bluuebunny/crossref_metadata_2025 huggingface dataset:
Copying clinic letters to psychiatric patients
Authors: Tahir Tayyeb A. , Bisson Jonathan I. , Wilcox Jodie
Published: August 2005

Aims and Method

To assess the views of patients and mental health professionals on the practice of copying clinical letters to patients. Patients and professionals from local community mental health teams were asked to complete a questionnaire regarding their views.

Results

The questionnaires were completed by 51 patients and 40 mental health professionals. Significantly more patients (83%) than staff (37%) thought that copying letters to patients was a good idea (OR=14.56, 95% CI 4.674 –45.158). Many staff appeared concerned that copying letters to patients could result in breakdown of the therapeutic relationship, causing distress and anxiety.

Clinical Implications

Considerable work is needed for clinicians to feel comfortable in copying letters to patients. The creation of working groups, including users, carers, managers and clinicians working in the field of mental health, would facilitate the development of guidelines for this practice.
High Rate of Durable Remissions After Treatment of Newly Diagnosed Aggressive Mantle-Cell Lymphoma With Rituximab Plus Hyper-CVAD Alternating With Rituximab Plus High-Dose Methotrexate and Cytarabine
Authors: Romaguera Jorge E. , Fayad Luis , Rodriguez Maria A. , Broglio Kristine R. , Hagemeister Frederick B. , Pro Barbara , McLaughlin Peter , Younes Anas , Samaniego Felipe , Goy Andre , Sarris Andreas H. , Dang Nam H. , Wang Michael , Beasley Virginia , Medeiros L. Jeffrey , Katz Ruth L. , Gagneja Harish , Samuels Barry I. , Smith Terry L. , Cabanillas Fernando F.
Published: September 2005

Purpose

To determine the response, failure-free survival (FFS), and overall survival rates and toxicity of rituximab plus an intense chemotherapy regimen in patients with previously untreated aggressive mantle-cell lymphoma (MCL).

Patients and Methods

This was a prospective phase II trial of rituximab plus fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD; considered one cycle) alternating every 21 days with rituximab plus high-dose methotrexate-cytarabine (considered one cycle) for a total of six to eight cycles.

Results

Of 97 assessable patients, 97% responded, and 87% achieved a complete response (CR) or unconfirmed CR. With a median follow-up time of 40 months, the 3-year FFS and overall survival rates were 64% and 82%, respectively, without a plateau in the curves. For the subgroup of patients ≤ 65 years of age, the 3-year FFS rate was 73%. The principal toxicity was hematologic. Five patients died from acute toxicity. Four patients developed treatment-related myelodysplasia/acute myelogenous leukemia, and three patients died while in remission from MCL. A total of eight treatment-related deaths (8%) occurred.

Conclusion

Rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine is effective in untreated aggressive MCL. Toxicity is significant but expected. Because of the shorter FFS concurrent with significant toxicity in patients more than 65 years of age, this regimen is not recommended as standard therapy for this age subgroup. Larger prospective randomized studies are needed to define the role of this regimen in the treatment of MCL patients compared with existing and new treatment modalities.
Is Leptin a Mediator of Adverse Prognostic Effects of Obesity in Breast Cancer?
Authors: Goodwin Pamela J. , Ennis Marguerite , Fantus I. George , Pritchard Kathleen I. , Trudeau Maureen E. , Koo Jarley , Hood Nicky
Published: August 2005

Purpose

Leptin, an adipocyte-derived cytokine that is elevated in obesity, has been associated with carcinogenesis, tumor migration and invasion, enhancement of angiogenesis, and increased aromatase activity. It has been suggested that leptin may mediate adverse prognostic effects of obesity in breast cancer.

Patients and Methods

Four hundred seventy-one women with surgically resected T1-3, N0-1, M0 breast cancer were studied. Leptin was assayed in stored fasting blood specimens obtained before adjuvant therapy. Women were followed prospectively for distant disease-free survival (DDFS) and overall survival (OS).

Results

Patients ranged from 26 to 74 years of age, and staging was as follows: T1 = 262, T2 = 151, T3 = 23, TX = 35, N0 = 323, and N1 = 148. Estrogen receptor was positive in 286 patients, and progesterone receptor was positive in 259 patients. One hundred forty-five patients received adjuvant chemotherapy, 146 received adjuvant tamoxifen, 46 received both, and 134 received neither. Mean leptin was 15.2 ± 10.1 ng/mL. Univariately, leptin was associated with OS (overall P = .049; P = .014 postmenopausal). Leptin was not associated with DDFS overall or in any menopausal subgroup (P ≥ .19). In multivariate Cox modeling, leptin was not significantly associated with DDFS or OS (P = .11 and 0.075, respectively). Adjustment for insulin or body mass index further reduced the association of leptin with outcome.

Conclusion

Although leptin is strongly correlated with obesity and insulin, we could not show that it is independently associated with prognosis in early-stage breast cancer. Because we cannot rule out modest prognostic effects, we recommend additional research to explore this potential association, particularly in postmenopausal women.
Occurrence of Second Cancers in Patients Treated With Radiotherapy for Rectal Cancer
Authors: Birgisson Helgi , Påhlman Lars , Gunnarsson Ulf , Glimelius Bengt
Published: August 2005

Purpose

To analyze the occurrence of second cancers in patients with rectal cancer treated with external radiotherapy (RT) in addition to surgery.

Patients and Methods

The analyses were based on the Uppsala Trial (completed in 1985), with patients randomly assigned to preoperative RT to all stages or postoperative RT for stage II and III cancers, and the Swedish Rectal Cancer Trial (completed in 1990), with patients randomly assigned to preoperative RT or surgery alone. Patients from the trials were matched against the Swedish Cancer Registry.

Results

A total of 115 (7%) of the 1,599 patients developed 122 second cancers. More patients treated with RT developed a second cancer (relative risk [RR], 1.85; 95% CI, 1.23 to 2.78). A significant increased risk for second cancers in the RT group was seen in organs within or adjacent to the irradiated volume (RR, 2.04; 95% CI, 1.10 to 3.79) but not outside the irradiated volume (RR, 1.78; 95% CI, 0.97 to 3.27). For the Swedish Rectal Cancer Trial, 20.3% of the RT patients got either a local recurrence or a second cancer, compared with 30.7% of the non-RT patients (RR, 0.55; 95% CI, 0.44 to 0.70).

Conclusion

An increased risk of second cancers was found in patients treated with RT in addition to surgery for a rectal cancer, which was mainly explained by an increase in the risk of second cancers in organs within or adjacent to the irradiated volume. However, a favorable effect of radiation seemed to dominate, as shown by the reduced risk of the sum of local recurrences and second cancers.
Molecular Classification and Molecular Forecasting of Breast Cancer: Ready for Clinical Application?
Authors: Brenton James D. , Carey Lisa A. , Ahmed Ahmed Ashour , Caldas Carlos
Published: September 2005

Profiling breast cancer with expression arrays has become common, and it has been suggested that the results from early studies will lead to understanding of the molecular differences between clinical cases and allow individualization of care. We critically review two main applications of expression profiling; studies unraveling novel breast cancer classifications and those that aim to identify novel markers for prediction of clinical outcome. Breast cancer may now be subclassified into luminal, basal, and HER2 subtypes with distinct differences in prognosis and response to therapy. However, profiling studies to identify predictive markers have suffered from methodologic problems that prevent general application of their results. Future work will need to reanalyze existing microarray data sets to identify more representative sets of candidate genes for use as prognostic signatures and will need to take into account the new knowledge of molecular subtypes of breast cancer when assessing predictive effects.
Randomized Trial Comparing Two Fractionation Schedules for Patients With Localized Prostate Cancer
Authors: Lukka Himu , Hayter Charles , Julian Jim A. , Warde Padraig , Morris W. James , Gospodarowicz Mary , Levine Mark , Sathya Jinka , Choo Richard , Prichard Hugh , Brundage Michael , Kwan Winkle
Published: August 2005

Purpose

The optimal radiation dose fractionation schedule for localized prostate cancer is unclear. This study was designed to compare two dose fractionation schemes (a shorter 4-week radiation schedule v a longer 6.5-week schedule).

Patients and Methods

Patients with early-stage (T1 or T2) prostate cancer were randomly assigned to 66 Gy in 33 fractions over 45 days (long arm) or 52.5 Gy in 20 fractions over 28 days (short arm). The study was designed as a noninferiority investigation with a predefined tolerance of −7.5%. The primary outcome was a composite of biochemical or clinical failure (BCF). Secondary outcomes included presence of tumor on prostate biopsy at 2 years, survival, and toxicity.

Results

From March 1995 to December 1998, 936 men were randomly assigned to treatment; 470 were assigned to the long arm, and 466 were assigned to the short arm. The median follow-up time was 5.7 years. At 5 years, the BCF probability was 52.95% in the long arm and 59.95% in the short arm (difference = −7.0%; 90% CI, −12.6% to −1.4%), favoring the long arm. No difference in 2-year postradiotherapy biopsy or in overall survival was detected between the arms. Acute toxicity was found to be slightly higher in the short arm (11.4%) compared with the long arm (7%; difference = −4.4%; 95% CI, −8.1% to −0.6%); however, late toxicity was similarly low in both arms (3.2%).

Conclusion

Given the results, we cannot exclude the possibility that the chosen hypofractionated radiation regimen may be inferior to the standard regimen. Further evaluation involving higher dose hypofractionated radiation regimens in contemporary radiation settings is necessary.
Incidence and Prognostic Impact of Amenorrhea During Adjuvant Therapy in High-Risk Premenopausal Breast Cancer: Analysis of a National Cancer Institute of Canada Clinical Trials Group Study—NCIC CTG MA.5
Authors: Parulekar Wendy R. , Day Andrew G. , Ottaway Jon A. , Shepherd Lois E. , Trudeau Maureen E. , Bramwell Vivien , Levine Mark , Pritchard Kathleen I.
Published: August 2005

Purpose

To investigate the therapeutic impact of chemotherapy-induced amenorrhea in premenopausal patients with breast cancer.

Patients and Methods

We conducted a retrospective cohort study of a National Cancer Institute of Canada Clinical Trials Group phase III trial involving premenopausal patients randomized to receive cyclophosphamide, methotrexate, and fluorouracil (CMF), versus intensive cyclophosphamide, epirubicin, and fluorouracil (CEF). The objectives of our study were to describe the incidence of amenorrhea at 6 and 12 months post-random assignment and to determine the association of amenorrhea with relapse-free and overall survival.

Results

Data on 442 patients were used in our analyses. Despite the higher cumulative dose of cyclophosphamide in the CMF treatment arm, at 6 months post–random assignment, the rate of amenorrhea was higher in the CEF group (relative risk, 1.2; 95% CI, 1.0 to 1.3), with no difference at 12 months. In the receptor-positive subgroup, 6-month amenorrhea rates were not associated with prognosis. In contrast, amenorrhea at 12 months was significantly associated with relapse-free survival (hazard ratio, 0.51; 95% CI, 0.32 to 0.82; P = .005) and overall survival (hazard ratio, 0.40; 95% CI, 0.22 to 0.72; P = .002).

Conclusion

Late chemotherapy-induced amenorrhea seems to be associated with improved outcome in patients with premenopausal, receptor-positive breast cancer.
Phase II Multicenter Study of Induction Chemotherapy Followed by Concurrent Efaproxiral (RSR13) and Thoracic Radiotherapy for Patients With Locally Advanced Non–Small-Cell Lung Cancer
Authors: Choy Hak , Nabid Abdenour , Stea Baldassarre , Scott Charles , Roa Wilson , Kleinberg Larry , Ayoub Joseph , Smith Colum , Souhami Luis , Hamburg Solomon , Spanos William , Kreisman Harvey , Boyd Adam P. , Cagnoni Pablo J. , Curran Walter J.
Published: August 2005

Purpose

Efaproxiral (RSR13) reduces hemoglobin oxygen–binding affinity, facilitates oxygen release, and increases tissue pO2. We conducted a phase II multicenter study that assessed the efficacy and safety of efaproxiral when administered with thoracic radiation therapy (TRT), following induction chemotherapy, for treatment of locally advanced non–small-cell lung cancer (NSCLC).

Patients and Methods

Fifty-one patients with locally advanced NSCLC were enrolled at 13 sites. Treatment comprised two cycles of paclitaxel (225 mg/m2) and carboplatin (area under the curve, 6), 3 weeks apart, followed by TRT (64 Gy/32 fractions) with concurrent efaproxiral (50 to 100 mg/kg). Survival results were compared with results of study Radiation Therapy Oncology Group (RTOG) 94-10.

Results

Overall response rate was 75% (37 of 49 patients). Complete and partial response rates were 6% (three of 49 patients) and 69% (34 of 49 patients), respectively. Median survival time (MST) was 20.6 months (95% CI, 14.0 to 24.2); overall survival rates at 1- and 2-years were 67% and 37%, respectively. Survival results were compared with the sequential (S-CRT) and concurrent (C-CRT) chemoradiotherapy arms of RTOG 94-10. MSTs for cases matched by stage, Karnofsky performance status, and age were: RT-010, 20.6 months; S-CRT, 15.1 months; and C-CRT, 17.9 months. Grade 3 to 4 toxicities related to efaproxiral that occurred in more than one patient included transient hypoxemia (19%), radiation pneumonitis (11%), and fatigue (4%).

Conclusion

Addition of efaproxiral to S-CRT represents a promising approach in NSCLC treatment, and a randomized study should be pursued. The low incidence of grade 3 to 4 toxicities suggests that the use of efaproxiral instead of a cytotoxic agent, as a radiation sensitizer, may be advantageous.
Multicenter Phase II Trial of ABI-007, an Albumin-Bound Paclitaxel, in Women With Metastatic Breast Cancer
Authors: Ibrahim Nuhad K. , Samuels Brian , Page Ray , Doval Dinesh , Patel Kirtikumar M. , Rao S.C. , Nair Madhavan Krishnan , Bhar Paul , Desai Neil , Hortobagyi Gabriel N.
Published: August 2005

Purpose

ABI-007 is a novel nanoparticle, albumin-bound paclitaxel that is free of solvents. This multicenter phase II study was designed to evaluate the efficacy and safety of ABI-007 for the treatment of metastatic breast cancer (MBC).

Patients and Methods

Sixty-three women with histologically confirmed and measurable MBC received 300 mg/m2 ABI-007 by intravenous infusion over 30 minutes every 3 weeks without premedication. Forty-eight patients received prior chemotherapy; 39 patients received no prior treatment for metastatic disease.

Results

Overall response rates (complete or partial responses) were 48% (95% CI, 35.3% to 60.0%) for all patients. For patients who received ABI-007 as first-line and greater than first-line therapy for their metastatic disease, the respective response rates were 64% (95% CI, 49.0% to 79.2%) and 21% (95% CI, 7.1% to 42.1%). Median time to disease progression was 26.6 weeks, and median survival was 63.6 weeks. No severe hypersensitivity reactions were reported despite the lack of premedication. Toxicities observed were typical of paclitaxel and included grade 4 neutropenia (24%), grade 3 sensory neuropathy (11%), and grade 4 febrile neutropenia (5%). Patients received a median of six treatment cycles; 16 patients had 25% dose reductions because of toxicities, and two of these patients had subsequent dose reductions.

Conclusion

ABI-007, the first biologically interactive albumin-bound form of paclitaxel in the nanoparticle state, uses the natural carrier albumin rather than synthetic solvents to deliver paclitaxel and allows for safe administration of high paclitaxel doses without premedication, resulting in significant antitumor activity in patients with MBC, including those receiving the drug as first-line therapy.
Adjuvant Therapy in Gastric Cancer
Authors: Lim Lionel , Michael Michael , Mann G. Bruce , Leong Trevor
Published: August 2005

Gastric cancer has a poor prognosis. The majority of patients will relapse after definitive surgery, and 5-year survival after surgery remains poor. The role of adjuvant therapy in gastric cancer has been controversial given the lack of significant survival benefit in many randomized studies so far. The results of a large North American study (Gastrointestinal Cancer Intergroup Trial INT 0116) reported that postoperative chemoradiotherapy conferred a survival advantage compared with surgery alone, which has led to the regimen being adopted as a new standard of care. However, controversies still remain regarding surgical technique, the place of more effective and less toxic chemotherapy regimens, and the use of more modern radiation planning techniques to improve treatment delivery and outcome in the adjuvant and neoadjuvant setting. This article reviews the current status of the adjuvant treatment for gastric cancer including discussion on the research directions aimed at optimizing treatment efficacy. Issues such as the identification of patients who are more likely to benefit from adjuvant therapy are also addressed. Further clinical trials are needed to move towards better consensus and standardization of care.
Outcome Analysis for Patients With Elevated Serum Tumor Markers at Postchemotherapy Retroperitoneal Lymph Node Dissection
Authors: Beck Stephen D.W. , Foster Richard S. , Bihrle Richard , Einhorn Lawrence H. , Donohue John P.
Published: August 2005

Purpose

To evaluate the therapeutic benefit of postchemotherapy retroperitoneal lymph node dissection (PCRPLND) in patients with persistently elevated serum tumor markers.

Patients and Methods

One hundred fourteen patients with metastatic germ cell cancer with elevated serum tumor markers after first-line (50 patients) or second-line chemotherapy (64 patients) who underwent PCRPLND between 1977 and 2000 with a minimum follow-up of 2-years were included in this retrospective study.

Results

The 5-year overall survival was 53.9%. Sixty-one patients (53.5%) are alive with a medium follow-up of 72 months. Fifty-three patients died of disease, with a medium time to death of 8.0 months. Mean preoperative serum alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (βHCG) levels were 483 ng/mL and 555 mU/mL, respectively, with no difference in 5-year survival (P = .2). Retroperitoneal pathology revealed germ cell cancer in 53.5% of patients, teratoma in 34.2% of patients, and fibrosis in 12.2% of patients, with 5-year survival rates of 31.4%, 77.5%, and 85.7%, respectively (P < .0001). Predictors of retroperitoneal pathology included an increasing serum AFP or βHCG, βHCG more than 100 ng/mL, redo retroperitoneal lymph node dissection (RPLND), and second-line chemotherapy. Poor prognostic variables by multivariable analysis included βHCG status, serum AFP level, redo RPLND, and germ cell cancer in the resected specimen.

Conclusion

A subset of patients with elevated serum tumor markers after chemotherapy is curable with surgery. The prognostic factors predictive of outcome in this analysis include an increasing βHCG, serum AFP level, redo RPLND, and germ cell cancer in the resected specimen. These factors, along with clinical and surgical experience, should aid in determining the appropriate integration of surgery and chemotherapy in this population.
Randomized Study on the Efficacy of Cognitive-Behavioral Therapy for Insomnia Secondary to Breast Cancer, Part II: Immunologic Effects
Authors: Savard Josée , Simard Sébastien , Ivers Hans , Morin Charles M.
Published: August 2005

Purpose

Cross-sectional studies suggest that clinical insomnia is associated with immune downregulation. However, there is a definite need for experimental studies on this question. The goal of this randomized controlled study was to assess the effect of an 8-week cognitive-behavioral therapy (CBT) for chronic insomnia on immune functioning of breast cancer survivors. Previous analyses of this study showed that CBT was associated with improved sleep and quality of life, and reduced psychological distress.

Patients and Methods

Fifty-seven women with chronic insomnia secondary to breast cancer were randomly assigned to CBT (n = 27) or to a waiting-list control condition (WLC; n = 30). Peripheral-blood samples were taken at baseline and post-treatment (and postwaiting for WLC patients), as well as at 3-, 6-, and 12-month follow-up for immune measures, including enumeration of blood cell counts (ie, WBCs, monocytes, lymphocytes, CD3+, CD4+, CD8+, and CD16+/CD56+) and cytokine production (ie, interleukin-1-beta [IL-1β] and interferon gamma [IFN-γ]).

Results

Patients treated with CBT had higher secretion of IFN-γ and lower increase of lymphocytes at post-treatment compared with control patients. Pooled data from both treated groups indicated significantly increased levels of IFN-γ and IL-1β from pre- to post-treatment. In addition, significant changes in WBCs, lymphocytes, and IFN-γ were found at follow-up compared with post-treatment.

Conclusion

This study provides some support to the hypothesis of a causal relationship between clinical insomnia and immune functioning. Future studies are needed to investigate the clinical impact of such immune alterations.
Late Side Effects of Short-Course Preoperative Radiotherapy Combined With Total Mesorectal Excision for Rectal Cancer: Increased Bowel Dysfunction in Irradiated Patients—A Dutch Colorectal Cancer Group Study
Authors: Peeters K.C.M.J. , van de Velde C.J.H. , Leer J.W.H. , Martijn H. , Junggeburt J.M.C. , Kranenbarg E. Klein , Steup W.H. , Wiggers T. , Rutten H.J. , Marijnen C.A.M.
Published: August 2005

Purpose

Preoperative short-term radiotherapy improves local control in patients treated with total mesorectal excision (TME). This study was performed to assess the presence and magnitude of long-term side effects of preoperative 5 × 5 Gy radiotherapy and TME. Also, hospital treatment was recorded for diseases possibly related to late side effects of rectal cancer treatment.

Patients and Methods

Long-term morbidity was assessed in patients from the prospective randomized TME trial, which investigated the efficacy of 5 × 5 Gy before TME surgery for mobile rectal cancer. Dutch patients without recurrent disease were sent a questionnaire.

Results

Results were obtained from 597 patients, with a median follow-up of 5.1 years. Stoma function, urinary function, and hospital treatment rates did not differ significantly between the treatment arms. However, irradiated patients, compared with nonirradiated patients, reported increased rates of fecal incontinence (62% v 38%, respectively; P < .001), pad wearing as a result of incontinence (56% v 33%, respectively; P < .001), anal blood loss (11% v 3%, respectively; P = .004), and mucus loss (27% v 15%, respectively; P = .005). Satisfaction with bowel function was significantly lower and the impact of bowel dysfunction on daily activities was greater in irradiated patients compared with patients who underwent TME alone.

Conclusion

Although preoperative short-term radiotherapy for rectal cancer results in increased local control, there is more long-term bowel dysfunction in irradiated patients than in patients who undergo TME alone. Rectal cancer patients should be informed on late morbidity of both radiotherapy and TME. Future strategies should be aimed at selecting patients for radiotherapy who are at high risk for local failure.
Phase I Trial of Bortezomib and Carboplatin in Recurrent Ovarian or Primary Peritoneal Cancer
Authors: Aghajanian C. , Dizon D.S. , Sabbatini P. , Raizer J.J. , Dupont J. , Spriggs D.R.
Published: August 2005

Purpose

To determine the maximum-tolerated dose, pharmacodynamics, and safety of the combination of bortezomib and carboplatin in recurrent ovarian cancer.

Patients and Methods

Fifteen patients were treated with a fixed dose of carboplatin (area under the curve [AUC] 5) and increasing doses of bortezomib (0.75, 1, 1.3, and 1.5 mg/m2/dose). Patients must have received upfront chemotherapy and up to two prior chemotherapy regimens for recurrent disease. Neurologic evaluation was performed at baseline and after every two cycles by the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group neurotoxicity questionnaire and examination by an attending neurologist. All patients received carboplatin alone in cycle 1 to establish baseline pharmacodynamics for nuclear factor-kappa B (NF-kB). Starting with cycle 2, patients were treated with carboplatin on day 1 and bortezomib on days 1, 4, 8, and 11.

Results

Diarrhea, rash, neuropathy, and constipation (with colonic wall thickening on computed tomography) were dose-limiting toxicities, occurring in the two patients treated at the 1.5 mg/m2/dose level. The Functional Assessment of Cancer Therapy/Gynecologic Oncology Group neurotoxicity questionnaire was helpful in guiding the need for dose reductions. Neurotoxicity was manageable through six cycles, with appropriate dose reductions. Carboplatin had no effect on bortezomib pharmacodynamics as measured by percent inhibition of the 20S proteasome. Bortezomib decreased carboplatin-induced NF-kB. The overall response rate to this combination was 47%, with two complete responses (CR) and five partial responses, including one CR in a patient with platinum-resistant disease.

Conclusion

The recommended phase II dose of bortezomib administered in combination with carboplatin (AUC 5) is 1.3 mg/m2/dose.
Free Fatty Acid-Induced Insulin Resistance in the Obese Is Not Prevented by Rosiglitazone Treatment
Authors: Dhindsa Sandeep , Tripathy Devjit , Sanalkumar Nishanth , Ravishankar Shreyas , Ghanim Husam , Aljada Ahmad , Dandona Paresh
Published: September 2005

Objective: Elevation of free fatty acids (FFAs) by the infusion of triglyceride-heparin emulsion infusion (TG-Hep) causes insulin resistance (IR). We examined the effect of insulin sensitizer (rosiglitazone) on FFA-induced IR.

Design: Nine obese subjects underwent a 6-h infusion of TG-Hep before and after 6 wk of rosiglitazone (8 mg/d) treatment. Hyperinsulinemic euglycemic clamps were performed during 0–2 and 4–6 h of TG-Hep.

Results: After rosiglitazone for 6 wk, fasting FFA concentration fell, but not significantly (489 ± 63 at 0 wk; 397 ± 58 μmol/liter at 6 wk; P = 0.16), whereas C-reactive protein (4.26 ± 0.95 at 0 wk; 2.03 ± 0.45 μg/ml at 6 wk) and serum amyloid A (17.36 ± 4.63 at 0 wk; 8.77 ± 1.63 μg/ml at 6 wk) decreased significantly. At 0 wk, TG-Hep infusion caused a decrease in glucose infusion rate (GIR) from 4.49 ± 0.95 mg/kg·min to 3.02 ± 0.59 mg/kg·min (P = 0.018). Rosiglitazone treatment resulted in an increase in baseline GIR to 6.29 ± 0.81 mg/kg·min (P = 0.03 vs. 0 wk), which decreased to 4.52 ± 0.53 mg/kg·min (P = 0.001) after 6 h of TG-Hep infusion. The decrease in GIR induced by TG-Hep infusion was similar before and after rosiglitazone therapy [1.47 ± 0.50 vs. 1.77 0.3 mg/kg·min (28.9 ± 6.5 vs. 26.4 ± 3.7%); P = 0.51]. The rise in FFAs and triglycerides after TG-Hep infusion was significantly lower at 6 wk (P = 0.006 for FFAs; P = 0.024 for triglycerides).

Conclusions: We conclude that rosiglitazone: 1) causes a significant increase in GIR; 2) induces a decrease in inflammatory mediators, C-reactive protein, and serum amyloid A; 3) decreases the rise in FFAs and triglycerides after TG-Hep infusion; and 4) does not prevent FFA-induced IR.
Corticotropin-Releasing Hormone (CRH) and Urocortin Act through Type 1 CRH Receptors to Stimulate Dehydroepiandrosterone Sulfate Production in Human Fetal Adrenal Cells
Authors: Sirianni Rosa , Mayhew Bobbie A. , Carr Bruce R. , Parker C. Richard , Rainey William E.
Published: September 2005

Context: Near term, the human fetal adrenal increases the production of cortisol and dehydroepiandrosterone sulfate (DHEAS). DHEAS, which acts as substrate for placental estrogen production, induces key changes involved in parturition.

Objective: The objective of this study was to determine quantitatively the effect of CRH on mRNA levels of enzymes needed for DHEAS production (steroidogenic acute regulatory protein, CYP11A, CYP17, and SULT2A1), to determine the CRH receptor (CRH-R) subtype(s) responsible for CRH action, and to determine the effect of CRH on CRH-R mRNA expression in human adrenal fetal zone (FZ) cells.

Design: Human adrenal FZ cells were treated with CRH, ACTH, urocortin (Unc), and CRH antagonists, and RNA was analyzed by microarray and real-time RT-PCR.

Setting: This study was performed at an academic research laboratory.

Main Outcome Measure: The main outcome measure was the expression of steroidogenic enzymes and CRH-R.

Results: Microarray analysis of human FZ cells treated for 24 h with CRH or ACTH showed increased mRNA expression levels of the genes needed for DHEAS production. Real-time RT-PCR analysis confirmed these data. Induction was lost in the presence of CRH-R1 antagonists, but not CRH-R2 antagonists. Stimulation was reproduced by Unc. The CRH-R1α mRNA splice variant was the only type 1 receptor isoform expressed in the fetal adrenal, and treatment with CRH up-regulates its mRNA levels.

Conclusions: CRH, Unc, and ACTH stimulate all elements of the DHEAS synthetic pathway and activate CRH-R1 as well. The resulting increased DHEAS levels can be used for placental estrogen synthesis and contribute to the process leading to parturition in humans.
Distinct cytoskeletal modulation and regulation of G1-S transition in the two life stages ofTrypanosoma brucei
Authors: Tu Xiaoming , Mancuso Joel , Cande W. Zacheus , Wang Ching C.
Published: September 2005

Procyclic-form Trypanosoma brucei is arrested in G1 phase with extended and/or branched posterior morphology when expression of its cdc2-related kinases 1 and 2 (CRK1 and CRK2) is knocked down by RNA interference. Transmission electron microscopy indicated that the mitochondrion in the cell is also extended and branched and associated with cortical microtubules in each elongated/branched posterior end. This posterior extension is apparently driven by the growing microtubule corset, as it can be blocked by rhizoxin, an inhibitor of microtubule assembly. In the bloodstream form of T. brucei, however, a knockdown of CRK1 and CRK2 resulted only in an enrichment of cells in G1 phase without cessation of DNA synthesis or elongated/branched posterior ends. A triple knockdown of CRK1, CRK2 and CycE1/CYC2 in the bloodstream form resulted in 15% of the cells arrested in G1 phase, but no cells had an abnormal posterior morphology. The double and triple knockdown bloodstream-form cells were differentiated in vitro into the procyclic form, and the latter thus generated bore the typical morphology of a procyclic form without an extended/branched posterior end, albeit arrested in the G1 phase as the bloodstream-form precursor. There is thus a major distinction in the mechanisms regulating G1-S transition and posterior morphogenesis between the two life stages of T. brucei.
Regulated expression of functional external guide sequences in mammalian cells using a U6 RNA polymerase III promoter
Authors: KOVRIGINA ELIZAVETA , YANG LI , PFUND EMMANUEL , ALTMAN SIDNEY
Published: August 2005

A regulatable promoter has been stably integrated into a human embryonic kidney cell line. The promoter is a pol III mouse promoter and is under the control of ponasterone A, an ecdysone inducer. The promoter controls transcription of an external guide sequence (EGS) targeted against Rpp38, a protein subunit of human RNase P, or of lamin A/C, a gene product located in the nucleus. The amounts of protein of both gene products are severely reduced when the EGSs are made. Several other, but not all, of the protein subunits of RNase P are also inhibited in both mRNA and protein levels when Rpp38 mRNA is targeted.
An in vitro RNA editing system from cauliflower mitochondria: Editing site recognition parameters can vary in different plant species
Authors: NEUWIRT JULIA , TAKENAKA MIZUKI , VAN DER MERWE JOHANNES A. , BRENNICKE AXEL
Published: August 2005

Most of the 400 RNA editing sites in flowering plant mitochondria are found in mRNAs. Consequently, the sequence vicinities of homologous sites are highly conserved between different species and are presumably recognized by likewise conserved trans-factors. To investigate the evolutionary adaptation to sequence variation, we have now analyzed the recognition elements of an editing site with divergent upstream sequences in the two species pea and cauliflower. This variation is tolerated at the site selected, because the upstream cis-elements reach into the 5′-UTR of the mRNA. To compare cis-recognition features in pea and cauliflower mitochondria, we developed a new in vitro RNA editing system for cauliflower. In vitro editing assays with deleted and mutated template RNAs show that the major recognition elements for both species are located within the conserved sequence. In cauliflower, however, the essential upstream nucleotides extend further upstream than they do in pea. In-depth analysis of single-nucleotide mutations reveals critical spacing of the editing site and the specific recognition elements, and shows that the +1 nucleotide identity is important in cauliflower, but not in pea.
RNA sequence and secondary structure participate in high-affinity CsrA–RNA interaction
Authors: DUBEY ASHOK K. , BAKER CAROL S. , ROMEO TONY , BABITZKE PAUL
Published: August 2005

The global Csr regulatory system controls bacterial gene expression post-transcriptionally. CsrA of Escherichia coli is an RNA binding protein that plays a central role in repressing several stationary phase processes and activating certain exponential phase functions. CsrA regulates translation initiation of several genes by binding to the mRNA leaders and blocking ribosome binding. CsrB and CsrC are noncoding regulatory RNAs that are capable of sequestering CsrA and antagonizing its activity. Each of the known target transcripts contains multiple CsrA binding sites, although considerable sequence variation exists among these RNA targets, with GGA being the most highly conserved element. High-affinity RNA ligands containing single CsrA binding sites were identified from a combinatorial library using systematic evolution of ligands by exponential enrichment (SELEX). The SELEX-derived consensus was determined as RUACARGGAUGU, with the ACA and GGA motifs being 100% conserved and the GU sequence being present in all but one ligand. The majority (51/55) of the RNAs contained GGA in the loop of a hairpin within the most stable predicted structure, an arrangement similar to several natural CsrA binding sites. Strikingly, the identity of several nucleotides that were predicted to form base pairs in each stem were 100% conserved, suggesting that primary sequence information was embedded within the base-paired region. The affinity of CsrA for several selected ligands was measured using quantitative gel mobility shift assays. A mutational analysis of one selected ligand confirmed that the conserved ACA, GGA, and GU residues were critical for CsrA binding and that RNA secondary structure participates in CsrA–RNA recognition.
Chemotherapy Dosing with Elevated Liver Function Test Results in Acute Leukemia
Authors: Comeau Terrance B , Phillips Debra L
Published: August 2005

OBJECTIVE:

To report a case of massive blast infiltration of the liver by acute lymphoblastic leukemia (ALL) manifested by worsening liver function test (LFT) results and concern over how to dose chemotherapy in this patient.

CASE SUMMARY:

A 36-year-old male presenting with productive cough, abdominal pain, and lower back pain was diagnosed with pre-B cell ALL. Of note, the patient developed worsening LFT results within the first few days of diagnosis. Because of concern over increasing liver dysfunction and the need to administer vincristine and daunorubicin with induction therapy, a transvenous liver biopsy was performed, revealing massive lymphoblast infiltration.

DISCUSSION:

A short course of prednisone was given to determine whether the LFT abnormalities would reverse with treatment. Once a downward trend in the abnormalities was noted, full-dose induction chemotherapy was administered.

CONCLUSIONS:

It is important to discern the cause of elevated LFT values in patients with acute leukemia who require induction chemotherapy, as this may affect treatment decisions and patient outcomes.
Potent Spinal Analgesia Elicited through Stimulation of NTS2 Neurotensin Receptors
Authors: Sarret Philippe , Esdaile Michael J. , Perron Amélie , Martinez Jean , Stroh Thomas , Beaudet Alain
Published: September 2005

Intrathecal administration of the neuropeptide neurotensin (NT) was shown previously to exert antinociceptive effects in a variety of acute spinal pain paradigms including hotplate, tail-flick, and writhing tests. In the present study, we sought to determine whether some of these antinociceptive effects might be elicited via stimulation of low-affinity NTS2 receptors. We first established, using immunoblotting and immunohistochemical techniques, that NTS2 receptors were extensively associated with putative spinal nociceptive pathways, both at the level of the dorsal root ganglia and of the superficial layers of the dorsal horn of the spinal cord. We then examined the effects of intrathecal administration of NT or selective NTS2 agonists on acute thermal pain. Both NT and NTS2 agonists, levocabastine and Boc-Arg-Arg-Pro-Tyrψ(CH2NH)Ile-Leu-OH (JMV-431), induced dose-dependent antinociceptive responses in the tail-flick test. The effects of levocabastine and of JMV-431 were unaffected by coadministration of the NTS1-specific antagonist 2-[(1-(7-chloro-4-quinolinyl)-5-(2,6-dimethoxy-phenyl)pyrazol-3-yl)carboxylamino]tricyclo)3.3.1.1.3.7)-decan-2-carboxylic acid (SR48692), confirming that they were NTS2 mediated. In contrast, the antinociceptive effects of NT were partly abolished by coadministration of SR48692, indicating that NTS1 and NTS2 receptors were both involved. These results suggest that NTS2 receptors play a role in the regulation of spinal nociceptive inputs and that selective NTS2 agonists may offer new avenues for the treatment of acute pain.
Cdh1/Hct1-APC Is Essential for the Survival of Postmitotic Neurons
Authors: Almeida Angeles , Bolaños Juan P. , Moreno Sergio
Published: September 2005

Cell division at the end of mitosis and G1is controlled by Cdh1/Hct1, an activator of the E3-ubiquitin ligase anaphase-promoting complex (APC) that promotes the ubiquitylation and degradation of mitotic cyclins and other substrates. Cdh1–APC is active in postmitotic neurons, where it regulates axonal growth and patterning in the developing brain. However, it remains unknown whether Cdh1–APC is involved in preventing cell-cycle progression in terminally differentiated neurons. To address this issue, we used the small hairpin RNA strategy to deplete Cdh1 in postmitotic neurons. We observed that Cdh1 silencing rapidly triggered apoptotic neuronal death. To investigate the underlying mechanism, we focused on cyclin B1, a major Cdh1–APC substrate. Our results demonstrate that Cdh1 is required to prevent the accumulation of cyclin B1 in terminally differentiated neurons. Moreover, by keeping cyclin B1 low, Cdh1 prevented these neurons from entering an aberrant S phase that led to apoptotic cell death. These results provide an explanation for the mechanism of cyclin B1 reactivation that occurs in the brain of patients suffering from neurodegenerative diseases, such as Alzheimer's disease.
Retrieval Attempts Transiently Interfere with Concurrent Encoding of Episodic Memories But Not Vice Versa
Authors: Allan Kevin , Allen Roy
Published: September 2005

In the rodent hippocampus, different phases of each theta activity cycle may be devoted to encoding and retrieval processes. These cycles of ∼3–8 Hz would allow equal processing time for each state and also provide temporal segregation to minimize their mutual interference. We show here that, by controlling the presentation asynchrony between verbal encoding and retrieval cues, theta-resolution (<100 ms) interference-free shifts between functional states are not expressed in hippocampally dependent, human “episodic” memory. Instead, retrieval attempts selectively and transiently interfere, for ∼450 ms, with the encoding of ongoing experiences. Analyses of scalp event-related potentials confirmed that the functional state of the brain during retrieval is largely unperturbed by concurrent encoding and also suggested that encoding impairments may last until a neocortical phase of retrieval can begin. The findings reveal the dynamic properties of interdependent encoding and retrieval functions that contribute to episodic memoryin vivoand, moreover, show that, in humans, this form of memory does not operate with either the equality, or the rapidity, intrinsic to the theta model of rodent hippocampal function.
Effects of Unilateral Prefrontal Lesions on Familiarity, Recollection, and Source Memory
Authors: Duarte Audrey , Ranganath Charan , Knight Robert T.
Published: September 2005

Recognition memory can be supported by both the assessment of the familiarity of an item and by recollection of the context in which an item was encountered. Some have hypothesized that the prefrontal cortex (PFC) disproportionately contributes to recollection, whereas an alternative view is that the PFC contributes to both recollection and familiarity. Here, we examined the effects of prefrontal lesions on recollection and familiarity. Patients with unilateral PFC lesions and age-, gender-, and education-matched controls encoded pictures of meaningful objects that were presented briefly to the left or right visual field and subsequently performed recognition tests for centrally presented objects. Laterality effects within the PFC were also assessed in relation to recollection and familiarity processes. Patients with prefrontal lesions showed impaired familiarity-based recognition, and this deficit was specific for objects encoded by the lesioned hemisphere. In addition, recollection of the context in which each item was encountered was impaired independent of the visual field of presentation in patients with left prefrontal lesions. Recollection measured by subjective reports (“remember”) was not impaired in either left or right frontal patients. These findings suggest that the PFC plays a critical role in recognition memory based on familiarity as well as recollection. Furthermore, these results suggest that left PFC regions are critical for source recollection.
Gating Reaction Mechanisms for NMDA Receptor Channels
Authors: Auerbach Anthony , Zhou Yu
Published: August 2005

NMDA receptors (NMDARs) mediate the slow component of excitatory transmission in the CNS and play key roles in synaptic plasticity and excitotoxicity. We investigated the gating reaction mechanism of fully liganded NR1/NR2A recombinant NMDARs (expressed inXenopusoocytes) by fitting all possible three-closed/two-open-state, noncyclic kinetic schemes to currents elicited by saturating concentrations of glutamate plus glycine. The adequacy of each scheme was assessed by maximum likelihood values and autocorrelation coefficients of single-channel currents, as well as by the predicted time courses of transient macroscopic currents. Two schemes provided the best description for NMDAR gating at both the single-channel and macroscopic levels. These two schemes had coupled open states, only one gateway between the closed and open aggregates, and at least two preopening closed states. These two models could be condensed into a cyclic reaction mechanism. Using a linear reaction scheme, the overall “gating” rates (from the initial stable closed state to the final stable open state) are 177 and 4.4 s–1.
Prolonged Epileptiform Discharges Induced by Altered Group I Metabotropic Glutamate Receptor-Mediated Synaptic Responses in Hippocampal Slices of a Fragile X Mouse Model
Authors: Chuang Shih-Chieh , Zhao Wangfa , Bauchwitz Robert , Yan Qijiang , Bianchi Riccardo , Wong Robert K. S.
Published: August 2005

Mutations inFMR1, which encodes the fragile X mental retardation protein (FMRP), are the cause of fragile X syndrome (FXS), an X-linked mental retardation disorder. Inactivation of the mouse geneFmr1confers a number of FXS-like phenotypes including an enhanced susceptibility to epileptogenesis during development. We find that in a FXS mouse model, in which the function of FMRP is suppressed, synaptically released glutamate induced prolonged epileptiform discharges resulting from enhanced group I metabotropic glutamate receptor (mGluR)-mediated responses in hippocampal slices. The induction of the group I mGluR-mediated, prolonged epileptiform discharges was inhibited in preparations that were pretreated with inhibitors of ERK1/2 (extracellular signal-regulated kinase 1/2) phosphorylation or of mRNA translation, and their maintenance was suppressed by group I mGluR antagonists. The results suggest that FMRP plays a key role in the control of signaling at the recurrent glutamatergic synapses in the hippocampus. The absence of this control causes the synaptically activated group I mGluRs to elicit translation-dependent epileptogenic activities.
Combinatorial Profiles of Oligodendrocyte-Selective Classes of Transcriptional Regulators Differentially Modulate Myelin Basic Protein Gene Expression
Authors: Gokhan Solen , Marin-Husstege Mireya , Yung Shau Yu , Fontanez Darah , Casaccia-Bonnefil Patrizia , Mehler Mark F.
Published: September 2005

Recent studies suggest that specific neural basic helix-loop-helix (HLH; i.e., Olig1 and Olig2, Mash1), associated inhibitory HLH (i.e., Id2 and Id4), high-mobility group domain (i.e., Sox10), and homeodomain (i.e., Nkx2.2) transcription factors are involved in oligodendrocyte (OL) lineage specification and progressive stages of maturation including myelination. However, the developmental interplay among these lineage-selective determinants, in a cell- and maturational stage-specific context, has not yet been defined. We show herein vivoandin vitrodevelopmental expression profiles for these distinct classes of transcriptional regulators of OLs. We show that progressive stages of OL lineage maturation are characterized by dynamic changes in the subcellular distribution of these transcription factors and by different permutations of combinatorial transcriptional codes. Transient transfections of these precise combinatorial codes with a luciferase reporter gene driven by the myelin basic protein promoter define how changes in the molecular composition of these transcriptional complexes modulate myelin gene expression. Our overall findings suggest that the dynamic interplay between developmental stage-specific classes of transcriptional activators and associated inhibitory factors orchestrate myelin gene expression during terminal maturation of the mammalian CNS.