A physiologic increase in brain glucagon action alters the hepatic gluconeogenic/glycogenolytic ratio but not glucagon's overall effect on glucose production.

It has been proposed that brain glucagon action inhibits glucagon-stimulated hepatic glucose production (HGP), which may explain, at least in part, why glucagon's effect on HGP is transient. However, the pharmacologic off-target effects of glucagon in the brain may have been responsible for previously observed effects. Therefore, the aim of this study was to determine if central glucagon action plays a physiologic role in the regulation of HGP. Insulin was maintained at baseline while glucagon was either infused into the carotid and vertebral arteries or into a peripheral (leg) vein at rates designed to increase glucagon in the head in one group, while keeping glucagon at the liver matched between groups. The extraction rate of glucagon across the head was high (double that of the liver), and hypothalamic cAMP increased twofold, in proportion to the exposure of the brain to increased glucagon, but HGP was not reduced by the increase in brain glucagon signaling, as had been suggested previously (the areas under the curve for HGP were 840 ± 14 vs. 871 ± 36 mg/kg/240 min in head vs. peripheral infusion groups, respectively). Central nervous system glucagon action reduced circulating free fatty acids and glycerol, and this was associated with a modest reduction in net hepatic gluconeogenic flux. However, offsetting autoregulation by the liver (i.e., a reciprocal increase in net hepatic glycogenolysis) prevented a change in HGP. Thus, while physiologic engagement of the brain by glucagon can alter hepatic carbon flux, it does not appear to be responsible for the transient fall in HGP that occurs following the stimulation of HGP during a square wave rise in glucagon.NEW & NOTEWORTHY Glucagon stimulates hepatic glucose production through its direct effects on the liver but may indirectly inhibit this process by acting on the brain. This was tested by delivering glucagon via the cerebral circulatory system. Central nervous system glucagon action reduced liver gluconeogenic flux, but glycogenolysis increased, resulting in no net change in hepatic glucose production. Surprisingly, brain glucagon also appeared to suppress lipolysis (plasma free fatty acid and glycerol levels were reduced).

Breast tissue analysis using a clinically compatible combined time-resolved fluorescence and diffuse reflectance (TRF-DR) system.

OBJECTIVE: This work aims to develop a clinically compatible system that can perform breast tissue analysis in a more time efficient process than conventional histopathological assessment. The potential for such a system to be used in vivo in the operating room or surgical suite to improve patient outcome is investigated. METHOD: In this work, 80 matched pairs of invasive ductal carcinoma and adjacent normal breast tissue were measured in a combined time-resolved fluorescence and diffuse reflectance (DA) system. Following measurement, the fluorescence intensity of collagen and flavin adenine dinucleotide (FAD); the fluorescence lifetime of collagen, nicotinamide adenine dinucleotide (NADH), and FAD; the DA; absorption coefficient; and reduced scattering coefficient were extracted. Samples then underwent histological processing and H&E staining to classify composition as tumor, fibroglandular, and/or adipose tissue. RESULTS: Statistically significant differences in the collagen and FAD fluorescence intensity, collagen and FAD fluorescence lifetime, DA, and scattering coefficient were found between each tissue group. The NADH fluorescence lifetime and absorption coefficient were statistically different between the tumor and fibroglandular groups, and the tumor and adipose groups. While many breast tissue analysis studies label fibroglandular and adipose together as "normal" breast tissue, this work indicates that some differences between tumor and fibroglandular tissue are not the same as differences between tumor and adipose tissue. Observations of the reduced scatter coefficient may also indicate further classification to include fibro-adipose may be necessary. Future work would benefit from the additional tissue classification. CONCLUSION: With observable differences in optical parameters between the three tissue types, this system shows promise as a breast analysis tool in a clinical setting. With further work involving samples of mixed composition, this combined system could potentially be used intraoperatively for rapid margin assessment.

Effect of special operational forces surgical resuscitation teams on combat casualty survival: A narrative review.

IMPORTANCE: The most common cause of preventable death on the conventional battlefield or on special operations force (SOF) missions is hemorrhage. SOF missions may take place in remote and austere locations. Many preventable deaths in combat occur within 30 min of wounding. Therefore, SOF damage control resuscitation (DCR) and damage control surgery (DCS) teams may improve combat casualty survival in the SOF environment. OBJECTIVE: To determine the effect of SOF DCR and DCS teams on combat casualty survival. Also, to describe commonalities in team structure, logistics, and blood product usage. DESIGN: A narrative review of the English literature used a Medline and Embase search strategy. The authors were contacted for more details as required. The risk of bias was assessed using the Cochrane Collaboration's ROBINS-I tool. Pooling of data was not done to the heterogeneity of studies. RESULTS: Weak evidence was identified showing a clinical benefit of SOF DCR and DCS teams. Conflicting evidence from less rigorous studies was also found. The overall risk of bias using ROBINS-I was serious to critical. Several commonalities in team structure, training, and logistics were found. CONCLUSIONS AND RELEVANCE: There is conflicting evidence regarding the effect SOF DCR and DCS teams have on combat casualty survival. There is no strong evidence that SOF DCR and DCS teams cause harm. More robust data collection is recommended to evaluate these teams.

The kinetics of glucagon action on the liver during insulin-induced hypoglycemia.

Glucagon's effect on hepatic glucose production (HGP), under hyperglycemic conditions, is time dependent such that after an initial burst of HGP, it slowly wanes. It is not known whether this is also the case under hypoglycemic conditions, where an increase in HGP is essential. This question was addressed using adrenalectomized dogs to avoid the confounding effects of other counterregulatory hormones. During the study, infusions of epinephrine and cortisol were given to maintain basal levels. Somatostatin and insulin (800 µU·kg-1·min-1) were infused to induce hypoglycemia. After 30 min, glucagon was infused at a basal rate (1 ng·kg-1·min-1, baGGN group, n = 5 dogs) or a rate eightfold basal (8 ng·kg-1·min-1, hiGGN group, n = 5 dogs) for 4 h. Glucose was infused to match the arterial glucose levels between groups (≈50 mg/dL). Our data showed that glucagon has a biphasic effect on the liver despite hypoglycemia. Hyperglucagonemia stimulated a rapid, transient peak in HGP (4-fold basal production) over ~60 min, which was followed by a slow reduction in HGP to a rate 1.5-fold basal. During the last 2 h of the experiment, hiGGN stimulated glucose production at a rate fivefold greater than baGGN (2.5 vs. 0.5 mg·kg-1·min-1, respectively), indicating a sustained effect of the hormone. Of note, the hypoglycemia-induced rises in norepinephrine and glycerol were smaller in hiGGN compared with the baGGN group despite identical hypoglycemia. This finding suggests that there is reciprocity between glucagon and the sympathetic nervous system such that when glucagon is increased, the sympathetic nervous response to hypoglycemia is downregulated.

Enterically delivered insulin tregopil exhibits rapid absorption characteristics and a pharmacodynamic effect similar to human insulin in conscious dogs.

AIMS: Current therapy fails to emulate rapid (first-phase) insulin release in relation to a meal, a key defect in types 1 and 2 diabetes. We aimed to quantify the pharmacokinetic (PK) and pharmacodynamic (PD) profile of insulin tregopil, an enterically-absorbed insulin analog that restores the normal distribution of insulin between the hepatic portal and peripheral circulations. MATERIALS AND METHODS: The PK and PD profiles of insulin tregopil were studied in overnight-fasted, catheterized, conscious canines using four approaches: (1) equimolar intraportal infusions of tregopil vs human insulin; (2) escalating doses of oral tregopil; (3) identical, consecutive enteric doses of tregopil; and (4) comparison of oral tregopil to inhaled and subcutaneous human insulin administration. RESULTS: Equimolar intraportal infusions of tregopil and human insulin resulted in very similar PK profiles and PD profiles were nearly identical. Enteric delivery of tregopil brought about rapid absorption with tmax = 20 minutes in most cases. Median tmax was 20 minutes for oral tregopil and inhaled insulin and 88 minutes for subcutaneous human insulin. The time required for arterial plasma insulin levels to return to baseline was approximately 90, 210 and 360 minutes for oral tregopil, inhaled insulin and subcutaneous insulin, respectively. CONCLUSIONS: Enterically delivered tregopil is rapidly absorbed and restores a portal-to-peripheral vascular distribution. These characteristics should improve postprandial hyperglycaemia in types 1 and 2 diabetes.

The biomechanical evaluation of a novel 3-strand docking technique for ulnar collateral ligament reconstruction in the elbow.

BACKGROUND AND HYPOTHESIS: The original 2-strand docking technique for elbow ulnar collateral ligament reconstruction has recently been modified to use a 3-strand graft. To date, no biomechanical study has compared the 2 techniques. We hypothesized that the 3-strand docking technique would restore valgus laxity to its native state, with comparable load-to-failure characteristics to the 2-strand docking technique. MATERIALS AND METHODS: Sixteen fresh cadaveric elbows were matched to the corresponding contralateral side from the same individual to create 8 matched pairs and were then randomized to undergo ulnar collateral ligament reconstruction using either the 2- or 3-strand technique. Valgus laxity and rotation measurements were quantified using a MicroScribe 3DLX digitizer at various flexion angles for the native state, transected state, and 1 of the 2 tested reconstructed ligaments. Each reconstruction was then tested to failure. RESULTS: Valgus laxity for the intact state at elbow flexion angles of 30°, 60°, 90°, and 120° was 7° ± 2°, 7° ± 2°, 6° ± 1°, and 5° ± 2°, respectively. These values were similar to those of both reconstruction techniques. On load-to-failure testing, there was no significant difference in any parameter recorded. Yield torques for the 3- and 2-strand reconstructions were 13.4 ± 4.80 N/m and 11.8 ± 4.76 N/m, respectively (P = .486). The ultimate torques were 15.7 ± 6.10 N/m and 14.4 ± 5.58 N/m for the 3- and 2-strand techniques, respectively (P = .582). CONCLUSION: The 3-strand docking technique was able to restore valgus laxity to the native state, with similar load-to-failure characteristics to the 2-strand docking technique.

Glucagon's effect on liver protein metabolism in vivo.

The postprandial state is characterized by a storage of nutrients in the liver, muscle, and adipose tissue for later utilization. In the case of a protein-rich meal, amino acids (AA) stimulate glucagon secretion by the α-cell. The aim of the present study was to determine the impact of the rise in glucagon on AA metabolism, particularly in the liver. We used a conscious catheterized dog model to recreate a postprandial condition using a pancreatic clamp. Portal infusions of glucose, AA, and insulin were used to achieve postprandial levels, while portal glucagon infusion was either maintained at the basal level or increased by three-fold. The high glucagon infusion reduced the increase in arterial AA concentrations compared with the basal glucagon level (-23%, P < 0.05). In the presence of high glucagon, liver AA metabolism shifted toward a more catabolic state with less protein synthesis (-36%) and increased urea production (+52%). Net hepatic glucose uptake was reduced modestly (-35%), and AA were preferentially used in gluconeogenesis, leading to lower glycogen synthesis (-54%). The phosphorylation of AMPK was increased by the high glucagon infusion (+40%), and this could be responsible for increasing the expression of genes related to pathways producing energy and lowering those involved in energy consumption. In conclusion, the rise in glucagon associated with a protein-rich meal promotes a catabolic utilization of AA in the liver, thereby, opposing the storage of AA in proteins.

Glucose autoregulation is the dominant component of the hormone-independent counterregulatory response to hypoglycemia in the conscious dog.

The contribution of hormone-independent counterregulatory signals in defense of insulin-induced hypoglycemia was determined in adrenalectomized, overnight-fasted conscious dogs receiving hepatic portal vein insulin infusions at a rate 20-fold basal. Either euglycemia was maintained (group 1) or hypoglycemia (≈45 mg/dl) was allowed to occur. There were three hypoglycemic groups: one in which hepatic autoregulation against hypoglycemia occurred in the absence of sympathetic nervous system input (group 2), one in which autoregulation occurred in the presence of norepinephrine (NE) signaling to fat and muscle (group 3), and one in which autoregulation occurred in the presence of NE signaling to fat, muscle, and liver (group 4). Average net hepatic glucose balance (NHGB) during the last hour for groups 1-4 was -0.7 ± 0.1, 0.3 ± 0.1 (P < 0.01 vs. group 1), 0.7 ± 0.1 (P = 0.01 vs. group 2), and 0.8 ± 0.1 (P = 0.7 vs. group 3) mg·kg-1·min-1, respectively. Hypoglycemia per se (group 2) increased NHGB by causing an inhibition of net hepatic glycogen synthesis. NE signaling to fat and muscle (group 3) increased NHGB further by mobilizing gluconeogenic precursors resulting in a rise in gluconeogenesis. Lowering glucose per se decreased nonhepatic glucose uptake by 8.9 mg·kg-1·min-1, and the addition of increased neural efferent signaling to muscle and fat blocked glucose uptake further by 3.2 mg·kg-1·min-1 The addition of increased neural efferent input to liver did not affect NHGB or nonhepatic glucose uptake significantly. In conclusion, even in the absence of increases in counterregulatory hormones, the body can defend itself against hypoglycemia using glucose autoregulation and increased neural efferent signaling, both of which stimulate hepatic glucose production and limit glucose utilization.

Differential Toxicities of Nickel Salts to the Nematode Caenorhabditis elegans.

This study focused on assessing whether nickel (Ni) toxicity to the nematode Caenorhabditis elegans was affected by the molecular structure of the Ni salt used. Nematodes were exposed to seven Ni salts [Ni sulfate hexahydrate (NiSO4·6H2O), Ni chloride hexahydrate (NiCl2·6H2O), Ni acetate tetrahydrate (Ni(OCOCH3)2·4H2O), Ni nitrate hexahydrate (N2NiO6·6H2O), anhydrous Ni iodide (NiI2), Ni sulfamate hydrate (Ni(SO3NH2)2·H2O), and Ni fluoride tetrahydrate (NiF2·4H2O)] in an aquatic medium for 24 h, and lethality curves were generated and analyzed. Ni fluoride, Ni iodide, and Ni chloride were most toxic to C. elegans, followed by Ni nitrate, Ni sulfamate, Ni acetate, and Ni sulfate. The LC50 values of the halogen-containing salts were statistically different from the corresponding value of the least toxic salt, Ni sulfate. This finding is consistent with the expected high bioavailability of free Ni ions in halide solutions. We recommend that the halide salts be used in future Ni testing involving aquatic invertebrates.

Tennis injuries: epidemiology, pathophysiology, and treatment.

Tennis places high loads on the joints of players, with supraphysiologic forces being generated at the shoulder and elbow hundreds of times per match. Acute injuries tend to affect the lower extremity; chronic injuries usually involve the upper extremity. Commonly encountered upper extremity conditions include rotator cuff injury, internal impingement, superior labral tears, and epicondylitis of the elbow. Serving is the most strenuous stroke in tennis, with the highest peak muscle activity in the shoulder and forearm occurring during this stroke. The kinetic chain links upper extremity, lower extremity, and core muscle segments by transmitting coordinated activation and motion; in this regard, any pathologic process that disturbs the groin, hip, and abdominal musculature can further result in an increased risk of injury to the shoulder and upper extremity. Evolution in equipment and in play surfaces has also affected the type and frequency of injuries. Prevention programs that address the muscular imbalances throughout the kinetic chain may help reduce the incidence of both acute and chronic injuries experienced by tennis athletes.

Canine body composition quantification using 3 tesla fat-water MRI.

PURPOSE: To test the hypothesis that a whole-body fat-water MRI (FWMRI) protocol acquired at 3 Tesla combined with semi-automated image analysis techniques enables precise volume and mass quantification of adipose, lean, and bone tissue depots that agree with static scale mass and scale mass changes in the context of a longitudinal study of large-breed dogs placed on an obesogenic high-fat, high-fructose diet. MATERIALS AND METHODS: Six healthy adult male dogs were scanned twice, at weeks 0 (baseline) and 4, of the dietary regiment. FWMRI-derived volumes of adipose tissue (total, visceral, and subcutaneous), lean tissue, and cortical bone were quantified using a semi-automated approach. Volumes were converted to masses using published tissue densities. RESULTS: FWMRI-derived total mass corresponds with scale mass with a concordance correlation coefficient of 0.931 (95% confidence interval = [0.813, 0.975]), and slope and intercept values of 1.12 and -2.23 kg, respectively. Visceral, subcutaneous and total adipose tissue masses increased significantly from weeks 0 to 4, while neither cortical bone nor lean tissue masses changed significantly. This is evidenced by a mean percent change of 70.2% for visceral, 67.0% for subcutaneous, and 67.1% for total adipose tissue. CONCLUSION: FWMRI can precisely quantify and map body composition with respect to adipose, lean, and bone tissue depots. The described approach provides a valuable tool to examine the role of distinct tissue depots in an established animal model of human metabolic disease.

Toxicity testing of neurotoxic pesticides in Caenorhabditis elegans.

The use of pesticides is ubiquitous worldwide, and these chemicals exert adverse effects on both target and nontarget species. Understanding the modes of action of pesticides, as well as quantifying exposure concentration and duration, is an important goal of clinicians and environmental health scientists. Some chemical exposures result in adverse effects on the nervous system. The nematode Caenorhabditis elegans (C. elegans) is a model lab organism well established for studying neurotoxicity, since the components of its nervous system are mapped and known, and most of its neurotransmitters correspond to human homologs. This review encompasses published studies in which C. elegans nematodes were exposed to pesticides with known neurotoxic actions. Endpoints measured include changes in locomotion, feeding behavior, brood size, growth, life span, and cell death. From data presented, evidence indicates that C. elegans can serve a role in assessing the effects of neurotoxic pesticides at the sublethal cellular level, thereby advancing our understanding of the mechanisms underlying toxicity induced by these chemicals. A proposed toxicity testing scheme for water-soluble chemicals is also included.

Prevalence and mutation analysis of short/branched chain acyl-CoA dehydrogenase deficiency (SBCADD) detected on newborn screening in Wisconsin.

Short/branched chain acyl-CoA dehydrogenase deficiency (SBCADD), also called 2-methylbutyryl CoA dehydrogenase deficiency (2-MBCDD), is a disorder of l-isoleucine metabolism of uncertain clinical significance. SBCADD is inadvertently detected on expanded newborn screening by elevated 2-methylbutyrylcarnitine (C5), which has the same mass to charge (m/s) on tandem mass spectrometry (MS/MS) as isovalerylcarnitine (C5), an analyte that is elevated in isovaleric acidemia (IVA), a disorder in leucine metabolism. SBCADD cases identified in the Hmong-American population have been found in association with the c.1165 A>G mutation in the ACADSB gene. The purposes of this study were to: (a) estimate the prevalence of SBCADD and carrier frequency of the c.1165 A>G mutation in the Hmong ethnic group; (b) determine whether the c.1165 A>G mutation is common to all Hmong newborns screening positive for SBCADD; and (c) evaluate C5 acylcarnitine cut-off values to detect and distinguish between SBCADD and IVA diagnoses. During the first 10years of expanded newborn screening using MS/MS in Wisconsin (2001-2011), 97 infants had elevated C5 values (≥0.44µmol/L), of whom five were Caucasian infants confirmed to have IVA. Of the remaining 92 confirmed SBCADD cases, 90 were of Hmong descent. Mutation analysis was completed on an anonymous, random sample of newborn screening cards (n=1139) from Hmong infants. Fifteen infants, including nine who had screened positive for SBCADD based on a C5 acylcarnitine concentration ≥0.44µmol/L, were homozygous for the c.1165 A>G mutation. This corresponds to a prevalence in this ethnic group of being homozygous for the mutation of 1.3% (95% confidence interval 0.8-2.2%) and of being heterozygous for the mutation of 21.8% (95% confidence interval 19.4-24.3%), which is consistent with the Hardy-Weinberg equilibrium. Detection of homozygous individuals who were not identified on newborn screening suggests that the C5 screening cut-off would need to be as low as 0.20µmol/L to detect all infants homozygous for the ACADSB c.1165 A>G mutation. However, lowering the screening cut-off to 0.20 would also result in five "false positive" (non-homozygous) screening results in the Hmong population for every c.1165 A>G homozygote detected. Increasing the cut-off to 0.60µmol/L and requiring elevated C5/C2 (acetylcarnitine) and C5/C3 (propionylcarnitine) ratios to flag a screen as abnormal would reduce the number of infants screening positive, but would still result in an estimated 5 infants with SBCADD per year who would require follow-up and additional biochemical testing to distinguish between SBCADD and IVA diagnoses. Further research is needed to determine the clinical outcomes of SBCADD detected on newborn screening and the c.1165 A>G mutation before knowing whether the optimal screening cut-off would minimize true positives or false negatives for SBCADD associated with this mutation.

B cells assist allograft rejection in the deficiency of protein kinase c-theta.

We have previously shown that mice deficient in protein kinase C theta (PKCθ) have the ability to reject cardiac allografts, but are susceptible to tolerance induction. Here we tested role of B cells in assisting alloimmune responses in the absence of PKCθ. Mouse cardiac allograft transplantations were performed from Balb/c (H-2d) to PKCθ knockout (PKCθ(-/-)), PKCθ and B cell double-knockout (PBDK, H-2b) mice and wild-type (WT) C57BL/6 (H-2b) mice. PBDK mice spontaneously accepted the allografts with the inhibition of NF-κB activation in the donor cardiac allograft. Anti-B cell antibody (rituximab) significantly delayed allograft rejection in PKCθ(-/-), but not in WT mice. Co-transfer of PKCθ(-/-) T plus PKCθ(-/-) B cells or primed sera triggered allograft rejection in Rag1(-/-) mice, and only major histocompatibility complex class II-enriched B cells, but not class I-enriched B cells, were able to promote rejection. This, together with the inability of PKCθ(-/-) and CD28(-/-) double-deficient (PCDK) mice to acutely reject allografts, suggested that an effective cognate interaction between PKCθ(-/-) T and B cells for acute rejection is CD28 molecule dependent. We conclude that T-B cell interactions synergize with PKCθ(-/-) T cells to mediate acute allograft rejection.

Bacteria pyruvate metabolism modulates AFB1 toxicity in Caenorhabditis elegans.

Aflatoxin B1 (AFB1), the most potent mycotoxin and Group 1 human carcinogen, continues to pose a significant public health burden, particularly in developing countries. Increasing evidence has shown the gut microbiota as a key mediator of AFB1 toxicity through multiple interactive host-microbiota activities. In our previous study we observed that disturbances in bacterial pyruvate metabolism might have a significant impact on AFB1 in the host. To further investigate the impact of the pyruvate pathway on AFB1 toxicity in C. elegans, we engineered two bacterial strains (triple-overexpressed and triple-knockout strains with aceB, lpd, and pflB). Additionally, we employed two mutant worm strains (pyk-1 and pdha-1 mutants) known to affect pyruvate metabolism. Our results revealed that the co-metabolism of pyruvate by the host and bacterial strains synergistically influences AFB1 toxicity. Remarkable, we found that bacterial pyruvate metabolism, rather than that of the host, plays a pivotal role in modulating AFB1 toxicity in C. elegans. Our study sheds light on the role of gut microbiota involved in pyruvate metabolism in influencing AFB1 toxicity in C. elegans.

Host-microbiota affects the toxicity of Aflatoxin B1 in Caenorhabditis elegans.

Aflatoxins are a group of potent fungal metabolites produced by Aspergillus and commonly contaminate groundnuts and cereal grains. Aflatoxin B1 (AFB1), the most potent mycotoxin, has been classified as Group 1 human carcinogen because it can be metabolically activated by the cytochrome P450 (CYP450) in the liver to form AFB1-DNA adducts and induce gene mutations. Increasing evidence has shown the gut microbiota as a key mediator of AFB1 toxicity through multiple interactive host-microbiota activities. To identify specific bacterial activity that modulates AFB1 toxicity in Caenorhabditis (C.) elegans, we established a 3-way (microbe-worm-chemical) high-throughput screening system using C. elegans fed E. coli Keio collection on an integrated robotic platform, COPAS Biosort. We performed 2-step screenings using 3985 Keio mutants and identified 73 E. coli mutants that modulated C. elegans growth phenotype. Four genes (aceA, aceB, lpd, and pflB) involved in the pyruvate pathway were identified from the screening and confirmed to increase the sensitivity of all animals to AFB1. Taking together, our results indicated that disturbances in bacterial pyruvate metabolism might have a significant impact on AFB1 toxicity in the host.

Multivariate analysis of breast tissue using optical parameters extracted from a combined time-resolved fluorescence and diffuse reflectance system for tumor margin detection.

Significance: Breast conservation therapy is the preferred technique for treating primary breast cancers. However, breast tumor margins are hard to determine as tumor borders are often ill-defined. As such, there exists a need for a clinically compatible tumor margin detection system. Aim: A combined time-resolved fluorescence and diffuse reflectance (TRF-DR) system has been developed to determine the optical properties of breast tissue. This study aims to improve tissue classification to aid in surgical decision making. Approach: Normal and tumor breast tissue were collected from 80 patients with invasive ductal carcinoma and measured in the optical system. Optical parameters were extracted, and the tissue underwent histopathological examination. In total, 761 adipose, 77 fibroglandular, and 347 tumor spectra were analyzed. Principal component analysis and decision tree modeling were performed using only TRF optical parameters, only DR optical parameters, and using the combined datasets. Results: The classification modeling using TRF data alone resulted in a tumor margin detection sensitivity of 72.3% and specificity of 88.3%. Prediction modeling using DR data alone resulted in greater sensitivity and specificity of 80.4% and 94.0%, respectively. Combining both datasets resulted in the improved sensitivity and specificity of 85.6% and 95.3%, respectively. While both sensitivity and specificity improved with the combined modeling, further study of fibroglandular tissue could result in improved classification. Conclusion: The combined TRF-DR system showed greater tissue classification capability than either technique alone. Further work studying more fibroglandular tissue and tissue of mixed composition would develop this system for intraoperative use for tumor margin detection.

Capturing the True Cost of Breast Cancer Treatment: Molecular Subtype and Stage-Specific per-Case Activity-Based Costing.

BACKGROUND: Breast cancer (BC) treatment is rapidly evolving with new and costly therapeutics. Existing costing models have a limited ability to capture current treatment costs. We used an Activity-Based Costing (ABC) method to determine a per-case cost for BC treatment by stage and molecular subtype. METHODS: ABC was used to proportionally integrate multidisciplinary evidence-based patient and provider treatment options for BC, yielding a per-case cost for the total duration of treatment by stage and molecular subtype. Diagnostic imaging, pathology, surgery, radiation therapy, systemic therapy, inpatient, emergency, home care and palliative care costs were included. RESULTS: BC treatment costs were higher than noted in previous studies and varied widely by molecular subtype. Cost increased exponentially with the stage of disease. The per-case cost for treatment (2023C$) for DCIS was C$ 14,505, and the mean costs for all subtypes were C$ 39,263, C$ 76,446, C$ 97,668 and C$ 370,398 for stage I, II, III and IV BC, respectively. Stage IV costs were as high as C$ 516,415 per case. When weighted by the proportion of molecular subtype in the population, case costs were C$ 31,749, C$ 66,758, C$ 111,368 and C$ 289,598 for stage I, II, III and IV BC, respectively. The magnitude of cost differential was up to 10.9 times for stage IV compared to stage I, 4.4 times for stage III compared to stage I and 35.6 times for stage IV compared to DCIS. CONCLUSION: The cost of BC treatment is rapidly escalating with novel therapies and increasing survival, resulting in an exponential increase in treatment costs for later-stage disease. We provide real-time, case-based costing for BC treatment which will allow for the assessment of health system economic impacts and an accurate understanding of the cost-effectiveness of screening.

Portal glucose delivery stimulates muscle but not liver protein metabolism.

Portal vein glucose delivery (the portal glucose signal) stimulates glucose uptake and glycogen storage by the liver, whereas portal amino acid (AA) delivery (the portal AA signal) induces an increase in protein synthesis by the liver. During a meal, both signals coexist and may interact. In this study, we compared the protein synthesis rates in the liver and muscle in response to portal or peripheral glucose infusion during intraportal infusion of a complete AA mixture. Dogs were surgically prepared with hepatic sampling catheters and flow probes. After a 42-h fast, they underwent a 3-h hyperinsulinemic (4× basal) hyperglucagonemic (3× basal) hyperglycemic (≈160 mg/dl) hyperaminoacidemic (hepatic load 1.5× basal; delivered intraportally) clamp (postprandial conditions). Glucose was infused either via a peripheral (PeG; n = 7) or the portal vein (PoG; n = 8). Protein synthesis was assessed with a primed, continuous [(14)C]leucine infusion. Net hepatic glucose uptake was stimulated by portal glucose infusion (+1 mg·kg(-1)·min(-1), P < 0.05) as expected, but hepatic fractional AA extraction and hepatic protein synthesis did not differ between groups. There was a lower arterial AA concentration in the PoG group (-19%, P < 0.05) and a significant stimulation (+30%) of muscle protein synthesis associated with increased expression of LAT1 and ASCT2 AA transporters and p70S6 phosphorylation. Concomitant portal glucose and AA delivery enhances skeletal muscle protein synthesis compared with peripheral glucose and portal AA delivery. These data suggest that enteral nutrition support may have an advantage over parenteral nutrition in stimulating muscle protein synthesis.