SNs (mean 1.8, median 1, range 1-6) and 202 pNSNs (mean 3.4, median 2, range 1-30) were removed at the same surgery. Twenty patients (33.9%) had metastases in either the SNs and/or pNSNs with 16 (80.0%) of these having metastases in the SNs alone. Sixteen patients proceeded to an ALND. There were 4 patients (6.8%, 95% CI 1.9-16.5%) who had SNs negative for tumor but pNSNs positive for tumor, and 4 (6.8%, 95% CI 1.9-16.5%) separate patients who had extracapsular extension (ECE) in their pNSNs but no ECE in the SNs. The pNSNs thus provided information altering operative treatment by American College of Surgeons Oncology Group (ACOSOG) Z0011 trial criteria in 8 patients (13.6%). Two patients (3.4%, 95% CI 0.4-11.7%) had ECE present in ALND nodes, but not present in either their SNs or pNSNs. Conclusion: pNSNs provide information that changes the surgical plan by ACOSOG Z0011 criteria in 14% of cases. Whether their removal changes patient outcomes remains unclear, especially as SNs and pNSNs may, together, be falsely-negative for ECE present within the axilla. While we recommend their removal at this time based upon the added information they provide, further study is required to determine whether the changes resulting from pNSN dissection (i.e. need for ALND) provide any outcome benefit in this era of effective systemic therapy. [ABSTRACT FROM AUTHOR] more...

Loss-of-function mutations in the ribonuclease angiogenin are associated with amyotrophic lateral sclerosis. Angiogenin has been shown to cleave transfer RNAs during stress to produce 'transfer-derived stress-induced RNAs'. Stress-induced tRNA cleavage is preserved from single-celled organisms to humans indicating it represents part of a highly conserved stress response. However, to date, the role of tRNA cleavage in amyotrophic lateral sclerosis remains to be fully elucidated. To this end, we performed small RNA sequencing on a human astrocytoma cell line to identify the complete repertoire of tRNA fragments generated by angiogenin. We found that only a specific subset of tRNAs is cleaved by angiogenin and identified 5'ValCAC transfer-derived stress-induced RNA to be secreted from neural cells. 5'ValCAC was quantified in spinal cord and serum from SOD1 G93A amyotrophic lateral sclerosis mouse models where we found it to be significantly elevated at symptom onset correlating with increased angiogenin expression, imbalanced protein translation initiation factors and slower disease progression. In amyotrophic lateral sclerosis patient serum samples, we found 5'ValCAC to be significantly higher in patients with slow disease progression, and interestingly, we find 5'ValCAC to hold prognostic value for amyotrophic lateral sclerosis patients. Here, we report that angiogenin cleaves a specific subset of tRNAs and provide evidence for 5'ValCAC as a prognostic biomarker in amyotrophic lateral sclerosis. We propose that increased serum 5'ValCAC levels indicate an enhanced angiogenin-mediated stress response within motor neurons that correlates with increased survival. These data suggest that the previously reported beneficial effects of angiogenin in SOD1 G93A mice may result from elevated levels of 5'ValCAC transfer RNA fragment., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.) more...

Amyotrophic lateral sclerosis (ALS) presents a poorly understood pathogenesis. Evidence from patients and mutant SOD1 mouse models suggests vascular damage may precede or aggravate motor dysfunction in ALS. We have previously shown angiogenin (ANG) treatment enhances motor neuron survival, delays motor dysfunction and prevents vascular regression in the SOD1 G93A ALS model. However, the existence of vascular defects at different stages of disease progression remains to be established in other ALS models. Here, we assessed vascular integrity in vivo throughout different disease stages, and investigated whether ANG treatment reverses vascular regression and prolongs motor neuron survival in the FUS (1-359) mouse model of ALS. Lumbar spinal cord tissue was collected from FUS (1-359) and non-transgenic control mice at postnatal day (P)50, P90 and P120. We found a significant decrease in vascular network density in lumbar spinal cords from FUS (1-359) mice by day 90, at which point motor neuron numbers were unaffected. ANG treatment did not affect survival or counter vascular regression. Endogenous Ang1 and Vegf expression were unchanged at P50 and P90; however, we found a significant decrease in miRNA 126 at P50, indicating vascular integrity in FUS mice may be compromised via an alternative pathway. Our study demonstrates that vascular regression occurs before motor neuron degeneration in FUS (1-359) mice, and highlights that heterogeneity in responses to novel ALS therapeutics can already be detected in preclinical mouse models of ALS.This article has an associated First Person interview with the joint first authors of the paper., Competing Interests: Competing interestsJ.H.M.P. is a beneficiary of patents relating to the use of angiogenin for the treatment of CNS diseases., (© 2019. Published by The Company of Biologists Ltd.) more...

Loss-of-function mutations in the angiogenin (ANG) gene have been identified in familial and sporadic ALS patients. Previous work from our group identified human ANG (huANG) to protect motoneurons in vitro, and provided proof-of-concept that daily intraperitoneal (i.p.) huANG injections post-symptom onset increased lifespan and delayed disease progression in SOD1 G93A mice. huANG's mechanism of action remains less well understood. Here, we implemented a preclinical in vivo design to validate our previous results, provide pharmacokinetic and protein distribution data after systemic administration, and explore potential pleiotropic activities of huANG in vivo. SOD1 G93A mice (n = 45) and non-transgenic controls (n = 31) were sex- age- and litter-matched according to the 2010 European ALS/MND group guidelines, and treated with huANG (1 μg, i.p., 3 times/week) or vehicle from 90 days on. huANG treatment increased survival and delayed motor dysfunction as assessed by rotarod in SOD1 G93A mice. Increased huANG serum levels were detectable 2 and 24 h after i.p. injection equally in transgenic and non-transgenic mice. Exogenous huANG localized to spinal cord astrocytes, supporting a glia-mediated, paracrine mechanism of action; uptake into endothelial cells was also observed. 1 μg huANG or vehicle were administered from 90 to 115 days of age for histological analysis. Vehicle-treated SOD1 G93A mice showed decreased motoneuron numbers and vascular length per ventral horn area, while huANG treatment resulted in improved vascular network maintenance and motoneuron survival. Our data suggest huANG represents a new class of pleiotropic ALS therapeutic that acts on the spinal cord vasculature and glia to delay motoneuron degeneration and disease progression., (Copyright © 2018 Elsevier Ltd. All rights reserved.) more...

Adult mice lacking functional GABAB receptors (GABAB1KO) have glucose metabolism alterations. Since GABAB receptors (GABABRs) are expressed in progenitor cells, we evaluated islet development in GABAB1KO mice. Postnatal day 4 (PND4) and adult, male and female, GABAB1KO, and wild-type littermates (WT) were weighed and euthanized, and serum insulin and glucagon was measured. Pancreatic glucagon and insulin content were assessed, and pancreas insulin, glucagon, PCNA, and GAD65/67 were determined by immunohistochemistry. RNA from PND4 pancreata and adult isolated islets was obtained, and Ins1, Ins2, Gcg, Sst, Ppy, Nes, Pdx1, and Gad1 transcription levels were determined by quantitative PCR. The main results were as follows: 1) insulin content was increased in PND4 GABAB1KO females and in both sexes in adult GABAB1KOs; 2) GABAB1KO females had more clusters (<500 μm(2)) and less islets than WT females; 3) cluster proliferation was decreased at PND4 and increased in adult GABAB1KO mice; 4) increased β-area at the expense of the α-cell area was present in GABAB1KO islets; 5) Ins2, Sst, and Ppy transcription were decreased in PND4 GABAB1KO pancreata, adult GABAB1KO female islets showed increased Ins1, Ins2, and Sst expression, Pdx1 was increased in male and female GABAB1KO islets; and 6) GAD65/67 was increased in adult GABAB1KO pancreata. We demonstrate that several islet parameters are altered in GABAB1KO mice, further pinpointing the importance of GABABRs in islet physiology. Some changes persist from neonatal ages to adulthood (e.g., insulin content in GABAB1KO females), whereas other features are differentially regulated according to age (e.g., Ins2 was reduced in PND4, whereas it was upregulated in adult GABAB1KO females). more...

γ-Aminobutyric acid (GABA) inhibits insulin secretion through GABA(B) receptors in pancreatic β-cells. We investigated whether GABA(B) receptors participated in the regulation of glucose homeostasis in vivo. BALB/c mice acutely pre-injected with the GABA(B) receptor agonist baclofen (7.5mg/kg, i.p.) presented glucose intolerance and diminished insulin secretion during a glucose tolerance test (GTT, 2g/kg body weight, i.p.). The GABA(B) receptor antagonist 2-hydroxysaclofen (15 mg/kg, i.p.) improved the GTT and reversed the baclofen effect. Also a slight increase in insulin secretion was observed with 2-hydroxysaclofen. In incubated islets 1.10(-5)M baclofen inhibited 20mM glucose-induced insulin secretion and this effect was reversed by coincubation with 1.10(-5)M 2-hydroxysaclofen. In chronically-treated animals (18 days) both the receptor agonist (5mg/kg/day i.p.) and the receptor antagonist (10mg/kg/day i.p.) induced impaired GTTs; the receptor antagonist, but not the agonist, also induced a decrease in insulin secretion. No alterations in insulin tolerance tests, body weight and food intake were observed with the treatments. In addition glucagon, insulin-like growth factor I, prolactin, corticosterone and growth hormone, other hormones involved in glucose metabolism regulation, were not affected by chronic baclofen or 2-hydroxysaclofen. In islets obtained from chronically injected animals with baclofen, 2-hydroxysaclofen or saline (as above), GABA(B2) mRNA expression was not altered. Results demonstrate that GABA(B) receptors are involved in the regulation of glucose homeostasis in vivo. Treatment with receptor agonists or antagonists, given acutely or chronically, altered glucose homeostasis and insulin secretion alerting to the need to evaluate glucose metabolism during the clinical use of these drugs., (Copyright © 2011 Elsevier B.V. All rights reserved.) more...

Purpose: DNA lesions produced by boron neutron capture therapy (BNCT) and those produced by gamma radiation in a colon carcinoma cell line were analyzed. We have also derived the relative biologic effectiveness factor (RBE) of the neutron beam of the RA-3- Argentine nuclear reactor, and the compound biologic effectiveness (CBE) values for p-boronophenylalanine ((10)BPA) and for 2,4-bis (α,β-dihydroxyethyl)-deutero-porphyrin IX ((10)BOPP)., Methods and Materials: Exponentially growing human colon carcinoma cells (ARO81-1) were distributed into the following groups: (1) BPA (10 ppm (10)B) + neutrons, (2) BOPP (10 ppm (10)B) + neutrons, (3) neutrons alone, and (4) gamma rays ((60)Co source at 1 Gy/min dose-rate). Different irradiation times were used to obtain total absorbed doses between 0.3 and 5 Gy (±10%) (thermal neutrons flux = 7.5 10(9) n/cm(2) sec)., Results: The frequency of micronucleated binucleated cells and the number of micronuclei per micronucleated binucleated cells showed a dose-dependent increase until approximately 2 Gy. The response to gamma rays was significantly lower than the response to the other treatments (p < 0.05). The irradiations with neutrons alone and neutrons + BOPP showed curves that did not differ significantly from, and showed less DNA damage than, irradiation with neutrons + BPA. A decrease in the surviving fraction measured by 3-(4,5-dimetiltiazol-2-il)-2,5-difeniltetrazolium bromide (MTT) assay as a function of the absorbed dose was observed for all the treatments. The RBE and CBE factors calculated from cytokinesis block micronucleus (CBMN) and MTT assays were, respectively, the following: beam RBE: 4.4 ± 1.1 and 2.4 ± 0.6; CBE for BOPP: 8.0 ± 2.2 and 2.0 ± 1; CBE for BPA: 19.6 ± 3.7 and 3.5 ± 1.3., Conclusions: BNCT and gamma irradiations showed different genotoxic patterns. To our knowledge, these values represent the first experimental ones obtained for the RA-3 in a biologic model and could be useful for future experimental studies for the application of BNCT to colon carcinoma., (Copyright © 2011. Published by Elsevier Inc.) more...

We describe techniques for making a diffractive optical element that produces a subdiffraction-limited spot size. We provide experimental verification, using a diffraction optical element that is constructed on a magneto-optic spatial light modulator. more...

This study describes a systematic comparison of intra-arterial digital subtraction angiography (DSA) of the main renal arteries with conventional angiography (CA), the currently accepted "gold standard" for the diagnosis of renal artery stenosis. Twenty-five patients scheduled for abdominal aortography for various indications underwent first DSA then CA. The DSA and CA images were evaluated for number of renal arteries, presence and grade of renal artery stenosis, presence of post-stenotic dilation or fibromuscular changes, and diagnostic and pictorial adequacy of the images. DSA was found to be diagnostically adequate in 92% of cases, compared with 96% for CA. In evaluating significant main renal artery stenosis, which the authors assumed to be any stenosis greater than 50%, there were 10 such stenoses seen by CA. DSA also detected 10 cases, but there was 1 false positive and 1 false negative, yielding a sensitivity of 90% and a specificity of 98%. There was also close correlation of DSA and CA for the few cases of post-stenotic dilatation and fibromuscular dysplasia encountered. The authors conclude that DSA is an acceptable substitute for CA in the evaluation of patients for main renal artery stenosis. more...

There are pulmonary changes documented by light and electron microscopy in a canine model of nonhypotensive shock induced by a lower limb tourniquet. These histopathologic changes are mediated, at least in part, when the dog is treated with indomethacin. more...

We present a patient with penetrating thoracic trauma who demonstrated an ill-defined, enlarging pulmonary opacity over several days. Computed tomography confirmed the clinical suspicion of a pulmonary artery aneurysm. more...