Formaldehyde production from isoprene oxidation across NOx regimes.

The chemical link between isoprene and formaldehyde (HCHO) is a strong, non-linear function of NOx (= NO + NO2). This relationship is a linchpin for top-down isoprene emission inventory verification from orbital HCHO column observations. It is also a benchmark for overall photochemical mechanism performance with regard to VOC oxidation. Using a comprehensive suite of airborne in situ observations over the Southeast U.S., we quantify HCHO production across the urban-rural spectrum. Analysis of isoprene and its major first-generation oxidation products allows us to define both a "prompt" yield of HCHO (molecules of HCHO produced per molecule of freshly-emitted isoprene) and the background HCHO mixing ratio (from oxidation of longer-lived hydrocarbons). Over the range of observed NOx values (roughly 0.1 - 2 ppbv), the prompt yield increases by a factor of 3 (from 0.3 to 0.9 ppbv ppbv-1), while background HCHO increases by a factor of 2 (from 1.6 to 3.3 ppbv). We apply the same method to evaluate the performance of both a global chemical transport model (AM3) and a measurement-constrained 0-D steady state box model. Both models reproduce the NOx dependence of the prompt HCHO yield, illustrating that models with updated isoprene oxidation mechanisms can adequately capture the link between HCHO and recent isoprene emissions. On the other hand, both models under-estimate background HCHO mixing ratios, suggesting missing HCHO precursors, inadequate representation of later-generation isoprene degradation and/or under-estimated hydroxyl radical concentrations. Detailed process rates from the box model simulation demonstrate a 3-fold increase in HCHO production across the range of observed NOx values, driven by a 100% increase in OH and a 40% increase in branching of organic peroxy radical reactions to produce HCHO.

The contribution of donor quality to differential graft survival in African American and Caucasian renal transplant recipients.

Although a number of factors contributing to the disparity in graft survival between African American (AA) and Caucasian kidney transplant recipients have been described, the role of donor quality is less well understood. This study was undertaken to determine the impact of donor quality differences on this disparity, based on review of UNOS (United Network for Organ Sharing) data on deceased donor renal transplantation from 2000 to 2010. Donor quality was determined by the kidney donor risk index (DRI), and was compared between AA and Caucasian recipients. There were 33,405 Caucasians and 22,577 African Americans in the study, with mean DRI of 1.17 versus 1.27 (p < 0.001), respectively. In analysis 2,446 recipients of each race matched by propensity scoring (based on medical, socioeconomic and immunologic covariates), mean DRI was 1.25 for Caucasians and 1.28 (p = 0.02) for AA. The hazard ratio (HR) for graft failure associated with AA race was 1.8 (p < 0.001) on unadjusted analysis, and decreased to 1.6 (p < 0.001) after matching for DRI. These results indicate a significant disparity in quality of kidneys received by African Americans, which propensity analysis indicates is partially explained by differences in medical, immunologic and socioeconomic factors. Furthermore, this difference in donor quality partially accounts for poorer graft survival in African Americans.

Graft vasculopathy in clinical hand transplantation.

Allogeneic hand transplantation is now a clinical reality. While results have been encouraging, acute rejection rates are higher than in their solid-organ counterparts. In contrast, chronic rejections, as defined by vasculopathy and/or fibrosis and atrophy of skin and other tissues, as well as antibody mediated rejection, have not been reported in a compliant hand transplant recipient. Monitoring vascularized composite allograft (VCA) hand recipients for rejection has routinely involved punch skin biopsies, vascular imaging and graft appearance. Our program, which has transplanted a total of 6 hand recipients, has experience which challenges these precepts. We present evidence that the vessels, both arteries and veins may also be a primary target of rejection in the hand. Two of our recipients developed severe intimal hyperplasia and vasculopathy early post-transplant. An analysis of events and our four other patients has shown that the standard techniques used for surveillance of rejection (i.e. punch skin biopsies, DSA and conventional vascular imaging studies) are inadequate for detecting the early stages of vasculopathy. In response, we have initiated studies using ultrasound biomicroscopy (UBM) to evaluate the vessel wall thickness. These findings suggest that vasculopathy should be a focus of frequent monitoring in VCA of the hand.

Analysis of BK viral infection after alemtuzumab induction for renal transplant.

UNLABELLED: Induction immunosuppression has provided great advances in reducing the incidence of acute rejection (AR) following kidney transplantation. Despite this success, there has been recent concern over possible increased rates of viral complications when such powerful immunosuppressive therapy is used. This study was undertaken to determine the incidence of BK viral infection following kidney transplantation under alemtuzumab induction therapy. METHODS: With institutional review board approval, a retrospective study was performed of all patients undergoing kidney transplantation under alemtuzumab induction at a single center. The incidence of BK viremia was determined, and univariate analysis was performed to determine factors associated with the development of BK viremia. Further analysis was undertaken, using standard statistical methods, to determine the rates of graft survival and hazard ratio (HR) for AR in patients with and without BK viremia. RESULTS: There were 456 patients in the current study, with a mean age of 51 years. The majority of these (61.8%) were male, and 73.5% were Caucasian. The overall incidence of BK viremia identified on routine screening was 6.6%. Univariate analysis failed to identify any significant predictors of BK viremia. One-, 3-, and 5-year graft survival for patients who developed BK viremia was 96.6%, 91.7%, and 91.7%, respectively, compared with 94.1%, 87.8%, and 80.2% for patients without BK viremia (P = 0.860). BK viremia was associated with a significantly increased risk for AR (HR 3.48, 95% confidence interval 1.24-9.76; P = 0.018). CONCLUSION: The incidence of BK viremia following alemtuzumab induction appears to be in concordance with the published literature, with satisfactory graft survival rates. BK viremia is, however, associated with an increased risk for AR.

Increased tumor establishment and growth after open vs laparoscopic surgery in mice may be related to differences in postoperative T-cell function.

BACKGROUND: Previous work has demonstrated that cell-mediated immune function in rats is better preserved after laparoscopic than open surgery. We have also shown that tumors are more easily established in mice and grow larger after sham laparotomy than after pneumoperitoneum. The purpose of this study is to determine if the functional status of the cell-mediated immune system influences postoperative tumor growth. METHODS: Immunocompetent (study 1) and T-cell deficient athymic (study 2) mice were injected with mouse mammary carcinoma cells in the dorsal skin. Mice then underwent either no procedure, midline laparotomy, or carbon dioxide pneumoperitoneum. Tumor masses on postoperative day 12 were compared. RESULTS: In immunocompetent mice, laparotomy group tumors were nearly twice as large as laparoscopy group tumors (p < 0.02), which were 1.5 times as large as control group tumors (NS). In the athymic model, however, differences between the sham laparotomy and pneumoperitoneum groups were lost (p > 0.5). Tumors grew much larger in the athymic control mice than in the immunocompetent control mice (p < 0.01). CONCLUSION: We conclude that T-cell function plays a significant role in host containment of mouse mammary carcinoma and in the mechanism of differences in tumor growth observed after laparotomy and pneumoperitoneum.

Long-term survival of a young woman with peripheral cholangiocarcinoma: a case report.

Cholangiocarcinoma is the second most common primary tumor of the liver after hepatocellular carcinoma and accounts for 5 to 25% of primary hepatic malignancies. Patients with intrahepatic or peripheral cholangiocarcinoma (ICC) most often present at an advanced stage leading to a poor prognosis. A review of the literature has produced only 10 patients who have survived over five years. We review the case of a young woman with a large cholangiocarcinoma, who has been disease free for eight years. The patient was treated with a right hepatic lobectomy, and received 4 cycles of 5-fluorouracil and levamisole postoperatively. Known factors associated with longer survival in patients with ICC include lack of evidence of local invasion (i.e. capsular, lymphatic, or vascular), negative margins, mucoblia, and well differentiation of the tumor, as well as the absence of lymph node metastases. Our patient had negative margins and lymph nodes, and showed no local invasion. However, no mucobilia was noted, and the tumor was only moderately differentiated. Young age has never been associated with increased survival. ICC remains a relatively uncommon tumor with an insidious onset and late presentation contributing to poor survival. Surgical resection remains the only therapeutic option. Since few patients are potentially resectable at the time of presentation, efforts at early diagnosis and options for adjuvant therapy are imperative.

A metastasizing model of anaplastic human Wilms tumor in the nude mouse.

Reproducible animal models of Wilms tumor have been difficult to establish. We describe a model in which cells, banked from a patient with metastatic Wilms tumor, were implanted into nude mice, resulting in the development of primary renal and metastatic pulmonary lesions. Pathologically, the lesions resembled the blastemal component of anaplastic Wilms tumor. Primary tumors showed a significant propensity for growth in the kidney as opposed to other organs. Pulmonary metastases, histologically similar to the primary lesions, were regularly observed. This represents the first reproducible model of anaplastic, metastasizing human Wilms tumor. This system may prove effective for the study of factors influencing growth and angiogenesis in aggressive variants of Wilms tumor.

Increased tumor establishment and growth after open vs laparoscopic bowel resection in mice.

BACKGROUND: Surgery can suppress immune function and facilitate tumor growth. Several studies have demonstrated better preservation of immune function following laparoscopic procedures. Our laboratory has also shown that tumors are more easily established and grow larger after sham laparotomy than after pneumoperitoneum in mice. The purpose of this study was to determine if the previously reported differences in tumor establishment and growth would persist in the setting of an intraabdominal manipulation. METHODS: Syngeneic mice received intradermal injections of tumor cells and underwent either an open or laparoscopic cecal resection. In study 1, the incidence of tumor development was observed after a low dose inoculum; whereas in study 2, tumor mass was compared on postoperative day 12 after a high-dose inoculum. RESULTS: In study 1, tumors were established in 5% of control mice, 30% of laparoscopy mice, and 83% of open surgery mice (p < 0.01 for all comparisons). In study 2, open surgery group tumors were 1.5 times as large as laparoscopy group tumors (p < 0.01), which were 1.5 times as large as control group tumors (p < 0.02). CONCLUSION: We conclude that tumors are more easily established and grow larger after open laparoscopic bowel resection in mice.

Liver metastases are enhanced in homozygous deletionally mutant ICAM-1 or LFA-1 mice.

BACKGROUND: Adhesion molecules play an integral role in tumor growth, invasion, and metastasis and have been shown to influence the immune response to malignant cells. The interaction of intercellular adhesion molecule-1 (ICAM-1) with lymphocyte function antigen-1 (LFA-1) is important for the adhesion of leukocytes, monocytes and lymphocytes to endothelial cells in vitro and in vivo. In order to explore the role of the ICAM-1/LFA-1 interaction in liver metastases, we utilized homozygous deletionally mutant (gene knockout) mice for ICAM-1 or LFA-1 which had been derived from the C57BL6/J background. MATERIALS AND METHODS: Wild-type C57BL6/J mice were used as controls. Animals were anesthetized and underwent a 1-cm midline lower abdominal incision. The ileocolic vein was identified and B16 melanoma cells (10(4)) were injected. The incisions were closed with skin clips. Two weeks following surgery, mice were sacrificed and their livers resected for gross and histological analysis. RESULTS: LFA-1 deficient mice developed 13 times the number of metastases compared to wild-type controls and ICAM-1 deficient mice developed 7 times that number [13.5 (n = 17) vs 1.0 (n = 19) and 36 (n = 10) vs 5.0 (n = 16), P values of 0.0003 and 0.0002 by Wilcoxon Rank Sum Test, respectively]: Histologically, multiple areas of inflammatory cells consisting of T-cells and macrophages were noted in wild-type mice. Only sparse inflammatory cells were noted surrounding the metastases in the null mice. CONCLUSIONS: Liver metastases of the B16 melanoma are markedly enhanced in ICAM-1 null and LFA-1 null mice. The ICAM-1/LFA-1 interaction is crucial to the immune response to liver metastases.

An overview of adenocarcinoma of the small intestine.

Even though the small intestine contains 90% of the gastrointestinal tract mucosa and is located between the stomach and large intestine, two organs with a high cancer incidence, adenocarcinoma of the small intestine is 1/50th as common as adenocarcinoma of the large bowel. In several other respects, small-intestinal adenocarcinoma resembles large bowel adenocarcinoma; eg, it arises from adenomatous polyps, co-occurs in the same individuals, and has a similar pattern of incidence rates by country. Small-intestinal adenocarcinoma is diagnosed prior to surgery in only about 50% of cases and often occurs in conjunction with small bowel obstruction. The mainstay of treatment is surgery; prognosis depends on stage at presentation. Little is known about the use of radiotherapy and chemotherapy in this malignancy, but most physicians utilize therapeutic strategies modeled on the management of large-intestinal adenocarcinoma. Clarification of the reason for the low incidence of small-intestinal adenocarcinoma could lead to new interventions for the prevention of colorectal cancer.

Detection of circulating thyroid cells in peripheral blood.

BACKGROUND: Detection of circulating malignant thyroid cells may provide a method to identify postoperative patients at risk for metastatic thyroid cancer. METHODS: On the basis of tissue specificity of thyroglobulin gene expression and the sensitivity of the reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, we performed RT-PCR using primers for thyroglobulin on blood samples from patients with thyroid disease to detect thyroglobulin RNA transcripts. Postoperative peripheral blood samples from 100 patients, including patients with known metastatic thyroid cancer (six papillary and three follicular), thyroid cancer and no evidence of current metastases (63 papillary, 10 follicular, and five patients with both papillary and follicular), benign thyroid disease (six nontoxic nodular goiters), and normal volunteers (seven). RESULTS: Thyroglobulin transcripts were detected in nine of nine patients with metastatic thyroid cancer, seven of 78 patients with thyroid cancer and no current metastases (although of these seven patients, five had a history of metastatic disease that had been previously treated by surgery, one had a coexisting parathyroid cancer, and one had both papillary and follicular thyroid cancers), zero of six patients with benign thyroid disease, and zero of seven normal volunteers. Identity of amplicons was confirmed by restriction enzyme digestion and by cloning and sequencing of RT-PCR amplified thyroglobulin fragment (the latter in a limited number of cases). CONCLUSIONS: These data indicate that RT-PCR can be used to detect thyroglobulin mRNA in peripheral blood. The presence of these transcripts correlates with the existence of extrathyroidal disease.

A novel tumor-derived mediator that sensitizes cytokine-resistant tumors to tumor necrosis factor.

Therapeutic successes following treatment of murine tumors with tumor necrosis factor-alpha (TNF) have not been easily applied to clinical oncology because the concentrations of TNF required in humans induces systemic toxicity. This has led us to identify mediators which could sensitize tumors to the effects of TNF, permitting administration of lower doses and possible realization of the therapeutic potential of this cytokine. Our study reports the ability of a novel cytokine, endothelial-monocyte-activating polypeptide II (EMAP II), to sensitize initially resistant murine and human tumors to TNF-induced regression employing a murine model. Recombinant (r) EMAP II was purified from Escherichia coli transformed with a plasmid expressing mature EMAP II. The B16 melanoma, raised in C57BL/6 mice, or a human fibrosarcoma (HT-1080), grown in immunocompromised mice, was injected intratumorally with either vehicle or rEMAP II/heat-treated EMAP II (50-100 micrograms) followed by systemic TNF/heat-treated TNF (5 micrograms) and assessed for tumor volume, hemorrhage, and histologic appearance. Both the B16 melanoma and the HT-1080 human fibrosarcoma underwent thrombohemorrhagic and acute inflammatory changes concomitant with regression or significantly slowed growth after administration of intratumor EMAP II followed by systemic TNF. Omission or inactivation of either cytokine abrogated this effect. These results demonstrate that local treatment of certain tumors with EMAP II results in enhanced susceptibility to TNF-mediated induction of thrombohemorrhage and regression.