Systemic cascades on inhomogeneous random financial networks.

This article presents a model of the financial system as an inhomogeneous random financial network (IRFN) with N nodes that represent different types of institutions such as banks or funds and directed weighted edges that signify counterparty relationships between nodes. The onset of a systemic crisis is triggered by a large exogenous shock to banks' balance sheets. Their behavioural response is modelled by a cascade mechanism that tracks the propagation of damaging shocks and possible amplification of the crisis, and leads the system to a cascade equilibrium. The mathematical properties of the stochastic framework are investigated for the first time in a generalization of the Eisenberg-Noe solvency cascade mechanism that accounts for fractional bankruptcy charges. New results include verification of a "tree independent cascade property" of the solvency cascade mechanism, and culminate in an explicit recursive stochastic solvency cascade mapping conjectured to hold in the limit as the number of banks N goes to infinity. It is shown how this cascade mapping can be computed numerically, leading to a rich picture of the systemic crisis as it evolves toward the cascade equilibrium.

Impact of asymptomatic COVID-19 carriers on pandemic policy outcomes.

This paper provides a mathematical model that makes it clearly visible why the underestimation of r, the fraction of asymptomatic COVID-19 carriers in the general population, may lead to a catastrophic reliance on the standard policy intervention that attempts to isolate all confirmed infectious cases. The SE(A+O)R model with infectives separated into asymptomatic and ordinary carriers, supplemented by a model of the data generation process, is calibrated to standard early pandemic datasets for two countries. It is shown that certain fundamental parameters, critically r, are unidentifiable with this data. A general analytical framework is presented that projects the impact of different types of policy intervention. It is found that the lack of parameter identifiability implies that some, but not all, potential policy interventions can be correctly predicted. In an example representing Italy in March 2020, a hypothetical optimal policy of isolating confirmed cases that aims to reduce the basic reproduction number R 0 of the outbreak from 4.4 to 0.8 assuming r = 0, only achieves 3.8 if it turns out that r = 40%.

COVID-19: Analytics of contagion on inhomogeneous random social networks.

Motivated by the need for robust models of the Covid-19 epidemic that adequately reflect the extreme heterogeneity of humans and society, this paper presents a novel framework that treats a population of N individuals as an inhomogeneous random social network (IRSN). The nodes of the network represent individuals of different types and the edges represent significant social relationships. An epidemic is pictured as a contagion process that develops day by day, triggered by a seed infection introduced into the population on day 0. Individuals' social behaviour and health status are assumed to vary randomly within each type, with probability distributions that vary with their type. A formulation and analysis is given for a SEIR (susceptible-exposed-infective-removed) network contagion model, considered as an agent based model, which focusses on the number of people of each type in each compartment each day. The main result is an analytical formula valid in the large N limit for the stochastic state of the system on day t in terms of the initial conditions. The formula involves only one-dimensional integration. The model can be implemented numerically for any number of types by a deterministic algorithm that efficiently incorporates the discrete Fourier transform. While the paper focusses on fundamental properties rather than far ranging applications, a concluding discussion addresses a number of domains, notably public awareness, infectious disease research and public health policy, where the IRSN framework may provide unique insights.

Disulphide formation on mitochondrial protein thiols.

A large number of proteins contain free thiols that can be modified by the formation of internal disulphides or by mixed disulphides with low-molecular-mass thiols. The majority of these latter modifications result from the interaction of protein thiols with the endogenous glutathione pool. Protein glutathionylation and disulphide formation are of significance both for defence against oxidative damage and in redox signalling. As mitochondria are central to both oxidative damage and redox signalling within the cell, these modifications of mitochondrial proteins are of particular importance. In the present study, we review the mechanisms and physiological significance of these processes.

Lipophilic triphenylphosphonium cations as tools in mitochondrial bioenergetics and free radical biology.

Lipophilic phosphonium cations were first used to investigate mitochondrial biology by Vladimir Skulachev and colleagues in the late 1960s. Since then, these molecules have become important tools for exploring mitochondrial bioenergetics and free radical biology. Here we review why these molecules are useful in mitochondrial research and outline some of the ways in which they are now being utilized.

Computational identification of human mitochondrial proteins based on homology to yeast mitochondrially targeted proteins.

MOTIVATION: Patients with defects of the mitochondrial respiratory chain due to mutations in nuclear genes are often undiagnosable due to the lack of information about the role of these genes. We therefore sought to produce a novel dataset of human nuclear-encoded mitochondrial proteins. RESULTS: We have used the web-based computer program Mitoprot to predict which proteins in the Saccharomyces cerevisiae genome are targeted to mitochondria. We then used this protein dataset to identify the homologous human proteins in the Unigene database using TBLASTN from NCBI. Human proteins with an Expectation value <10(-5) and an Identity >30% were accepted as true homologues of the yeast proteins. These human proteins were then reanalyzed with Mitoprot. The final set of proteins comprises a dataset of 361 human mitochondrially targeted proteins with homology to all S.cerevisiae mitochondrially targeted proteins. One hundred twenty eight of these proteins are novel and are of unknown function. SUPPLEMENTARY INFORMATION: Supplementary tables will be available from http://www.sickkids.ca/Robinsonlab/

Abundance of Alnus incana ssp. rugosa in Adirondack Mountain shrub wetlands and its influence on inorganic nitrogen.

The purpose of this research was to determine the abundance of the nitrogen-fixing shrub, Alnus incana ssp. rugosa (speckled alder), in shrub wetlands of the Adirondack Mountain region of New York State and to determine whether its abundance affects the concentration or accumulation of inorganic nitrogen in wetland substrates. Alder/willow wetlands are the second most common wetland type in the Adirondack region. The Adirondack Park Agency's digital GIS database of wetland types was used to determine the areal extent of alder/willow wetlands in the Adirondacks. Randomly selected wetlands were sampled to determine the size and abundance of alder. Alder densities averaged approximately 7000 stems ha(-1) and alder was present in 75% of the wetlands. As an indication of short-term accumulation of NO(3-) and NH4(+) in wetland substrates, ion exchange resins were used to sample ground water in high and low alder density wetlands as well as from wetlands lacking alder and dominated by conifers. Additionally, NO(3-) and NH(4+) concentrations in ground water samples were measured. NH(4+) accumulation levels from exchange resins were low for all wetland types while groundwater NH(4+) concentration was highest in the low-density alder sites. Wetlands with high alder density had approximately six times higher NO(3-) accumulation than other wetlands. Substrate groundwater NO(3-) concentrations in wetlands of high-density alder exceeded by three times levels in low or no alder wetlands, showing the importance of alder to local N budgets. To assess the recovery of shrub wetlands from acidification, future studies should determine the fate of fixed N in wetland systems.

Is MUGA scan necessary in patients with low-risk breast cancer before doxorubicin-based adjuvant therapy? Multiple gated acquisition.

Doxorubicin-based chemotherapy in the adjuvant treatment of breast cancer has become standard. Use of doxorubicin is limited by cardiac dysfunction; however, the incidence is dramatically reduced by limiting the dose to less than 550 mg/m(2). Although the cumulative dose in breast cancer is typically 240 mg/m(2), multiple gated acquisition (MUGA) scans are still recommended for determining cardiac functional status in these patients. To examine the need for this practice, we reviewed 296 patients who underwent surgery for breast cancer at Roswell Park Cancer Institute between July 1997 and December 1998. Fifty-nine of 95 (62%) patients receiving doxorubicin-based regimens, and 3 of 39 (7%) receiving nondoxorubicin regimens had pretreatment MUGA scans. The MUGA scans showed normal results in 58 patients and low-normal in 4 (6.5%), with no wall motion abnormalities encountered. There were no cases where doxorubicin was not used because of an abnormal MUGA scan. There were no cardiac complications in the 59 women who received doxorubicin-based chemotherapy. MUGA will screen out few, if any, women under consideration for doxorubicin-based adjuvant therapy; the decision to avoid doxorubicin can be made based on age and preexisting comorbidity. Guidelines recommending routine use of MUGA before the administration of doxorubicin for adjuvant therapy for breast cancer should be reconsidered.

Accuracy of sentinel node biopsy in predicting nodal status in patients with breast carcinoma.

BACKGROUND AND OBJECTIVES: While sentinel lymph node biopsy is considered by many to have replaced axillary node dissection in the management of breast cancer, concerns remain regarding false-negative results. METHODS: To investigate the accuracy of sentinel node biopsy, we reexamined all sentinel and nonsentinel nodes with multilevel sectioning and immunohistochemical staining in 42 consecutive cases of breast cancer in which sentinel node biopsy was performed and followed by axillary dissection. RESULTS: By routine hematoxylin and eosin (H&E) staining, 34% of patients were found to be node positive, with no cases of false-negative sentinel node biopsy. Reevaluation of 775 negative sentinel and nonsentinel nodes with an additional two levels and immunohistochemistry identified three "node-negative" patients who had micrometastases in the sentinel node, increasing detection in 8% of cases. More important, is the fact however, that there were no cases where additional sections and immunohistochemistry identified metastases in nonsentinel nodes that had bypassed the sentinel node. The accuracy of the sentinel node in predicting the nodal status was 100%. CONCLUSIONS: Cytokeratin immunohistochemistry will identify more patients with nodal micrometastases; however, it was unable to identify any cases where micrometastases were present in nonsentinel nodes when the sentinel node was negative. The status of the sentinel node accurately identifies the status of the axillary basin.

Intraoperative pathologic evaluation of a breast cancer sentinel lymph node biopsy as a determinant for synchronous axillary lymph node dissection.

BACKGROUND: Intraoperative pathologic evaluation of a breast cancer sentinel lymph node (SLN) biopsy permits synchronous axillary lymph node dissection (ALND), but frozen section is time consuming and potentially inaccurate. This study evaluated intraoperative gross examination and touch prep analysis (TPA) of a breast cancer SLN biopsy as determinants for synchronous ALND. METHODS: Intraoperative gross examination/TPA were performed on the SLN of consecutive breast cancer patients from 1997 to 2000. Patients with an intraoperative "positive" SLN underwent synchronous ALND. Intraoperative results were compared with the final pathology. RESULTS: Thirty-seven of 150 patients had a positive SLN on final pathology. Intraoperative gross examination/TPA identified 54% (20 of 37) of these patients. All intraoperative "positive" patients underwent synchronous ALND. Of 17 "false-negative" findings, 53% (9 of 17) had micrometastatic disease. There were no "false-positive" results. Overall sensitivity and specificity were 54% and 100%, respectively. CONCLUSIONS: Gross examination/TPA are simple, rapid techniques for the intraoperative evaluation of a breast cancer SLN. As there were no false-positive results, the rationale behind SLN biopsy was preserved. These techniques permitted synchronous ALND in over half of all patients with a positive SLN. This represents a potential benefit to the patient by eliminating a second hospitalization for delayed ALND.

Breast cancer risk factors and HER2 over-expression in tumors.

Few epidemiologic studies have investigated the potential role of HER2 in the etiology of breast cancer. We conducted a case-case study of 156 women with incident, invasive ductal carcinoma. Multivariate unconditional logistic regression was used to estimate the odds ratios for a HER2 positive tumor in relation to known and putative risk factors of breast cancer. HER2 status was detected by immunohistochemistry on archival tissue. HER2 positive breast cancers tended to be larger and were less likely to express estrogen receptors, and the incidence rate was higher in patients less than 40 years old. We observed an association between a self-reported history of benign breast disease and the occurrence of HER2 positive breast cancer (OR, 2.1;95% CI, 1.1-4.1). We did not detect associations between HER2 over-expression and family history of breast cancer, parity, late age at first birth, ever having breast fed an infant, or oral contraceptive use. Our findings merit consideration in light of recent evidence of HER2 amplification or over-expression in benign breast disease. Should the link to breast cancer be established, HER2 positive benign breast disease could potentially serve as an early marker for preventive intervention.

Symbiotic N2 fixation of Alnus incana ssp. rugosa in shrub wetlands of the Adirondack Mountains, New York, USA.

Surface waters in forested watersheds in the Adirondack Mountains and northern New York State are susceptible to nitrogen (N) saturation. Atmospheric deposition of N to watersheds in this region has been measured but the extent of internal N inputs from symbiotic N2 fixation in alder-dominated wetlands is not known. We estimated N2 fixation by speckled alder in these wetlands by the 15N natural abundance method and by acetylene reduction using a flow-through system. Foliar N derived from fixation (%Ndfa) was estimated for five wetlands. The δ15N of speckled alder foliage from four of the five sites did not differ significantly (P≤0.05) from that of nodulated speckled alders grown in N-free water culture (-1.2±0.1‰). Estimates from the 15N natural abundance method indicated that alders at these sites derive 85-100% of their foliar N from N2 fixation. At one of the sites, we also measured biomass and N content and estimated that the alder foliage contained 43 kg N ha-1 of fixed N in 1997. This estimate was based on a foliar N content of 55.4±7 kg N ha-1 (mean±SE), 86±4%Ndfa, and an assumption that 10% of foliar N was derived from reserves in woody tissues. At this site, we further estimated via acetylene reduction that 37±10 kg N ha-1 was fixed by speckled alders in 1998. This estimate used the theoretical 4:1 C2H2 reduction to N2 fixation ratio and assumed no night-time fixation late in the season. Nitrogen inputs in wet and dry deposition at this site are approximately 8 kg N ha-1 year-1. We conclude that speckled alder in wetlands of northern New York State relies heavily on N2 fixation to meet N demands, and symbiotic N2 fixation in speckled alders adds substantial amounts of N to alder-dominated wetlands in the Adirondack Mountains. These additions may be important for watershed N budgets, where alder-dominated wetlands occupy a large proportion of watershed area.

Postexcision mammography is indicated after resection of ductal carcinoma-in-situ of the breast.

BACKGROUND: The adequacy of excision of ductal carcinoma-in-situ (DCIS) usually is confirmed with specimen mammography and histopathological assessment of specimen margins. Postexcision mammography of the involved breast is used at some centers. The objective of this study was to evaluate the impact of postexcision mammography in DCIS. METHODS: We conducted a retrospective chart review of all patients treated for DCIS at our institution from 1995 to 1998. RESULTS: Sixty-seven patients had postexcision mammography performed. Residual microcalcifications were identified in 16 patients (24%). Further surgery was precluded by precise mammographic-pathological correlation by using sliced-specimen mammography in two patients. Twelve patients had repeat wide excision, and two patients underwent mastectomy. Residual DCIS was identified at re-excision in 9 of 14 patients (64%). The margin status of the initial resection was negative in three of nine patients (33%) and positive or unknown in six of nine patients (67%). CONCLUSIONS: Postexcision mammography is a valuable technique that complements specimen mammography and histopathological margin assessment in confirming that an adequate excision of DCIS has been performed. Postexcision mammography should be performed in all patients with DCIS associated with mammographic calcifications who are treated with breast-conserving therapy.

Breast cancer imaging.

The role of the surgeon in the diagnosis and management of breast cancer continues to evolve as office based diagnostic procedures gain more prominence. This article outlines the basic clinical and technical aspects of mammography and ultrasound. The evaluation and management of several challenging breast problems are discussed.

Impact of extensive intraductal component on recurrence and survival in patients with stage I or II breast cancer treated with breast conservation therapy.

BACKGROUND: The relationship between an extensive intraductal component (EIC) and recurrence and survival in patients with stage I or II breast cancer treated with breast conservation therapy has not been clearly defined. METHODS: 133 patients with stage I or II breast cancer who underwent breast conservation therapy between 1978 and 1990 at The University of Texas M. D. Anderson Cancer Center were retrospectively studied. All pathology slides were reviewed to determine tumor size, nuclear grade, extent of intraductal component, number of positive lymph nodes, and histologic margins. EIC was defined as ductal carcinoma in situ (DCIS) occupying 25% or more of the area encompassed by the infiltrating tumor and DCIS present in grossly normal adjacent breast tissue. RESULTS: 110 patients are alive, and 23 have died, with a median follow-up of 7 years; 85 of 133 patients had an intraductal component, but only 18 had an EIC. Locoregional control and disease-free and overall survival were not adversely affected by the presence of an EIC. Five of 133 patients had a locoregional recurrence, but only one had an EIC. CONCLUSIONS: EIC, if negative margins can be achieved, does not adversely affect disease-free or overall survival or local control rates.

The evaluation of palpable breast masses: common pitfalls and management guidelines.

The management of a palpable breast mass starts with identification of the lesion and a suspicion of malignancy. While seemingly simple, the initial evaluation can significantly impact upon treatment options and outcomes. The management of two patients recently referred to this Institution highlights common pitfalls and technical considerations in the diagnosis and treatment of palpable breast masses. The case histories of two patients referred after open breast biopsy were examined. The English language medical literature was searched manually and by Medline for publications related to the evaluation of palpable breast masses. Imaging, diagnostic techniques and technical considerations in the management of palpable lesions were reviewed. The initial use of carefully selected diagnostic and therapeutic measures is critical in optimizing outcomes measured in improved quality of life and survival. Inappropriate choices at this first stage can have extremely negative consequences. The early evaluation of two patients highlighted these considerations. Management pitfalls included serial examination of a suspicious lesion, failure to obtain a mammogram prior to excisional biopsy and unnecessary testing. Technical problems included piecemeal excision of the tumor with positive margins, use of a drain, closure of deep tissues with dimpling of the breast, and incision placement in a location that subsequently necessitated mastectomy. Careful adherence to the clinical and operative principles of breast cancer management optimizes outcomes in the evaluation of palpable breast masses.

Temporal relationship of hepatocellular dysfunction and ischemia in sepsis.

To determine whether hepatic dysfunction in sepsis results from hypoperfusion or direct cellular injury, Sprague-Dawley rats underwent either cecal ligation and puncture or sham operation. After either two or six hours, effective hepatic blood flow was measured using the galactose clearance method. Hepatocytes were isolated and intracellular sodium and potassium and glucose production were measured. Hepatic blood flow in septic rats decreased as early as two hours after sepsis when compared with sham-operated rats (3.8 +/- 1.4 vs 8.7 +/- 3.1 mL/min/100 g body weight). Intracellular sodium and potassium levels and glucose production in septic rats were not significantly different when compared with controls at two hours. After six hours, hepatic blood flow remained depressed and intracellular sodium level was increased compared with sham-operated rats (41.7 +/- 10.4 vs 31.4 +/- 5.9 mmol/L [41.7 +/- 10.4 vs 31.4 +/- 5.9 mEq/L]) and potassium decreased compared with controls (90.7 +/- 7.9 vs 111.5 +/- 6.7 mmol/L [90.7 +/- 7.9 vs 111.5 +/- 6.7 mEq/L]). Glucose production was decreased in septic rats after six hours when compared with controls (4.7 +/- 1.5 vs 15.4 +/- 6.4 mumol/g hepatocytes). These data suggest that hepatic blood flow is decreased before alterations in intracellular sodium and potassium as well as glucose production.