Modifying Choroidal Neovascularization Development with a Nutritional Supplement in Mice

We examined the effect of nutritional supplements (modified Age Related Eye Disease Study (AREDS)-II formulation containing vitamins, minerals, lutein, resveratrol, and omega-3 fatty acids) on choroidal neovascularization (CNV). Supplements were administered alone and combined with intravitreal anti-VEGF in an early-CNV (diode laser-induced) murine model. Sixty mice were evenly divided into group V (oral vehicle, intravitreal saline), group S (oral supplement, intravitreal saline), group V + aVEGF (oral vehicle, intravitreal anti-VEGF), and group S + aVEGF (oral supplement, intravitreal anti-VEGF). Vehicle and nutritional supplements were administered daily for 38 days beginning 10 days before laser. Intravitreal injections were administered 48 h after laser. Fluorescein angiography (FA) and flat-mount CD31 staining evaluated leakage and CNV lesion area. Expression of VEGF, MMP-2 and MMP-9 activity, and NLRP3 were evaluated with RT-PCR, zymography, and western-blot. Leakage, CNV size, VEGF gene and protein expression were lower in groups V + aVEGF, S + aVEGF, and S than in V (all p < 0.05). Additionally, MMP-9 gene expression differed between groups S + aVEGF and V (p < 0.05) and MMP-9 activity was lower in S + aVEGF than in V and S (both p < 0.01). Levels of MMP-2 and NLRP3 were not significantly different between groups. Nutritional supplements either alone or combined with anti-VEGF may mitigate CNV development and inhibit retinal disease involving VEGF overexpression and CNV.     

Loss of discoidin domain receptor 2 promotes hepatic fibrosis after chronic carbon tetrachloride through altered paracrine interactions between hepatic stellate cells and liver-associated macrophages

Hepatic stellate cells (HSCs) interact with fibrillar collagen through the discoidin domain receptor 2 (DDR2) in acute hepatic injury, generating increased fibrosis. However, the contribution of DDR2 signaling to chronic liver fibrosis in vivo is unclear, despite its relevance to chronic human liver disease. We administered carbon tetrachloride (CCl(4)) to DDR2(+/+) and DDR2(-/-) mice twice weekly, and liver tissues and isolated HSCs were analyzed. In contrast to changes seen in acute injury, after chronic CCl(4) administration, DDR2(-/-) livers had increased collagen deposition, gelatinolytic activity, and HSC density. Increased basal gene expression of osteopontin, transforming growth factor-β1, monocyte chemoattractant protein-1, and IL-10 and reduced basal gene expression of matrix metalloproteinase-2, matrix metalloproteinase-13, and collagen type I in quiescent DDR2(-/-) HSCs were amplified further after chronic CCl(4). In concordance, DDR2(-/-) HSCs isolated from chronically injured livers had enhanced in vitro migration and proliferation, but less extracellular matrix degradative activity. Macrophages from chronic CCl(4)-treated DDR2(-/-) livers showed stronger chemoattractive activity toward DDR2(-/-) HSCs than DDR2(+/+) macrophages, increased extracellular matrix degradation, and higher cytokine mRNA expression. In conclusion, loss of DDR2 promotes chronic liver fibrosis after CCl(4) injury. The fibrogenic sinusoidal milieu generated in chronic DDR2(-/-) livers recruits more HSCs to injured regions, which enhances fibrosis. Together, these findings suggest that DDR2 normally orchestrates gene programs and paracrine interactions between HSCs and macrophages that together attenuate chronic hepatic fibrosis.     

Intronic delay is essential for oscillatory expression in the segmentation clock

Proper timing of gene expression is essential for many biological events, but the molecular mechanisms that control timing remain largely unclear. It has been suggested that introns contribute to the timing mechanisms of gene expression, but this hypothesis has not been tested with natural genes. One of the best systems for examining the significance of introns is the oscillator network in the somite segmentation clock, because mathematical modeling predicted that oscillating expression depends on negative feedback with a delayed timing. The basic helix-loop-helix repressor gene Hes7 is cyclically expressed in the presomitic mesoderm (PSM) and regulates the somite segmentation. Here, we found that introns lead to an ～19-min delay in the Hes7 gene expression, and mathematical modeling suggested that without such a delay, Hes7 oscillations would be abolished. To test this prediction, we generated mice carrying the Hes7 locus whose introns were removed. In these mice, Hes7 expression did not oscillate but occurred steadily, leading to severe segmentation defects. These results indicate that introns are indeed required for Hes7 oscillations and point to the significance of intronic delays in dynamic gene expression.     

Different types of oscillations in Notch and Fgf signaling regulate the spatiotemporal periodicity of somitogenesis

Somitogenesis is controlled by cyclic genes such as Notch effectors and by the wave front established by morphogens such as Fgf8, but the precise mechanism of how these factors are coordinated remains to be determined. Here, we show that effectors of Notch and Fgf pathways oscillate in different dynamics and that oscillations in Notch signaling generate alternating phase shift, thereby periodically segregating a group of synchronized cells, whereas oscillations in Fgf signaling released these synchronized cells for somitogenesis at the same time. These results suggest that Notch oscillators define the prospective somite region, while Fgf oscillators regulate the pace of segmentation.     

Activity of soluble aminopeptidase A and dipeptidyl peptidase IV and membrane-bound aminopeptidase B and pyroglutamyl peptidase I in adenoid hyperplasia, tonsillar hyperplasia and chronic tonsillitis

Objective

To analyze soluble and membrane-bound peptidase activities in the tonsils and adenoids removed from patients with adenoid hyperplasia, tonsillar hyperplasia and chronic tonsillitis.

Methods

A total of 48 tissue samples from patients undergoing adenoidectomy and tonsillectomy for adenoid hyperplasia, tonsillar hyperplasia or chronic tonsillitis were analyzed. The catalytic activity of a pool of peptidases in the soluble (dipeptidyl peptidase IV, aminopeptidase A, aminopeptidase N and cystinyl aminopeptidase) and membrane-bound (prolyl endopeptidase, aspartyl aminopeptidase, aminopeptidase B and pyroglutamyl peptidase I) fractions was measured fluorometrically.

Results

The activity of membrane-bound aminopeptidase B was higher in cases of chronic tonsillitis and adenoid hyperplasia than in tonsillar hyperplasia, p = 0.004. Soluble dipeptidyl peptidase IV and membrane-bound pyroglutamyl peptidase I were found to be more active in tissues from male chronic tonsillitis tissues, p < 0.05, while membrane-bound aminopeptidase B activity was higher in tissues of females with tonsillar hyperplasia, p < 0.001. In the case of chronic tonsillitis, soluble aminopeptidase A was found to have a higher level of activity in tissues from children than those from adults, p = 0.005.

Conclusions

Our results suggest a potential role of soluble aminopeptidase A, soluble dipeptidyl peptidase IV, membrane-bound aminopeptidase B and membrane-bound pyroglutamyl peptidase I in the pathobiology of adenoid hyperplasia, tonsillar hyperplasia and chronic tonsillitis that is differently regulated as a function of gender. These finfings may modify in the future the clinical approach to these diseases.     

Exploiting domain information for Word Sense Disambiguation of medical documents

Objective

Current techniques for knowledge-based Word Sense Disambiguation (WSD) of ambiguous biomedical terms rely on relations in the Unified Medical Language System Metathesaurus but do not take into account the domain of the target documents. The authors'' goal is to improve these methods by using information about the topic of the document in which the ambiguous term appears.

Design

The authors proposed and implemented several methods to extract lists of key terms associated with Medical Subject Heading terms. These key terms are used to represent the document topic in a knowledge-based WSD system. They are applied both alone and in combination with local context.

Measurements

A standard measure of accuracy was calculated over the set of target words in the widely used National Library of Medicine WSD dataset.

Results and discussion

The authors report a significant improvement when combining those key terms with local context, showing that domain information improves the results of a WSD system based on the Unified Medical Language System Metathesaurus alone. The best results were obtained using key terms obtained by relevance feedback and weighted by inverse document frequency.     

Weight Difference Between Double Parathyroid Adenomas Is the Cause of False-positive IOPTH Test After Resection of the First Lesion

Background  

Some patients with double parathyroid adenoma show a greater than 50% decline in intraoperative parathyroid hormone (IOPTH) after resection of the first lesion. The present study was designed to test the hypothesis that significant adenoma weight differences may explain this inappropriate decline of IOPTH.     

Inflammatory Myofibroblastic Tumor of the Temporal Bone: A Histologically Nonmalignant Lesion with Fatal Outcome

Introduction: Inflammatory myofibroblastic tumor (IMFT) of the temporal bone is an unusual but distinct clinicopathologic entity. Case Report: We report the case of a 75-year-old patient with an IMFT located in the temporal bone. Symptoms included VI, X, XI, and XII cranial nerves palsies. Computed tomography and magnetic resonance images are described. The lesion was locally aggressive and outcome was fatal. IMFT was identified by analysis of postmortem specimen with histopathologic and immunohistochemical confirmation. Discussion: IMFT can be locally destructive lesions. Involvement of the skull base and cervical spine is indistinguishable from an aggressive infection or a malignant tumor and can be fatal as in our case report. The difficulties in establishing clinicopathologic diagnosis, radiological imaging characteristics, and treatment are discussed.     

A multicentre randomized pilot trial on the effectiveness of different levels of cooling in comatose survivors of out-of-hospital cardiac arrest: the FROST-I trial

Purpose

To obtain initial data on the effect of different levels of targeted temperature management (TTM) in out-of-hospital cardiac arrest (OHCA).

Methods

We designed a multicentre pilot trial with 1:1:1 randomization to either 32 °C (n?=?52), 33 °C (n?=?49) or 34 °C (n?=?49), via endovascular cooling devices during a 24-h period in comatose survivors of witnessed OHCA and initial shockable rhythm. The primary endpoint was the percentage of subjects surviving with good neurologic outcome defined by a modified Rankin Scale (mRS) score of?≤?3, blindly assessed at 90 days.

Results

At baseline, different proportions of patients who had received defibrillation administered by a bystander were assigned to groups of 32 °C (13.5%), 33 °C (34.7%) and 34 °C (28.6%; p?=?0.03). The percentage of patients with an mRS?≤?3 at 90 days (primary endpoint) was 65.3, 65.9 and 65.9% in patients assigned to 32, 33 and 34 °C, respectively, non-significant (NS). The multivariate Cox proportional hazards model identified two variables significantly related to the primary outcome: male gender and defibrillation by a bystander. Among the 43 patients who died before 90 days, 28 died following withdrawal of life-sustaining therapy, as follows: 7/16 (43.8%), 10/13 (76.9%) and 11/14 (78.6%) of patients assigned to 32, 33 and 34 °C, respectively (trend test p?=?0.04). All levels of cooling were well tolerated.

Conclusions

There were no statistically significant differences in neurological outcomes among the different levels of TTM. However, future research should explore the efficacy of TTM at 32 °C.

Clinical trial registration

ClinicalTrials.gov unique identifier: NCT02035839 (http://clinicaltrials.gov).