Propagation of TDP-43 proteinopathy in neurodegenerative disorders

Neurodegenerative disorders are characterized by disruptions to neuronal function and circuitry,leading to a variety of clinical syndromes depending on the affected neuroanatomic regions(Geula,1998).Many proteinopathies implicated in neurodegenerative diseases are characterized by the pathologic accumulation of proteins into inclusions that are initially deposited in specific areas of the brain and spread widely with disease progression.     

Outer Breast Quadrants Demonstrate Increased Levels of Genomic Instability

Background: Theory holds that the upper outer quadrant of the breast develops more malignancies because of increased tissue volume. This study evaluated genomic patterns of loss of heterozygosity (LOH) and allelic imbalance (AI) in non-neoplastic tissues from quadrants of diseased breasts following mastectomy to characterize relationships between genomic instability and the propensity for tumor development.Methods: Tissues from breast quadrants were collected from 21 patients with various stages of breast carcinoma. DNA was isolated from non-neoplastic tissues using standard methods and 26 chromosomal regions commonly deleted in breast cancer were examined to assess genomic instability.Results: Genomic instability was observed in breast quadrants from patients with ductal carcinomas in situ and advanced carcinomas. Levels of instability by quadrant were not predictive of primary tumor location (P = .363), but outer quadrants demonstrated significantly higher levels of genomic instability than did inner quadrants (P = .017). Marker D8S511 on chromosome 8p22– 21.3, one of the most frequently altered chromosomal regions in breast cancer, showed a significantly higher level of instability (P = .039) in outer compared with inner quadrants.Conclusions: Non-neoplastic breast tissues often harbor genetic changes that can be important to understanding the local breast environment within which cancer develops. Greater genomic instability in outer quadrants can partially explain the propensity for breast cancers to develop there, rather than simple volume-related concepts. Patterns of field cancerization in the breast appear to be complex and are not a simple function of distance from a developing tumor.     

Quantification of Radio-tracer Uptake in Axillary Lymph Nodes using Breast Specific Gamma Imaging (BSGI): Benign Radio-tracer Extravasation versus Uptake Secondary to Breast Cancer

Abstract:  To develop a means of quantifying axillary radio-tracer uptake in patients undergoing breast specific gamma imaging. This may help differentiate uptake secondary to extravasation of the radio-tracer at the injection from increased uptake as a result of breast cancer metastatic to lymph nodes. A retrospective analysis of patients who had undergone breast specific gamma imaging was performed. Scans from 26 patients showing increased axillary uptake of radio-tracer were identified from 939 patients reviewed. Eighteen of these patients had increased axillary uptake ipsilateral to the side of tracer injection in the absence of breast cancer on that side. Of these 18 cases, eight patients had pathologic proven axillary metastatic disease with increased axillary uptake contralateral to the side of tracer injection. The maximum signal intensity for each region of increased radio-tracer uptake was measured using the net maximum uptake per region of interest and the two groups of patients were compared. Statistical significance was determined using a two-tailed p-value and 95% confidence intervals were considered statistically significant. The calculated means of the "net maximum uptake per region of interest" in the subjects with increased radio-tracer uptake secondary to radio-tracer extravasation and metastatic breast cancer were 177.89 and 117.25, respectively. Comparison of the means yielded a two-tailed p-value of 0.0498, which is statistically significant. There is a statistically significant greater intensity of axillary radio-tracer uptake when the uptake occurs secondary to extravasation when compared with metastases to axillary lymph nodes.     

CXC chemokine expression and synthesis in skeletal muscle during ischemia/reperfusion

BACKGROUND: The chemokines keratinocyte-Derived Cytokine (KC) and macrophage inflammatory protein (MIP)-2, murine equivalents of human interleukin 8, have been implicated in remote injury after acute hind limb ischemia/reperfusion (I/R). These studies were designed to determine whether the cytokines responsible for remote tissue injury are also synthesized and accumulate in the ischemic or reperfused hind limb. METHODS: B6, 129SF2/J mice were subjected to either 3 hours of unilateral hind limb ischemia alone (IA) or 3 hours of ischemia followed by 4 or 24 hours of reperfusion (I/R). After IA or I/R, experimental and control (nonischemic) contralateral hind limbs were harvested for analysis of protein content, messenger RNA (mRNA), tissue edema, and viability. RESULTS: IA did not increase KC or MIP-2 mRNA or protein levels. In contrast, I/R resulted in a 15- and 10-fold increase in KC mRNA after 4 and 24 hours of reperfusion, respectively. KC protein levels were increased 10-fold after 4 hours of reperfusion and 30-fold after 24 hours (vs IA or sham; P < .001). MIP-2 mRNA transiently increased 42-fold after 4 hours of reperfusion but decreased to basal levels after 24 hours of reperfusion. Despite the relative increase in MIP-2 mRNA by 4 hours of reperfusion, significantly increased (8- to 10 fold) MIP-2 protein levels were not detected until 24 hours of reperfusion only in the reperfused limbs. Tissue edema was increased significantly (P < .01) compared with sham after just 4 hours of reperfusion and remained increased at 24 hours. Tissue viability decreased 52% after 4 hours of reperfusion and did not change significantly by 24 hours. CONCLUSIONS: Skeletal muscle is a site of significant ongoing chemokine synthesis during reperfusion. The persistent increase in muscle chemokine levels at 24 hours of reperfusion was not associated with increased edema or injury. The role of these chemokines during reperfusion may be further investigated by local or oral administration of chemokines or chemokine receptor antagonists. CLINICAL RELEVANCE: I/R injury remains an important clinical problem across a variety of surgical specialties. In the critical care arena, serum levels of proinflammatory cytokines have been useful in predicting the mortality associated with acute respiratory distress syndrome and sepsis. In this article, the data presented indicate that murine skeletal muscle produces potent proinflammatory neutrophil and macrophage chemokines during reperfusion, but not during ischemia. These findings suggest that measurement of tissue and/or serum levels of chemokines during reperfusion may be an important adjunct to predicting tissue injury along with ongoing inflammation during the clinical course of reperfusion injury. Within the vascular system, severe inflammatory responses are usually associated with thrombotic events. New techniques to noninvasively image thrombin activation (by using magnetic resonance imaging) in reperfused limbs may coincide with the pattern of murine skeletal muscle chemokine expression in humans. The data suggest that reperfusion is when chemokine mRNA and protein synthesis increase. Within the time periods studied in these experiments, the chemokine component of the inflammatory response remained in the reperfused, rather than the systemic nonreperfused, tissue. This observation may underestimate the degree of the systemic response to ischemia because the single mouse hind limb represents only 7% of the mouse total body area, whereas the human limb represents nearly 18% of the adult body area. Despite this shortcoming, these data provide potential temporal and quantitative information regarding the location and magnitude of chemokine synthesis in skeletal muscle during reperfusion.     

The Genomic Heritage of Lymph Node Metastases: Implications for Clinical Management of Patients with Breast Cancer

Background Metastatic breast cancer is an aggressive disease associated with recurrence and decreased survival. To improve outcomes and develop more effective treatment strategies for patients with breast cancer, it is important to understand the molecular mechanisms underlying metastasis. Methods We used allelic imbalance (AI) to determine the molecular heritage of primary breast tumors and corresponding metastases to the axillary lymph nodes. Paraffin-embedded samples from primary breast tumors and matched metastases (n = 146) were collected from 26 patients with node-positive breast cancer involving multiple axillary nodes. Hierarchical clustering was used to assess overall differences in the patterns of AI, and phylogenetic analysis inferred the molecular heritage of axillary lymph node metastases. Results Overall frequencies of AI were significantly higher (P < 0.01) in primary breast tumors (23%) than in lymph node metastases (15%), and there was a high degree of discordance in patterns of AI between primary breast carcinomas and the metastases. Metastatic tumors in the axillary nodes showed different patterns of chromosomal changes, suggesting that multiple molecular mechanisms may govern the process of metastasis in individual patients. Some metastases progressed with few genomic alterations, while others harbored many chromosomal alterations present in the primary tumor. Conclusions The extent of genomic heterogeneity in axillary lymph node metastases differs markedly among individual patients. Genomic diversity may be associated with response to adjuvant therapy, recurrence, and survival, and thus may be important in improving clinical management of breast cancer patients.     

Aprotinin in cardiac surgery patients: is the risk worth the benefit?

Background: Aprotinin is the only Food and Drug Administration-approved agent to reduce haemorrhage related to cardiac surgery and its safety and efficacy has been extensively studied. Our study sought to compare the efficacy, early and late mortality and major morbidity associated with aprotinin compared with e-aminocaproic acid (EACA) in cardiac surgery operations. Methods: Between January 2002 and December 2006, 2101 patients underwent coronary artery bypass grafting (CABG), valve surgery or CABG and valve surgery in our institution with the use of aprotinin (1898 patients) or EACA (203 patients). Logistic regression and propensity score analysis were used to adjust for imbalances in the patients’ preoperative characteristics. The propensity score-adjusted sample included 570 patients who received aprotinin and 114 who received EACA (1–5 matching). Results: Operative mortality was higher in the aprotinin group in univariate (aprotinin 4.3% vs EACA 1%, p = 0.023) but not propensity score-adjusted multivariate analysis (4% vs 0.9%, p = 0.16). In propensity score-adjusted analysis, aprotinin was also associated with a lower rate of blood transfusion (38.8% vs 50%, p = 0.04), a lower rate of haemorrhage-related re-exploration (3.7% vs 7.9%, p = 0.04) and a higher risk of in-hospital cardiac arrest (3.7% vs 0%, p = 0.03) and a marginally but not statistically significantly higher risk of acute renal failure (6.8% vs 2.6%, p = 0.09). In Cox proportional hazards regression analysis, the risk of late death was higher in the aprotinin compared to EACA group (hazard ratio = 4.33, 95% confidence interval (CI) = 1.60–11.67, p = 0.004). Conclusion: Aprotinin decreases the rate of postoperative blood transfusion and haemorrhage-related re-exploration, but increases the risk of in-hospital cardiac arrest and late mortality after cardiac surgery when compared to EACA. Cumulative evidence suggests that the risk associated with aprotinin may not be worth the haemostatic benefit.     

Predictors and outcomes of jejunostomy tube placement at the time of pancreatoduodenectomy

BackgroundClinically relevant postoperative pancreatic fistula and delayed gastric emptying cause substantial morbidity after pancreatoduodenectomy. Per international guidelines, the placement of jejunostomy tubes may be considered for patients at risk for malnutrition, such as those with a high risk for clinically relevant postoperative pancreatic fistula and related complications. This study determined predictors and postoperative outcomes of jejunostomy tube placement.MethodsPatients undergoing pancreatoduodenectomy in 2014 to 2015 were identified using the American College of Surgeons National Surgical Quality Improvement Program and Procedure-Targeted Pancreatectomy Participant Use Files. Multivariable logistic regressions were used to identify factors associated with concurrent jejunostomy tube placement and postoperative outcomes.ResultsOf 3,600 patients, 8.9% underwent jejunostomy tube placement. Patients given a jejunostomy tube were more likely white (odds ratio 1.46, P = .016), to have low preoperative serum albumin levels (odds ratio 2.13, P < .001), to have received neoadjuvant radiotherapy (odds ratio 2.14, P < .001), and to have received an intraoperative transfusion (odds ratio 1.50, P = .004). We observed no association between jejunostomy tube placement and an increasing number of risk factors for clinically relevant postoperative pancreatic fistula (P = .96) or delayed gastric emptying (P = .54). Overall, jejunostomy tube placement was associated with increased morbidity (odds ratio 1.34, P = .020) and duration of stay (P < .001), but not mortality (P = .12). Among patients with low serum albumin or those who developed clinically relevant postoperative pancreatic fistula or delayed gastric emptying, jejunostomy tube utilization was not associated with morbidity or mortality.ConclusionJejunostomy tube placement during pancreatoduodenectomy was not driven by risk factors for clinically relevant postoperative pancreatic fistula or delayed gastric emptying, suggesting that practice patterns play a role. Among patients with at-risk preoperative albumin or who developed these complications, jejunostomy tube placement was not associated with worse outcomes, supporting selective utilization per guideline recommendations.