Constraints on the fundamental string coupling from B-mode experiments.

We study signatures of cosmic superstring networks containing strings of multiple tensions and Y junctions, on the cosmic microwave background (CMB) temperature and polarization spectra. Focusing on the crucial role of the string coupling constant g(s), we show that the number density and energy density of the scaling network are dominated by different types of string in the g(s) ~ 1 and g(s) ≪ 1 limits. This can lead to an observable shift in the position of the B-mode peak--a distinct signal leading to a direct constraint on g(s). We forecast the joint bounds on g(s) and the fundamental string tension µ(F) from upcoming and future CMB polarization experiments, as well as the signal to noise in detecting the difference between B-mode signals in the limiting cases of large and small g(s). We show that such a detectable shift is within reach of planned experiments.

Surgical wound healing in radio-tagged adult Pacific lamprey Entosphenus tridentatus held on different substrata.

Radio-tagged adult Pacific lamprey Entosphenus tridentatus held in a raceway with Plexiglas-lined walls and bottom healed more slowly and retained sutures longer than fish held in an all-concrete raceway or one with Plexiglas walls and a cobble-lined bottom. On all substrata, healing depended on when sutures were lost, and fish that lost their sutures in <14 days post-surgery healed faster than those that kept sutures longer. Long-term suture retention led to tissue trauma, infection and poor survival.

hTID-1 defines a novel regulator of c-Met Receptor signaling in renal cell carcinomas.

The c-Met receptor tyrosine kinase (MetR) is frequently overexpressed and constitutively phosphorylated in a number of human malignancies. Activation of the receptor by its ligand, hepatocyte growth factor (HGF), leads to increased cell proliferation, motility, survival and disruption of adherens junctions. In this study, we show that hTid-1, a DNAJ/Hsp40 chaperone, represents a novel modulator of the MetR signaling pathway. hTid-1 is a co-chaperone of the Hsp70 family of proteins, and has been shown to regulate a number of cellular signaling proteins including several involved in tumorigenic and apoptotic pathways. In this study we demonstrate that hTid-1 binds to unphosphorylated MetR and becomes dissociated from the receptor upon HGF stimulation. Overexpression of the short form of hTid-1 (hTid-1(S)) in 786-0 renal clear cell carcinomas (RCCs) enhances MetR kinase activity leading to an increase in HGF-mediated cell migration with no discernible effect on cell proliferation. By contrast, knockdown of hTid-1 markedly impairs both the onset and amplitude of MetR phosphorylation in response to HGF without altering receptor protein levels. hTid-1-depleted cells display defective migratory properties, coincident with inhibition of ERK/MAP kinase and STAT3 pathways. Taken together, our findings denote hTid-1(S) as an essential regulatory component of MetR signaling. We propose that the binding of hTid-1(S) to MetR may stabilize the receptor in a ligand-competent state and this stabilizing function may influence conformational changes that take place during the catalytic cycle that promote kinase activation. Given the prevalence of HGF/MetR pathway activation in human cancers, targeted inhibition of hTid-1 may be a useful therapeutic in the management of MetR-dependent malignancies.

Use of an automated circuit for isolated limb infusion for malignancy.

BACKGROUND: Isolated limb infusion (ILI) for recurrent or in-transit melanoma is an accepted technique that allows high-dose chemotherapy to be delivered to an extremity with minimal systemic toxicity. Current infusion systems have relied on manual delivery of drugs and circulation of blood during the treatment. Herein, we document our initial results with an automated circuit for ILI as an alternative to the manual technique. METHODS: Patients undergoing ILI with an automated circuit for recurrent or advanced malignancy were identified. ILI was performed utilizing a Sarns 8000 roller pump attached to a Cobe 4:1 cardioplegia set with heat exchanger with a total priming volume of 80 ml. Melphalan (7.5 mg/L) and Dactinomycin (75 µg/L) doses which were corrected for ideal body weight were delivered via the infusion circuit after limb temperature reached 38 °C. RESULTS: Fourteen lower extremity infusion procedures were performed in 10 patients. Successful infusion procedures were completed in all patients using the automated circuit. Constant flow rates of 50-70 cc/minute were achievable with the automated circuit. Acute toxicity and clinical results were similar to that reported with manual delivery systems. CONCLUSION: ILI for advanced malignancy utilizing an automated circuit is feasible and safe. This automated system offers a safe and reliable alternative to the manual infusion technique.

Collisions of strings with Y junctions.

We study the dynamics of Nambu-Goto strings with junctions at which three strings meet. In particular, we exhibit one simple exact solution and examine the process of intercommuting of two straight strings in which they exchange partners but become joined by a third string. We show that there are important kinematical constraints on this process. The exchange cannot occur if the strings meet with very large relative velocity. This may have important implications for the evolution of cosmic superstring networks and non-Abelian string networks.

The hottest sentinel lymph node is not always the positive node.

The technique of identifying the sentinel lymph node (SLN) varies from each individual institution. Generally, the highest isotope count in a lymph node is considered the SLN, whereas other radioactive nodes might also be removed. The purpose of our study was to determine if the hottest node was always the tumor-containing node. Two hundred forty-seven breast cancer patients underwent SLN biopsy from April 1998 to April 2002. Lymphatic mapping involved a radiocolloid injection and lymphoscintigraphy followed by intraoperative assessment with a hand-held gamma probe. All SLN(s) with radioactive counts 10 per cent or more of the ex vivo counts of the most radioactive SLN were removed. The SLN were sliced at 2-mm intervals with 4-microm step-sections (92-microm spacing) and evaluated by microscopy and immunohistochemistry. One hundred twenty (49%) of the 247 patients had 2 or more nodes resected. Of these 120 patients, 33 (28%) had a tumor-bearing node. In 25 (74%) cases, the tumor-bearing node was the most radioactive; however, in 8 (26%) cases, the positive node was a lesser reactive node. Although the most radioactive node in a draining basin is considered the SLN, this is often not the metastatic node. Therefore, all nodes with significant radioactive counts must be removed to ensure accurate staging.

Model-independent dark energy differentiation with the integrated Sachs-Wolfe effect.

We study the integrated Sachs-Wolfe effect using a model-independent parametrization of the dark energy equation of state, w(z). Cosmic variance severely restricts the class of models distinguishable from one based on cold dark matter and a cosmological constant unless w(z) currently satisfies w(o)(Q)>-0.8, or exhibits a rapid, late-time, transition at redshifts z<3. Because of the degeneracy with other cosmological parameters, models with a slowly varying w(z) cannot be differentiated from each other or from a cosmological constant. This may place a fundamental limit on our understanding of the origin of the currently observed acceleration.

Competency-based student self-assessment on a surgery rotation.

BACKGROUND: Although self-assessment is an essential component of self-directed adult learning, few data exist regarding the ability of medical students to perform this important task. Therefore, the purpose of this study was to evaluate the ability of medical students to perform self-assessment during a third-year surgery clerkship. METHODS: Sixty-eight (34 male, 34 female) third-year medical students assessed their progress at the midpoint of an 8-week surgery clerkship using an 11-item, competency-based evaluation. Students compared perceptions of their performance with a faculty member's assessment using the identical evaluation form. RESULTS: Male students tended to overestimate their midclerkship performance compared with faculty formative and summative evaluations (3.31 +/- 0.03 vs 3.23 +/- 0.03 and 3.28 +/- 0.03) although this did not reach statistical significance. Female students significantly underestimated their midclerkship performance compared with faculty formative and summative evaluations (3.06 +/- 0.03 vs 3.40 +/- 0.03 and 3.45 +/- 0.03, P < 0.05 vs faculty evaluations). Preclerkship academic performance (first- and second-year grade point averages and NBME Part 1 scores) was not predictive of student self-assessment. Finally, women statistically outperformed men on the surgery clerkship (86.6% +/- 0.75 vs 83.2% +/- 1.20, P < 0.05 vs male students). CONCLUSIONS: Female students tend to underestimate their midclerkship performance compared with male students on a surgery rotation. Despite lower self-assessment, female students actually outperform male students. Women may underreport their capabilities when compared with men as a result of gender differences in socialization. These gender differences in self-assessment may be important to recognize when faculty provide feedback to students.

Institutional validation of breast cancer treatment guidelines.

Several groups have developed clinical guidelines for the management of breast cancer, yet little data exist regarding their validation. Therefore, we examined the effect of published National Comprehensive Cancer Network (NCCN) guidelines for invasive breast cancer on survival, quality of life (QOL), and hospital cost. From 260 consecutive breast cancer patients, 129 patients were identified for analysis: 93 patients (72%) were treated according to the guidelines (NCCN+), while the treatment of 36 patients (28%), with a similar stage distribution, deviated from the guidelines (NCCN-). Patients were excluded from analysis with a diagnosis of carcinoma in situ, inflammatory cancer, stage IV disease, and comorbid conditions that affected treatment. The 5-year survival was 87.6% for the NCCN+ patients versus 83.3% for NCCN- patients (P = 0.319 by Kaplan-Meier). Twelve QOL parameters were evaluated using a Likert-type scale (1 = severe and 5 = none). NCCN+ patients had a cumulative QOL score of 4.18 +/- 0.08 versus 4.24 +/- 0.14 for NCCN- patients (P = 0.745). Treatment-related costs were $20,300 +/- 1800 for NCCN+ patients versus $59,700 +/- 25,200 for NCCN- patients (P = 0.016 by t test). Although deviation from NCCN breast cancer guidelines had no effect on perceived quality of life or survival, there was a significant decrease in cost in the NCCN+ group. These findings suggest that adherence to NCCN guidelines can significantly reduce the cost of breast cancer care without adversely affecting either survival or quality of life.

Nuclear factor-kappa B is upregulated in colorectal cancer.

BACKGROUND: Chemoresistance may involve the anti-apoptotic transcriptional regulator, nuclear factor-kappa B (NF-kappa B). The purpose of this study was to determine whether chemotherapy induces NF-kappa B activation in a human colon cancer cell line (SW48) and whether NF-kappa B is constitutively activated in colorectal cancer. METHODS: SW48 cells were incubated with gemcitabine hydrochloride (Gemzar) in the presence and absence of the 26s proteasome inhibitor, MG132, and NF-kappa B binding (electrophoretic mobility shift assay), DNA synthesis (tritiated thymidine uptake), cell viability (3-[4,5-dimethylthiazol-2-yl]-diphenyl-tetrazolium bromide assay), and apoptosis (caspase-3 activity) were measured at 24 hours. NF-kappa B binding (electrophoretic mobility shift assay) was also assayed in 10 colorectal cancer tumors. RESULTS: SW48 cells demonstrated constitutive NF-kappa B binding that was enhanced by gemcitabine hydrochloride in a dose-dependent manner. MG132 inhibited NF-kappa B binding and enhanced gemcitabine hydrochloride's inhibition of DNA synthesis (gemcitabine hydrochloride = 73% +/- 1.4% vs gemcitabine hydrochloride + MG132 = 6% +/- 0.4%, P <.05), cell killing (gemcitabine hydrochloride = 87% +/- 2.0 vs gemcitabine hydrochloride + MG132 = 25% +/- 1.3%, P <.05), and caspase-3 activity (gemcitabine hydrochloride = 870 +/- 17.4 vs gemcitabine hydrochloride + MG132 = 1075 +/- 20.4, P <.05). NF-kappa B binding was increased in 8 of 10 colorectal cancer tumors compared with adjacent normal mucosa. CONCLUSIONS: Gemcitabine hydrochloride enhances NF-kappa B binding in a colorectal cancer cell line, whereas inhibition of NF-kappa B enhances gemcitabine hydrochloride's antitumor activity. NF-kappa B is also activated in human colorectal cancer. NF-kappa B may identify chemoresistant tumors, whereas inhibition of NF-kappa B may be a novel, biologically based therapy. (Surgery 2001;130:363-9).

Adenoviral delivery of human and viral IL-10 in murine sepsis.

Adenovirus (Ad) gene therapy has been proposed as a drug-delivery system for the targeted administration of protein-based therapies, including growth factors and biological response modifiers. However, inflammation associated with Ad transduction has raised concern about its safety and efficacy in acute inflammatory diseases. In the present report, intratracheal and i.v. administration of a first-generation adenoviral recombinant (E1,E3 deleted) either containing an empty cassette or expressing the anti-inflammatory cytokines viral or human IL-10 (IL-10) was administered to mice subjected to zymosan-induced multisystem organ failure or to acute necrotizing pancreatitis. Pretreatment of mice with the intratracheal instillation of Ad expressing human IL-10 or viral IL-10 reduced weight loss, attenuated the proinflammatory cytokine response, and reduced mortality in the zymosan-induced model, whereas pretreatment with a control adenoviral recombinant did not significantly exacerbate the response. Pretreatment of mice with pancreatitis using adenoviral vectors expressing IL-10 significantly reduced the degree of pancreatic and liver injury and liver inflammation when administered systemically, but not intratracheally. We conclude that adenoviral vectors can be administered prophylactically in acute inflammatory syndromes, and expression of the anti-inflammatory protein IL-10 can be used to suppress the underlying inflammatory process.

Conservative treatment of rectal adenocarcinoma.

Endocavitary radiotherapy and transrectal excision are highly effective treatments for properly selected patients with favorable early-stage rectal adenocarcinoma. The likelihood of local control and survival after treatment with either modality is similar, and differences among various series probably reflect selection. The parameter most predictive of local control and survival in the authors' series was tumor configuration. As has been previously observed, "selection is the silent partner of success." Suitable candidates for endocavitary radiotherapy or wide local excision are patients whose tumors are 3 cm or less in diameter, well-to-moderately differentiated, exophytic, mobile, limited to the submucosa on transrectal ultrasound, and within 10 cm of the anal verge. The advantages of endocavitary irradiation are (1) it is an outpatient procedure, (2) it does not require anesthesia, and (3) it is less expensive than transrectal excision. The advantages of transrectal excision are (1) it may be performed during one brief hospitalization (as opposed to four outpatient visits), and (2) a small subset of patients will have pathologic findings predicting an increased risk of regional lymph node involvement, revealing the need to treat the nodes with external-beam radiotherapy. A disadvantage of wide local excision is that some patients who would be suitable for a local procedure alone must be subjected to a course of external-beam radiotherapy when they are found to have equivocal or positive margins. Patients who are treated with transrectal excision and external-beam radiotherapy have less favorable lesions and are not comparable with patients who are treated with endocavitary radiotherapy or wide local excision alone. They are best compared with patients who have undergone major surgery consisting of abdominoperineal resection or low anterior resection. Because the risk of positive nodes is significantly increased with adverse pathologic findings such as poor differentiation, invasion of the muscularis propria, and endothelial-lined space invasion, a subset of these patients treated with wide local excision would have positive nodes. This subset of patients is not comparable with patients with stage pT1N0 and pT2N0 tumors treated with major surgery. The latter group of patients undergo complete surgical staging, whereas the pathologic staging for patients who undergo wide local excision and radiotherapy is limited to the extent of the primary tumor. With this caveat in mind, wide local excision and radiotherapy seem to result in locoregional control and survival rates similar to the rates obtained with major surgery for patients with pT1 and pT2 cancers (Table 5). Patients who should receive postoperative irradiation have tumors that exhibit one or more of the following characteristics: size greater than 3 cm in diameter, poorly differentiated, invasion of the muscularis propria, endothelial-lined space invasion, fragmented resection, equivocal or positive margins, or perineural invasion. Patients with gross residual disease are not suitable candidates for radiotherapy and require further surgery. The authors' policy is to treat these patients with chemoradiation followed by resection. Patients thought to have transmural invasion before treatment are probably best treated with preoperative chemoradiation combined with major surgery, although a subset of patients can be downstaged and rendered suitable for a wide local excision.

Towards dynamic coating of glass microchip chambers for amplifying DNA via the polymerase chain reaction.

As microchip technology evolves to allow for the integration of more complex processes, particularly the polymerase chain reaction (PCR), it will become necessary to define simple approaches for minimizing the effects of surfaces on the chemistry/processes to be performed. We have explored alternatives to silanization of the glass surface with the use of additives that either dynamically coat or adsorb to the glass surface. Polyethylene glycol, polyvinylpyrrolidone (PVP), and hydroxyethylcellulose (HEC) have been explored as potential dynamic coatings and epoxy (poly)dimethylacrylamide (EPDMA) evaluated as an adsorbed coating. By carrying out analysis of the PCR products generated under different conditions via microchip electrophoresis, we demonstrate that these coating agents adequately passivate the glass surface in a manner that prevents interference with the subsequent PCR process. While several of the agents tested allowed for PCR amplification of DNA in glass, the EPDMA was clearly superior with respect to ease of preparation. However, more efficient PCR (larger mass of amplified product) could be obtained by silanizing the glass surface.

Extended lung expression and increased tissue localization of viral IL-10 with adenoviral gene therapy.

IL-10 is a pleiotropic cytokine that acts as an important regulator of macrophage, T cell, and natural killer cell functions. Human IL-10 (hIL-10) has both stimulatory and inhibitory effects on a wide variety of cell types. Viral IL-10 (vIL-10) possesses only a subset of hIL-10's activities, predominantly its suppression of cytokine synthesis by T helper type 1 clones. In the present report, we evaluated tissue accumulation and biological activity of hIL-10 and vIL-10 in vivo in individual organs by using a first-generation adenoviral (Ad) vector administered intratracheally and intravenously. We report the observation that Ad vectors delivering vIL-10, but not hIL-10, are associated with prolonged expression in the lung (>42 days) when delivered intratracheally. In contrast, there was no prolongation in vIL-10 expression when Ad vectors were intravenously administered, although vIL-10 levels in the tissue, but not serum, were markedly increased relative to hIL-10. Moreover, we report an augmented capacity of expressed vIL-10 versus hIL-10 to suppress the acute inflammatory responses in the lung to intratracheal administration of Ad. These findings confirm fundamental differences in Ad-induced expression of vIL-10 and hIL-10 when administered to the lungs. The results further suggest that Ad vectors expressing vIL-10 may have a role as anti-inflammatory agents in the treatment of acute and chronic lung inflammation.

Local excision and postoperative radiation therapy for rectal adenocarcinoma.

Sixty-seven patients with early-stage adenocarcinoma of the rectum who had lesions thought to be unsuitable for either local excision alone or endocavitary irradiation were treated with local excision followed by postoperative radiation therapy. The purpose of this study was to evaluate the effectiveness of local excision followed by radiation therapy for treatment of rectal adenocarcinoma. The patients were treated between 1974 and 1999; follow-up time was 6 to 273 months (median, 65 months). All living patients had follow-up for at least 2 years. The indications for postoperative irradiation included equivocal or positive margins, invasion of the muscularis propria, endothelial-lined space invasion, poorly differentiated histology, and perineural invasion. Cox proportional hazards regression analysis was performed using six explanatory variables including tumor size, configuration (exophytic vs. ulcerative), histologic differentiation, pathologic T stage, endothelial-lined space invasion, and margin status. The time interval between treatment and development of recurrent disease was in the range of 11 to 48 months. The 5-year results were as follows: local-regional control, 86%; ultimate local-regional control, 93%; distant metastasis-free survival, 93%; absolute survival, 80%; and cause-specific survival, 90%. When the Cox proportional hazards regression analysis was performed for these endpoints, margin status influenced absolute survival (P = 0.0074), cause-specific survival (P = 0.0405), and ultimate local-regional control (P = 0.0439). Tumor configuration marginally influenced cause-specific survival (P = 0.0577). None of the variables had an influence on the endpoints' local-regional control, ultimate local-regional control with sphincter preservation, or distant metastasis. Five patients (7%) had severe complications; no complication was fatal. Local excision and postoperative radiation therapy results in a high probability of local-regional control and survival for selected patients with relatively early-stage rectal adenocarcinoma. Patients with ulcerative tumors may have a lower likelihood of cause-specific survival.

Glucocorticoid and Fas ligand induced mucosal lymphocyte apoptosis after burn injury.

BACKGROUND: The purpose of this study was to examine the effects of a steam burn injury on apoptosis in gut-associated lymphoid tissue and to determine whether endogenous glucocorticoid and Fas ligand signaling were involved in this process. METHODS: Histologic analysis, in situ deoxynucleotidyl transferase dUTP nick-end labeling staining and annexin V and 7-amino-actinomycin-D flow cytometry of lymphocyte populations were evaluated in intraepithelial lymphocytes and Peyer's patch. Additional mice were pretreated with a glucocorticoid receptor antagonist (mifepristone) before the steam burn. Similarly, C3H/HeJ-FasL(gld) mice lacking functional Fas ligand were also studied. RESULTS: Apoptosis was significantly increased in intraepithelial lymphocytes and Peyer's patch after the burn injury. Mifepristone pretreatment significantly reduced apoptosis in both T- and B-cell populations in intraepithelial lymphocytes after the burn injury. In contrast, the increased apoptosis seen in B-cells from Peyer's patch was not seen in C3H/HeJFasL(gld) mice, whereas the increased apoptosis in CD8+ T-cells was unaffected. CONCLUSION: Both corticosteroids and FasL contribute to the apoptosis in gut-associated lymphoid tissues early after burn injury.

Inhibition of 1,2-dimethylhydrazine-induced oxidative DNA damage in rat colon mucosa by black tea complex polyphenols.

The effect of black tea polyphenols on 1,2-dimethylhydrazine (DMH)-induced oxidative DNA damage in rat colon mucosa has been investigated. Fischer 344 rats were treated orally with thearubigin (TR) or theafulvin (TFu) for 10 days (40 mg/kg), injected ip with DMH (20 mg/kg) or saline and sacrificed 24 hr after DMH administration. The levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) were measured in colonic mucosa DNA and expressed as a ratio relative to 2'-deoxyguanosine (2dG). Control rat mucosa had 8-OHdG values of 1.12 +/- 0.14/10(5) dG (mean +/- SEM, n=11), whereas DMH-treated rats significantly higher values (1.52 +/- 0.14/10(5) dG, n=26, P<0.05). Pretreatment of rats with TR had significantly inhibited DMH-induced oxidative DNA damage 0.99 +/- 0.09/10(5) dG, n=10, P<0.05) and a similar, although less marked, effect was observed with TFu (1.15 +/- 0.19/10(5), n=9, P=0.06). These findings confirm that DMH causes oxidative DNA damage in the colon mucosa of rats and demonstrate that this effect is prevented by the consumption of complex polyphenols from black tea.

The relationship between visceral ischemia, proinflammatory cytokines, and organ injury in patients undergoing thoracoabdominal aortic aneurysm repair.

OBJECTIVES: Plasma proinflammatory, anti-inflammatory cytokine, and soluble tumor necrosis factor (TNF) receptor concentrations were examined in hospitalized patients after abdominal and thoracoabdominal aortic aneurysm (TAAA) repair, with and without left atrial femoral bypass. Changes in plasma cytokine concentrations were related to the duration of visceral ischemia and the frequency rate of postoperative, single, or multiple system organ dysfunction (MSOD). DESIGN: Prospective, observational study. SETTING: Two academic referral centers in the United States and The Netherlands. PATIENTS: We included 16 patients undergoing TAAA repair without left atrial femoral bypass, 12 patients undergoing TAAA repair with left atrial femoral bypass, and nine patients undergoing infrarenal aortic aneurysm repair. MEASUREMENTS AND MAIN RESULTS: Timed, arterial blood sampling for proinflammatory and anti-inflammatory cytokine and soluble TNF receptor concentrations (p55 and p75), and prospective assessment of postoperative single and MSOD. Plasma appearance of TNF-alpha, interleukin (IL)-6, IL-8, and IL-10 peaked 1 to 4 hrs after TAAA repair, and concentrations were significantly elevated compared with infrarenal abdominal aortic aneurysm repair (p < .05). Left atrial femoral bypass significantly reduced the duration of visceral ischemia (p < .05) and the systemic TNF-alpha, p75, and IL-10 responses (p < .05). Plasma TNF-alpha concentrations >150 pg/mL were more common in patients with extended visceral ischemia times (>40 mins). Additionally, patients with early peak TNF-alpha concentrations >150 pg/mL and IL-6 levels >1,000 pg/mL developed MSOD more frequently than patients without these elevated plasma cytokine levels (both p < .05). CONCLUSIONS: Thoracoabdominal aortic aneurysm repair results in the increased plasma appearance of TNF-alpha, IL-6, IL-8, IL-10, and shed TNF receptors. The frequency and magnitude of postoperative organ dysfunction after TAAA repair is associated with an increased concentration of the cytokines, TNF-alpha, and IL-6 and the increased plasma levels of these cytokines appear to require extended visceral ischemia times.