Myosteatosis evaluation using erector spinae and psoas muscles to predict adverse events during adjuvant chemotherapy for breast cancer.

BACKGROUND: Myosteatosis (intramuscular adiposity) is predictive of chemotherapy toxicity in women undergoing adjuvant chemotherapy for breast cancer (BC). We evaluated a novel, user-friendly and cost-effective technique utilizing a Picture Archiving and Communication Systems (PACS) tool that is readily available in the electronic medical record (EMR), using skeletal muscle density (SMD) to detect myosteatosis and then compared PACS results with those derived from widely used body composition software (SliceOMatic, QC, Canada). METHODS: Using retrospective data from a sample of women with early BC (Stage I-III) who had CT scan and received chemotherapy. Pearson correlation coefficients were used to compare SliceOMatic with PACS results. Associations of PACS results with chemotherapy-related adverse events were evaluated using multivariable (MV) log-binomial models adjusted for age, race, BMI, anthracycline-based therapy, and number of comorbidities. RESULTS: In 338 patients, mean age was 51, 32% were non-white, and 40% had obesity (BMI ≥ 30 kg/m2). Correlation of SMD using SliceOMatic whole muscle measurements with PACS psoas muscle was 0.76 (p < .0001) and with PACS erector spinae muscle 0.91 (p < .0001). Using PACS psoas muscle, myosteatosis was associated with any adverse event [RR 1.66, CI 1.22-2.26 (p < .0001)], dose reduction [RR 1.63, CI 1.01-2.65 (p = .05)], and early treatment discontinuation [RR 2.14, CI 1.10-4.14 (p = 0.03)]. Using PACS erector spinae muscle, myosteatosis was associated any adverse event [RR 1.59, CI 1.11-2.27 (p = 0.01)] and dose reduction [RR 1.91, CI 1.07-3.42 (p = .03)]. CONCLUSION AND RELEVANCE: Skeletal muscle density measures using PACS correlated strongly with SliceOMatic results and both are similarly predictive of chemotherapy-related adverse events.

Disrupting LXRα phosphorylation promotes FoxM1 expression and modulates atherosclerosis by inducing macrophage proliferation.

Macrophages are key immune cells for the initiation and development of atherosclerotic lesions. However, the macrophage regulatory nodes that determine how lesions progress in response to dietary challenges are not fully understood. Liver X receptors (LXRs) are sterol-regulated transcription factors that play a central role in atherosclerosis by integrating cholesterol homeostasis and immunity. LXR pharmacological activation elicits a robust antiatherosclerotic transcriptional program in macrophages that can be affected by LXRα S196 phosphorylation in vitro. To investigate the impact of these transcriptional changes in atherosclerosis development, we have generated mice carrying a Ser-to-Ala mutation in myeloid cells in the LDL receptor (LDLR)-deficient atherosclerotic background (M-S196ALdlr-KO). M-S196ALdlr-KO mice fed a high-fat diet exhibit increased atherosclerotic plaque burden and lesions with smaller necrotic cores and thinner fibrous caps. These diet-induced phenotypic changes are consistent with a reprogramed macrophage transcriptome promoted by LXRα-S196A during atherosclerosis development. Remarkably, expression of several proliferation-promoting factors, including the protooncogene FoxM1 and its targets, is induced by LXRα-S196A. This is consistent with increased proliferation of plaque-resident cells in M-S196ALdlr-KO mice. Moreover, disrupted LXRα phosphorylation increases expression of phagocytic molecules, resulting in increased apoptotic cell removal by macrophages, explaining the reduced necrotic cores. Finally, the macrophage transcriptome promoted by LXRα-S196A under dietary perturbation is markedly distinct from that revealed by LXR ligand activation, highlighting the singularity of this posttranslational modification. Overall, our findings demonstrate that LXRα phosphorylation at S196 is an important determinant of atherosclerotic plaque development through selective changes in gene transcription that affect multiple pathways.

Pigeon Circovirus over Three Decades of Research: Bibliometrics, Scoping Review, and Perspectives.

The pigeon circovirus (PiCV), first described in the literature in the early 1990s, is considered one of the most important infectious agents affecting pigeon health. Thirty years after its discovery, the current review has employed bibliometric strategies to map the entire accessible PiCV-related research corpus with the aim of understanding its present research landscape, particularly in consideration of its historical context. Subsequently, developments, current knowledge, and important updates were provided. Additionally, this review also provides a textual analysis examining the relationship between PiCV and the young pigeon disease syndrome (YPDS), as described and propagated in the literature. Our examination revealed that usages of the term 'YPDS' in the literature are characterizations that are diverse in range, and neither standard nor equivalent. Guided by our understanding of the PiCV research corpus, a conceptualization of PiCV diseases was also presented in this review. Proposed definitions and diagnostic criteria for PiCV subclinical infection (PiCV-SI) and PiCV systemic disease (PiCV-SD) were also provided. Lastly, knowledge gaps and open research questions relevant to future PiCV-related studies were identified and discussed.

Genetic regulation of the immune response to hepatitis B surface antigen (HBsAg). IV. Distinct H-2-linked Ir genes control antibody responses to different HBsAg determinants on the same molecule and map to the I-A and I-C subregions.

We have previously demonstrated that the murine humoral immune responses to the group-specific a and subtype-specific d/y determinants of hepatitis B surface antigen (HBsAg) are controlled by H-2-linked immune response (Ir) genes. High responder (H-2d,q), intermediate responder (H-2a greater than b greater than k) and nonresponder (H-2f,s) haplotypes have been identified (8, 9). The kinetics and specificity of in vivo antibody production after HBsAg immunization in congeneic, H-2-recombinant strains was analyzed to further define relevant Ir genes and their influence on the immune response to distinct antigenic determinants. These studies indicate that the humoral anti-HBs response is regulated by at least two Ir genes, one in the I-A subregion (Ir-HBs-1) and one in the I-C subregion (Ir-HBs-2) of the murine H-2 complex. Ir-HBs-1 regulates the primary responses to all HBsAg determinants, whereas the influence of Ir-HBs-2 is determinant specific, affecting the responses to the d or y determinants. The anti-a response is regulated exclusively by Ir-HBs-1. Strains possessing only the Ir-HBs-2 gene [B10.S(9R) and B10.HTT] produce no anti-a response and a subtype-specific antibody response is detected only after secondary or tertiary immunization. In contrast, the influence of Ir-HBs-2 in the presence of Ir-HBs-1 is detected upon primary immunization and is additive rather than exclusive. There is also suggestive evidence that the presence of the Ek molecule, at least in the context of I-Ak, may have a suppressive influence on the anti-HBs response. Additionally, HBsAg-specific, T cell proliferative responses were H-2 restricted and the kinetics and specificity of T cell proliferative responses paralleled in vivo antibody production. These data indicate that, although the I-A subregion exerts a dominant influence, distinct Ir-HBs genes, mapping in separate I subregions, control immune responses to alternate HBsAg determinants on the same protein molecule.

Modeling the aneuploidy control of cancer.

BACKGROUND: Aneuploidy has long been recognized to be associated with cancer. A growing body of evidence suggests that tumorigenesis, the formation of new tumors, can be attributed to some extent to errors occurring at the mitotic checkpoint, a major cell cycle control mechanism that acts to prevent chromosome missegregation. However, so far no statistical model has been available quantify the role aneuploidy plays in determining cancer. METHODS: We develop a statistical model for testing the association between aneuploidy loci and cancer risk in a genome-wide association study. The model incorporates quantitative genetic principles into a mixture-model framework in which various genetic effects, including additive, dominant, imprinting, and their interactions, are estimated by implementing the EM algorithm. RESULTS: Under the new model, a series of hypotheses tests are formulated to explain the pattern of the genetic control of cancer through aneuploid loci. Simulation studies were performed to investigate the statistical behavior of the model. CONCLUSIONS: The model will provide a tool for estimating the effects of genetic loci on aneuploidy abnormality in genome-wide studies of cancer cells.

The Mdm1 Locus and Maize Resistance to Maize dwarf mosaic virus.

Previously, Mdm1, a gene controlling resistance to Maize dwarf mosaic virus (MDMV), was identified in the inbred line Pa405. The gene was tightly linked to the restriction fragment length polymorphism marker umc85 on the short arm of chromosome 6. This chromosomal region is also the location of resistance genes to two other viruses in the family Potyviridae, Sugarcane mosaic virus (SCMV) and Wheat streak mosaic virus (WSMV). A diverse collection of 115 maize inbred lines was evaluated for resistance to MDMV and SCMV, and for MDMV resistance loci on chromosome 6S. Forty-six resistant inbred lines were crossed to three MDMVsusceptible inbred lines to develop F2 populations. The F2 populations were inoculated with MDMV and scored for infection and symptom type. Environmental factors influenced both the rate and type of symptom development. Bulked segregant analysis of each F2 population indicated that, in 42 of 43 MDMV-resistant lines, chromosome 6S markers found in the resistant parent also were present in the bulked resistant but not the susceptible tissue. Markers previously associated with resistance to both SCMV and WSMV on chromosome 3 and to WSMV on chromosome 10 were associated with resistance in nine and seven of the F2 populations, respectively. These data suggest that Mdm1 or closely linked genes on chromosome 6S are associated with MDMV resistance in most germplasm, but that other loci also may affect resistance.

The histone demethylase KDM4B regulates peritoneal seeding of ovarian cancer.

Epithelial ovarian cancer (EOC) has poor prognosis and rapid recurrence because of widespread dissemination of peritoneal metastases at diagnosis. Multiple pathways contribute to the aggressiveness of ovarian cancer, including hypoxic signaling mechanisms. In this study, we have determined that the hypoxia-inducible histone demethylase KDM4B is expressed in ∼60% of EOC tumors assayed, including primary and matched metastatic tumors. Expression of KDM4B in tumors is positively correlated with expression of the tumor hypoxia marker CA-IX, and is robustly induced in EOC cell lines exposed to hypoxia. KDM4B regulates expression of metastatic genes and pathways, and loss of KDM4B increases H3K9 trimethylation at the promoters of target genes like LOXL2, LCN2 and PDGFB. Suppressing KDM4B inhibits ovarian cancer cell invasion, migration and spheroid formation in vitro. KDM4B also regulates seeding and growth of peritoneal tumors in vivo, where its expression corresponds to hypoxic regions. This is the first demonstration that a Jumonji-domain histone demethylase regulates cellular processes required for peritoneal dissemination of cancer cells, one of the predominant factors affecting prognosis of EOC. The pathways regulated by KDM4B may present novel opportunities to develop combinatorial therapies to improve existing therapies for EOC patients.

Complex replication error causes p53 mutation in a Li-Fraumeni family.

We demonstrated a germline p53 replication error in two generations of a Li-Fraumeni family affected with liposarcoma, adrenocortical carcinoma, and osteosarcoma. The trinucleotide repeat mutation changed 5'-AGT GTG GTG GTG-3' at codons 215-218 to 5'-AGT TGG TTG GTG GTG-3'. The predicted protein would be elongated by one amino acid (val216-->trp leu) without a change in charge. Detection of p53 in the adrenal tumor by immunostaining suggested that the mutant protein was expressed. Persistence of the mutation in the germline may suggest a defect in DNA repair in the family member first affected. This is the first report where germline transmission of replication-damaged p53 trinucleotide repeats is associated with the Li-Fraumeni syndrome.

ErbB3 upregulation by the HNSCC 3D microenvironment modulates cell survival and growth.

Head and neck squamous carcinomas (HNSCC) present as dense epithelioid three-dimensional (3D) tumor nests that can mediate signals via the human epidermal growth factor receptor (ErbB) tyrosine kinase family to promote intratumoral survival and growth. We examined the role of the tumor microenvironment on ErbB receptor family expression and found that the status of intercellular organization altered the receptor profile. We showed that HNSCC cells forced into tumor island-like 3D aggregates strongly upregulated ErbB3 at the level of transcription. Not only was the elevated ErbB3 responsive to HRG-ß1-induced enhanced signaling mechanism, but also analysis by siRNA-knockdown and kinase inhibitor strategies revealed that the ErbB3/AKT signaling pathway was sufficient to enhance tumor cell survival and growth potential. Elevated ErbB3 expression in the high-density 3D culture system was strongly associated with hypoxia-induced HIF-1α. Hypoxia-regulated ErbB3 expression was mediated by the HIF-1α-binding consensus sequence in the ErbB3 proximal promoter. The findings show that the local 3D tumor microenvironment can trigger reprograming and switching of ErbB family members and thereby influence ErbB3-driven tumor growth.

Tumor necrosis factor-alpha inhibits leptin production in subcutaneous and omental adipocytes from morbidly obese humans.

This study was undertaken to examine the regulation of leptin production from human adipocytes by tumor necrosis factor-alpha (TNFalpha). Adipocytes were isolated from adipose tissue obtained during bariatric surgical procedures (17 women and 3 men; body mass index, 52.5 +/- 2.4 kg/m2; age, 40 +/- 3 yr) and cultured in suspension. Leptin release from sc adipocytes was inhibited 17.7 +/- 5.2% (P < 0.01), 21.6 +/- 4.3% (P < 0.005), and 37.1 +/- 7.2% (P < 0.05) by 1, 10, and 100 ng/mL TNFalpha, respectively, after 48 h in culture. At 100 ng/mL, significant inhibition of leptin release (25.8 +/- 9.7%; P < 0.05) was detected by 24 h. TNFalpha (10 ng/mL) had no effect on dexamethasone (0.1 micromol/L)-stimulated leptin production in sc adipocytes. In omental adipocytes TNFalpha inhibited leptin release 21.0 +/- 9.6% and 40.8 +/- 6.3% at 10 and 100 ng/mL by 48 h (P < 0.05). Significant inhibition ofleptin release from omental adipocytes was observed at 24 h with 100 ng/mL TNFalpha (P < 0.05). Anti-TNFalpha antibody completely blocked TNFalpha inhibition of leptin release. The ob messenger ribonucleic acid was significantly reduced (23.6 +/- 5.9%) after 48 h of TNFalpha (100 ng/mL) treatment (P < 0.025). TNFalpha had no effect on glucose uptake or lactate production in sc and omental adipocytes. The data suggest that the direct paracrine effect of adipose-derived TNFalpha is inhibition of leptin production.

Inactivation of viruses in therapeutic products derived from human plasma.

Alpha-1-proteinase inhibitor concentrates have been prepared from pooled human plasma for therapeutic applications. Pasteurization (60 degrees C, 10 hours) conditions have been defined to reduce risks of transmission of viral agents without significant loss of biologic activity of the purified product. Human clinical data collected to date support the model virus inactivation studies regarding viral safety.

Antibody levels in reduced/alkylated intravenous immune globulin.

Antibody titers, found in representative lots of a reduced and alkylated intravenous immune globulin, against a variety of common microorganisms are presented. With the more frequently occurring pathogens the specific antibody level does not vary significantly between lots. Depending upon the type of assay used, antibody titers per se may or may not reflect the therapeutic activity of the preparation against a specific microorganism.

Malignant nerve sheath tumor containing endocrine cells.

A malignant nerve sheath tumor occurred in the thigh of a 29-year-old man who had the stigmata of von Recklinghausen's neurofibromatosis. Chondroid foci, rhabdomyoblasts, and mucus-containing acini were identified in the tumor. Argyrophil cells and somatostatin-immunoreactive cells were present in acinar epithelium. Endocrine type granules were found in epithelial cells on ultrastructural examination. This is an example of a so-called "glandular schwannoma" and is unique in that it contained somatostatin-immunoreactive cells. A neural crest derivation is suggested for this complex tumor.

Effects of drugs on glucose measurements with handheld glucose meters and a portable glucose analyzer.

Thirty drugs used primarily in critical care and hospital settings were tested in vitro to observe interference on glucose measurements with 6 hand-held glucose meters and a portable glucose analyzer. Paired differences of glucose measurements between drug-spiked samples and unspiked control samples were calculated to determine bias. A criterion of +/- 6 mg/dL was used as the cutoff for interference. Ascorbic acid interfered with the measurements on all glucose devices evaluated. Acetaminophen, dopamine, and mannitol interfered with glucose measurements on some devices. Dose-response relationships help assessment of drug interference in clinical use. High dosages of these drugs may be given to critically ill patients or self-administered by patients without medical supervision. Package inserts for the glucose devices may not provide adequate warning information. Hence, we recommend that clinicians choose glucose devices carefully and interpret results cautiously when glucose measurements are performed during or after drug interventions.

Transmission of viral RNA and DNA to maize kernels by vascular puncture inoculation.

Vascular puncture inoculation (VPI) is an effective technique for transmission of maize viruses without using arthropods or other biological vectors. It involves using a jeweler's engraving tool to push minuten pins through a droplet of virus inoculum toward the major vascular bundle in the scutellum of germinating kernels. Here, VPI is shown to be useful for introducing RNA and DNA viral genomes into maize. Maize dwarf mosaic potyvirus (MDMV) virions, MDMV genomic RNA, foxtail mosaic potexvirus (FoMV) genomic RNA and maize streak geminivirus (MSV) DNA were introduced into kernels by VPI, and infection rates determined. At high concentrations, both MDMV virion and genomic RNA preparations produced 100% infection of susceptible maize. However, MDMV genomic RNA was transmitted with about 100-fold lower efficiency than virions. FoMV genomic RNA and MSV DNA were transmitted at lower efficiency than the MDMV RNA, and the highest transmission rates were about 50%. Ribonuclease A pretreatment prevented genomic MDMV and FoMV RNA transmission, but not MDMV virion transmission indicating the viral RNA was the infectious entity. Proteinase K (ProK) pretreatment reduced transmission of MDMV RNA suggesting that integrity of the viral genomic protein bound covalently to the viral RNA may be important for efficient transmission.

The first hit: circumstances surrounding initiation into injecting.

Initiation into injecting is a crucial event for continued reproduction of an injecting drug using (IDU) population and for exposure to blood-borne viruses, but little is known about how this happens. Three hundred young injectors were interviewed in Melbourne by peer workers within the first few years of beginning to inject, about the circumstances surrounding their initiation. Most had indications of social disruption, including having left school early, unemployment, family disruption, homelessness and incarceration. First drug injected was most often amphetamines (average age 16 years), most having already used amphetamines by a different route of administration, but with a steady movement thereafter to heroin as the drug of choice. The most common scenario was one in which injecting was unplanned but the person was active in bringing about the initiation. Most identified a significant other who initiated them (few of whom were dealers), and over half had subsequently initiated others into injecting, on average 0.6 per year; after 5 years 237 young injectors had initiated at least 420 others. Those who initiated multiple others were more likely to be unemployed, to inject multiple drugs and to have dealt. Modelling injecting as a communicable phenomenon, where appropriate, may help estimate population dynamics among IDUs. Peer education programmes are likely to be the most effective harm reduction approach among new injectors.

Oxygen effects on glucose measurements with a reference analyzer and three handheld meters.

Oxygen may affect glucose meter and reference analyzer measurements. We evaluated the effects of changes in blood oxygen tension (Po2) on Accu-Chek Comfort Curve (Roche Diagnostics, Indianapolis, IN), Precision G, (Abbott Laboratories, Bedford, MA) and One Touch II (Lifescan, Milpitas, CA) glucose meter measurements, and on Yellow Springs Instruments (YSI) (Yellow Springs, OH) reference analyzer measurements. Venous blood drawn from healthy volunteers was adjusted to three glucose levels of 80, 200, and 400 mg/dL, each tonometered with six different Po2 levels (40, 80, 160, 240, 320, and 400 torr). To quantitate oxygen effects on reference analyzer measurements, glucose differences between test sample (Po2 changed) and control (Po2 80 torr) were calculated (YSItest-YSIcontrol). The threshold for determination of oxygen effects was +/-2 SD, where 2 SD was fro

Comparing the costs between provider types of episodes of back pain care.

STUDY DESIGN: This study was a prospective, community-based, observational design. OBJECTIVES: The authors compared the costs of episodes of back pain care between different provider types in a population representative of the U.S. SUMMARY OF BACKGROUND DATA: Previous comparisons between provider types of the costs for back pain care have been restricted to the worker's compensation population or have used something other than the episode as the unit of analysis. METHODS: Data from the RAND Health Insurance Experiment (HIE) were analyzed. Insurance claims forms were examined for all visits specified by the patient as occurring for back pain. Visits were grouped into episodes using decision rules and clinical judgment. The primary provider was defined as the provider who delivered most of the care. Comparisons of costs between provider types were made. RESULTS: There were 1020 episodes of back pain care made by 686 different persons and encompassing 8825 visits. Chiropractors and general practitioners were the primary providers for 40% and 26% of episodes, respectively. Chiropractors had a significantly greater mean number of visits per episode (10.4) than did other practitioners. Orthopedic physicians and "other" physicians were significantly more costly on a per visit basis. Orthopedists had the highest mean total cost per episode, and general practitioners the lowest. Chiropractors had the highest, and general practitioners the lowest mean outpatient cost per episode. CONCLUSIONS: These are economically significant differences in the costs of back pain care of persons seeing chiropractors, general practitioners, internists, and orthopedists.

An epidemiologic study of episodes of back pain care.

STUDY DESIGN: This was a prospective community-based, observational design. OBJECTIVE: To describe the epidemiology and risk/prognostic factors for back pain episodes of care in a population representing the nonelderly in the United States. SUMMARY OF BACKGROUND DATA: Previous United States studies of the epidemiology of back pain care have used defined industrial populations or have relied on the patient's recall of symptoms and care. METHODS: Claims forms from the RAND Health Insurance Experiment, a randomized controlled trial of the use of health services, were analyzed. Claims forms were selected if one of the patient-designated reasons for the visit was back pain. Visits were grouped into episodes of care. Descriptive statistics were calculated for episodes. Multivariate logistic regression was used to calculate adjusted odds ratios for independent explanatory sociodemographic and health status variables associated with back pain episodes of care. RESULTS: The 3105 adults in the Health Insurance Experiment had a combined 11,171 person-years of exposure. Six-hundred-eighty-six persons (22%) had a total 1020 episodes of back pain care, representing 8825 visits. Seventy-one percent of persons had a single episode during the Health Insurance Experiment, and 40% of these episodes consisted of a single visit. There were 9.1 episodes per 100 person-years. Insurance status, geographic site, white race, lesser education, poorer physical functioning, and greater pain at base-line all were independently associated with having a back pain episode of care. CONCLUSIONS: Back pain episodes of care occur commonly in the adult U.S. population, but usually are brief and recur infrequently.

Effects of different hematocrit levels on glucose measurements with handheld meters for point-of-care testing.

OBJECTIVES: To determine the effects of low, normal, and high hematocrit levels on glucose meter measurements and to assess the clinical risks of hematocrit errors. DESIGN: Changes in glucose measurements between low and high hematocrit levels were calculated to determine hematocrit effects. The differences between glucose measured with meters and with a plasma glucose method (YSI 2300) also were compared. SETTING: Six hand-held glucose meters were assessed in vitro at low (19.1%), normal (38.5%), and high (58.3%) hematocrit levels, and at 6 glucose concentrations ranging from 2.06 mmol/L (37.1 mg/dL) to 30.24 mmol/L (544.7 mg/dL). RESULTS: Most systems, regardless of the reference to which they were calibrated, demonstrated positive bias at lower hematocrit levels and negative bias at higher hematocrit levels. Low, normal, and high hematocrit levels progressively lowered Precision G and Precision QID glucose measurements. Hematocrit effects on the other systems were more dependent on the glucose concentration. Overall, Accu-Chek Comfort Curve showed the least sensitivity to hematocrit changes, except at the lowest glucose concentration. CONCLUSIONS: We strongly recommend that clinical professionals choose glucose systems carefully and interpret glucose measurements with extreme caution when the patient's hematocrit value changes, particularly if there is a simultaneous change in glucose level.