bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II Trial of Cisplatin, Gemcitabine, and Bevacizumab As First-Line Therapy for Metastatic Urothelial Carcinoma: Hoosier Oncology Group GU 04-75
Authors: Hahn Noah M. , Stadler Walter M. , Zon Robin T. , Waterhouse David , Picus Joel , Nattam Sreenivasa , Johnson Cynthia S. , Perkins Susan M. , Waddell Mary Jane , Sweeney Christopher J.
Published: March 2011

Purpose

Novel approaches are needed for patients with metastatic urothelial cancer (UC). This trial assessed the efficacy and toxicity of bevacizumab in combination with cisplatin and gemcitabine (CGB) as first-line treatment for patients with metastatic UC.

Patients and Methods

Chemotherapy-naive patients with metastatic or unresectable UC received cisplatin 70 mg/m2 on day 1, gemcitabine 1,000 to 1,250 mg/m2 on days 1 and 8, and bevacizumab 15 mg/kg on day 1, every 21 days.

Results

Forty-three patients with performance status of 0 (n = 26) or 1 (n = 17) and median age of 66 years were evaluable for toxicity and response. Grade 3 to 4 hematologic toxicity included neutropenia (35%), thrombocytopenia (12%), anemia (12%), and neutropenic fever (2%). Grade 3 to 5 nonhematologic toxicity included deep vein thrombosis/pulmonary embolism (21%), hemorrhage (7%), cardiac (7%), hypertension (5%), and proteinuria (2%). Three treatment-related deaths (CNS hemorrhage, sudden cardiac death, and aortic dissection) were observed. Best response by Response Evaluation Criteria in Solid Tumors was complete response in eight patients (19%) and partial response in 23 patients (53%), for an overall response rate of 72%. Stable disease lasting ≥ 12 weeks occurred in four patients (9%), and progressive disease occurred in six patients (14%). With a median follow-up of 27.2 months (range, 3.5 to 40.9 months), median progression-free survival (PFS) was 8.2 months (95% CI, 6.8 to 10.3 months) with a median overall survival (OS) time of 19.1 months (95% CI, 12.4 to 22.7 months). The study-defined goal of 50% improvement in PFS was not met.

Conclusion

CGB demonstrates promising OS and antiangiogenic treatment-related toxicities in the phase II setting of metastatic UC. The full risk/benefit profile of CGB in patients with metastatic UC will be determined by an ongoing phase III intergroup trial.
Vitamin D Status in Patients With Stage IV Colorectal Cancer: Findings From Intergroup Trial N9741
Authors: Ng Kimmie , Sargent Daniel J. , Goldberg Richard M. , Meyerhardt Jeffrey A. , Green Erin M. , Pitot Henry C. , Hollis Bruce W. , Pollak Michael N. , Fuchs Charles S.
Published: March 2011

Purpose

Previous studies have suggested that higher plasma 25-hydroxyvitamin D3 [25(OH)D] levels are associated with decreased colorectal cancer risk and improved survival, but the prevalence of vitamin D deficiency in advanced colorectal cancer and its influence on outcomes are unknown.

Patients and Methods

We prospectively measured plasma 25(OH)D levels in 515 patients with stage IV colorectal cancer participating in a randomized trial of chemotherapy. Vitamin D deficiency was defined as 25(OH)D lower than 20 ng/mL, insufficiency as 20 to 29 ng/mL, and sufficiency as ≥ 30 ng/mL. We examined the association between baseline 25(OH)D level and selected patient characteristics. Cox proportional hazards models were used to calculate hazard ratios (HR) for death, disease progression, and tumor response, adjusted for prognostic factors.

Results

Among 515 eligible patients, 50% of the study population was vitamin D deficient, and 82% were vitamin D insufficient. Plasma 25(OH)D levels were lower in black patients compared to white patients and patients of other race (median, 10.7 v 21.1 v 19.3 ng/mL, respectively; P < .001), and females compared to males (median, 18.3 v 21.7 ng/mL, respectively; P = .0005). Baseline plasma 25(OH)D levels were not associated with patient outcome, although given the distribution of plasma levels in this cohort, statistical power for survival analyses were limited.

Conclusion

Vitamin D deficiency is highly prevalent among patients with stage IV colorectal cancer receiving first-line chemotherapy, particularly in black and female patients.
Tolerability-Adapted Imatinib 800 mg/d Versus 400 mg/d Versus 400 mg/d Plus Interferon-α in Newly Diagnosed Chronic Myeloid Leukemia
Authors: Hehlmann Rüdiger , Lauseker Michael , Jung-Munkwitz Susanne , Leitner Armin , Müller Martin C. , Pletsch Nadine , Proetel Ulrike , Haferlach Claudia , Schlegelberger Brigitte , Balleisen Leopold , Hänel Mathias , Pfirrmann Markus , Krause Stefan W. , Nerl Christoph , Pralle Hans , Gratwohl Alois , Hossfeld Dieter K. , Hasford Joerg , Hochhaus Andreas , Saußele Susanne
Published: March 2011

Purpose

Treatment of chronic-phase (CP) chronic myeloid leukemia (CML) with imatinib 400 mg/d can be unsatisfactory. Optimization of treatment is warranted.

Patients and Methods

In all, 1,014 newly diagnosed CP-CML patients were randomly assigned to imatinib 800 mg/d (n = 338), imatinib 400 mg/d (n = 325), or imatinib 400 mg/d plus interferon alfa (IFN-α; n = 351). Dose adaptation to avoid higher-grade toxicity was recommended. First primary end point was major molecular remission (MMR) at 12 months.

Results

A higher rate of MMR at 12 months occurred with tolerability-adapted imatinib 800 mg/d than with imatinib 400 mg/d (59% [95% CI, 53% to 65%] v 44% [95% CI, 37% to 50%]; P < .001) or imatinib 400 mg/d plus IFN-α (59% v 46% [95% CI, 40% to 52%]; P = .002). Median dose in the 800-mg/d arm was 628 mg/d with a maximum dose of 737 mg/d during months 4 to 6 and a maintenance dose of 600 mg/d. All three treatment approaches were well tolerated with similar grade 3 and 4 adverse events. Independent of treatment approach, MMR at 12 months showed better progression-free survival (99% v 94%; P = .0023) and overall survival (99% v 93%; P = .0011) at 3 years when compared with > 1% on the international scale or no MMR but showed no difference in 0.1% to < 1% on the international scale, which closely correlates with complete cytogenetic remission.

Conclusion

Treatment of early-phase CML with imatinib can be optimized. Early high-dose therapy followed by rapid adaptation to good tolerability increases the rate of MMR at 12 months. Achievement of MMR by month 12 is directly associated with improved survival.
Long-Term Benefits of 5 Years of Tamoxifen: 10-Year Follow-Up of a Large Randomized Trial in Women at Least 50 Years of Age With Early Breast Cancer
Authors: Hackshaw Allan , Roughton Michael , Forsyth Sharon , Monson Kathryn , Reczko Krystyna , Sainsbury Richard , Baum Michael
Published: March 2011

Purpose

The Cancer Research UK “Over 50s” trial compared 5 and 2 years of tamoxifen in women with early breast cancer. Results are reported after median follow-up of 10 years.

Patients and Methods

Between 1987 and 1997, 3,449 patients age 50 to 81 years with operable breast cancer who had been taking 20 mg of tamoxifen for 2 years were randomly assigned to either stop or continue for an additional 3 years, if they were alive and recurrence free. Data on recurrences, new tumors, deaths, and cardiovascular events were obtained (April 2010).

Results

There were 1,103 recurrences, 755 deaths as a result of breast cancer, 621 cardiovascular (CV) events, and 236 deaths as a result of CV events. Fifteen years after starting treatment, for every 100 women who received tamoxifen for 5 years, 5.8 fewer experienced recurrence, compared with those who received tamoxifen for 2 years. The risk of contralateral breast cancer was significantly reduced (hazard ratio, 0.70; 95% CI, 0.48 to 1.00). Among women age 50 to 59 years, there was a 35% reduction in CV events (P = .005) and 59% reduction in death as a result of a CV event (P = .02); in older women, the effect was much smaller and not statistically significant.

Conclusion

Taking tamoxifen for the recommended 5 years reduces the risk of recurrence or contralateral breast cancer 15 years after starting treatment. It also lowers the risk of CV disease and death as a result of a CV event, particularly among those age 50 to 59 years. Women should therefore be encouraged to complete the full course. Although aromatase inhibitors improve disease-free survival, tamoxifen remains a cheap and highly effective alternative, particularly in developing countries.
Early Prediction of Nonprogression in Advanced Non–Small-Cell Lung Cancer Treated With Erlotinib By Using [18F]Fluorodeoxyglucose and [18F]Fluorothymidine Positron Emission Tomography
Authors: Zander Thomas , Scheffler Matthias , Nogova Lucia , Kobe Carsten , Engel-Riedel Walburga , Hellmich Martin , Papachristou Irini , Toepelt Karin , Draube Andreas , Heukamp Lukas , Buettner Reinhard , Ko Yon D. , Ullrich Roland T. , Smit Egbert , Boellaard Ronald , Lammertsma Adriaan A. , Hallek Michael , Jacobs Andreas H. , Schlesinger Andreas , Schulte Karin , Querings Silvia , Stoelben Erich , Neumaier Bernd , Thomas Roman K. , Dietlein Markus , Wolf Jürgen
Published: March 2011

Purpose

Positron emission tomography (PET) with both 2′-deoxy-2′-[18F]fluoro-d-glucose (FDG) and 3′-[18F]fluoro-3′-deoxy-l-thymidine (FLT) was evaluated with respect to the accuracy of early prediction of nonprogression following erlotinib therapy, independent from epidermal growth factor receptor (EGFR) mutational status, in patients with previously untreated advanced non–small-cell lung cancer (NSCLC).

Patients and Methods

Thirty-four patients with untreated stage IV NSCLC were evaluated in this phase II trial. Changes in FDG and FLT uptake after 1 (early) and 6 (late) weeks of erlotinib treatment were compared with nonprogression measured by computed tomography after 6 weeks of treatment, progression-free survival (PFS), and overall survival (OS).

Results

Changes in FDG uptake after 1 week of therapy predicted nonprogression after 6 weeks of therapy with an area under the receiver operating characteristic curve of 0.75 (P = .02). Furthermore, patients with an early metabolic FDG response (cutoff value: 30% reduction in the peak standardized uptake value) had significantly longer PFS (hazard ratio [HR], 0.23; 95% CI, 0.09 to 0.59; P = .002) and OS (HR, 0.36; 95% CI, 0.13 to 0.96; P = .04). Early FLT response also predicted significantly longer PFS (HR, 0.31; 95% CI, 0.10 to 0.95; P = .04) but not OS and was not predictive for nonprogression after 6 weeks of therapy.

Conclusion

Early FDG-PET predicts PFS, OS, and nonprogression after 6 weeks of therapy with erlotinib in unselected, previously untreated patients with advanced NSCLC independent from EGFR mutational status.
Paraplegia and Paraparesis From Intrathecal Methotrexate and Cytarabine Contaminated With Trace Amounts of Vincristine in China During 2007
Authors: Zeng Guang , Ma Huilai , Wang Xiangbo , Yan Huifang , Wan Xinhua , Jiang Bin , Fontaine Robert E. , Wu Zhenglai , Lin Shaobin , Ruan Feng , Liu Huihui
Published: March 2011

Purpose

The production and administration of drugs used intrathecally requires special care to prevent contamination with neurotoxic agents. In 2007, we investigated a widespread outbreak of paraplegia and paraparesis among Chinese patients who received intrathecal drugs to identify the presumed contaminant and its source to prevent further cases.

Patients and Methods

We defined a case as onset from January 1 to October 31, 2007, of bilateral flaccid paraparesis or paraplegia or retention and incontinence of stool or urine, in a patient receiving intrathecal drugs. Using a retrospective cohort approach, we selected 12 hospitals from all hospitals that had reported cases. In these hospitals, we identified all 448 patients (including 107 cases) who received intrathecal chemotherapy or chemoprophylaxis in 2007. We calculated attack rates and Mantel-Haenszel adjusted risk ratios for intrathecal drug type and lot.

Results

All 12 hospitals used intrathecal methotrexate or cytarabine produced by one pharmaceutical plant. Only two lots of each drug were associated with cases. Lot-specific attack rates ranged from 42% to 100% (risk ratio, ∞; lower confidence bounds, 1.8 to 7.3). Vincristine production had immediately preceded production of the implicated lots on the same equipment. By using ultra performance liquid chromatography, we detected vincristine (0.28 to 18 μg) in unused vials from implicated lots of methotrexate and cytarabine.

Conclusion

Trace amounts of vincristine that contaminated intrathecal drugs caused a large outbreak of severe neurologic damage. Vincristine and other neurotoxic drugs should not be produced on any equipment that is also used for producing drugs that are to be administered intrathecally.
Digoxin Use and the Risk of Breast Cancer in Women
Authors: Biggar Robert J. , Wohlfahrt Jan , Oudin Anna , Hjuler Thomas , Melbye Mads
Published: March 2011

Purpose

Digoxin resembles estrogen chemically and may have estrogenic effect. We hypothesized that digoxin use might increase breast cancer incidence and examined if use might be associated with risk of breast cancer, categorized by estrogen receptor (ER) status. To determine if being under care for heart disease biased the findings, rate ratios in users of angina drugs were similarly evaluated as a control exposure group.

Patients and Methods

Women using digoxin and angina drugs were identified in the nationwide Danish Prescription Database, available between 1995 and 2008. Incident breast cancers were identified in the Danish Cancer Registry and further classifying by ER status. Relative risks (RR) were compared to nonusers using age- and period-adjusted incidence rate ratios.

Results

Two thousand one hundred forty-four of 104,648 women using digoxin developed breast cancer. Current digoxin users were at increased risk of breast cancer (RR, 1.39; 95% CI, 1.32 to 1.46), but risk was not increased in former users (RR, 0.91; 95% CI, 0.83 to 1.00). The increased risks in digoxin users were marginally higher for ER-positive breast cancers (RR, 1.35; 95% CI, 1.26 to 1.45) and ER unknown breast cancers (RR, 1.51; 95% CI, 1.38 to 1.64) than for ER-negative breast cancers (RR, 1.20; 95% CI, 1.03 to 1.40). Among 137,493 women exposed to angina drugs only (a comparison group with cardiovascular disease; n = 2,658 breast cancers), incidence was not increased in current or former users.

Conclusion

Women currently using digoxin had a significantly increased risk of breast cancer. Risk normalized when digoxin was stopped. No risk increases were observed in women using angina drugs only. The higher risk of developing ER-positive breast cancers supports an estrogen-mimicking mechanism.
Molecular Mapping of the Neural Pathways Linking Leptin to the Neuroendocrine Reproductive Axis
Authors: Louis Gwendolyn W. , Greenwald-Yarnell Megan , Phillips Rebecca , Coolen Lique M. , Lehman Michael N. , Myers Martin G.
Published: March 2011

Negative energy balance and insufficient adipose energy stores decrease the production of leptin, thereby diminishing the leptin-supported secretion of GnRH from the hypothalamus and promoting decreased reproductive function. Leptin acts via its receptor (LepRb) to support the neuroendocrine reproductive axis, but the nature and location of the relevant LepRb neurons remain poorly understood. Possibilities include the direct or indirect action of leptin on hypothalamic GnRH neurons, or on kisspeptin (Kiss1) neurons that are major regulators of GnRH neurons. To evaluate these potential mechanisms, we employed immunohistochemical analysis of the female brain from various molecular mouse models and sheep. Our analysis revealed no LepRb in GnRH neurons or in anteroventral periventricular Kiss1 neurons, and very limited (0–6%) colocalization with arcuate nucleus Kiss1 cells, suggesting that leptin does not modulate reproduction by direct action on any of these neural populations. LepRb neurons, primarily in the hypothalamic ventral premammillary nucleus and a subregion of the preoptic area, lie in close contact with GnRH neurons, however. Furthermore, an unidentified population or populations of LepRb neurons lie in close contact with arcuate nucleus and anteroventral periventricular Kiss1 neurons. Taken together, these findings suggest that leptin communicates with the neuroendocrine reproductive axis via multiple populations of LepRb neurons that lie afferent to both Kiss1 and GnRH neurons.
The poly(A) polymerase GLD2 is required for spermatogenesis in Drosophila melanogaster
Authors: Sartain Caroline V. , Cui Jun , Meisel Richard P. , Wolfner Mariana F.
Published: March 2011

The DNA of a developing sperm is normally inaccessible for transcription for part of spermatogenesis in many animals. In Drosophila melanogaster, many transcripts needed for late spermatid differentiation are synthesized in pre-meiotic spermatocytes, but are not translated until later stages. Thus, post-transcriptional control mechanisms are required to decouple transcription and translation during spermatogenesis. In the female germline, developing germ cells accomplish similar decoupling through poly(A) tail alterations to ensure that dormant transcripts are not prematurely translated: a transcript with a short poly(A) tail will remain untranslated, whereas elongating the poly(A) tail permits protein production. In Drosophila, the ovary-expressed cytoplasmic poly(A) polymerase WISPY is responsible for stage-specific poly(A) tail extension in the female germline. Here, we examine the possibility that a recently derived testis-expressed WISPY paralog, GLD2, plays a similar role in the Drosophila male germline. We show that knockdown of Gld2 transcripts causes male sterility, as GLD2-deficient males do not produce mature sperm. Spermatogenesis up to and including meiosis appears normal in the absence of GLD2, but post-meiotic spermatid development rapidly becomes abnormal. Nuclear bundling and F-actin assembly are defective in GLD2 knockdown testes and nuclei fail to undergo chromatin reorganization in elongated spermatids. GLD2 also affects the incorporation of protamines and the stability of dynamin and transition protein transcripts. Our results indicate that GLD2 is an important regulator of late spermatogenesis and is the first example of a Gld-2 family member that plays a significant role specifically in male gametogenesis.
Regulation of PCDH15 function in mechanosensory hair cells by alternative splicing of the cytoplasmic domain
Authors: Webb Stuart W. , Grillet Nicolas , Andrade Leonardo R. , Xiong Wei , Swarthout Lani , Della Santina Charley C. , Kachar Bechara , Müller Ulrich
Published: March 2011

Protocadherin 15 (PCDH15) is expressed in hair cells of the inner ear and in photoreceptors of the retina. Mutations in PCDH15 cause Usher Syndrome (deaf-blindness) and recessive deafness. In developing hair cells, PCDH15 localizes to extracellular linkages that connect the stereocilia and kinocilium into a bundle and regulate its morphogenesis. In mature hair cells, PCDH15 is a component of tip links, which gate mechanotransduction channels. PCDH15 is expressed in several isoforms differing in their cytoplasmic domains, suggesting that alternative splicing regulates PCDH15 function in hair cells. To test this model, we generated three mouse lines, each of which lacks one out of three prominent PCDH15 isoforms (CD1, CD2 and CD3). Surprisingly, mice lacking PCDH15-CD1 and PCDH15-CD3 form normal hair bundles and tip links and maintain hearing function. Tip links are also present in mice lacking PCDH15-CD2. However, PCDH15-CD2-deficient mice are deaf, lack kinociliary links and have abnormally polarized hair bundles. Planar cell polarity (PCP) proteins are distributed normally in the sensory epithelia of the mutants, suggesting that PCDH15-CD2 acts downstream of PCP components to control polarity. Despite the absence of kinociliary links, vestibular function is surprisingly intact in the PCDH15-CD2 mutants. Our findings reveal an essential role for PCDH15-CD2 in the formation of kinociliary links and hair bundle polarization, and show that several PCDH15 isoforms can function redundantly at tip links.
The triterpene glycosides of Holothuria forskali: usefulness and efficiency as a chemical defense mechanism against predatory fish
Authors: Van Dyck Séverine , Caulier Guillaume , Todesco Maïté , Gerbaux Pascal , Fournier Isabelle , Wisztorski Maxence , Flammang Patrick
Published: March 2011

More than 100 triterpene glycosides (saponins) have been characterized in holothuroids in the past several decades. In particular, Holothuria forskali contains 26 saponins in its Cuvierian tubules and 12 in its body wall. This high diversity could be linked to a chemical defense mechanism, the most commonly accepted biological role for these secondary metabolites. We performed an integrated study of the body-wall saponins of H. forskali. The saponins are mainly localized in the epidermis and in the mesothelium of the body wall and appear to be released when the holothuroid is stressed. Among the saponins present in the epidermis, one (holothurinoside G) was detected in the seawater surrounding non-stressed holothuroids and three others (holohurinosides C and F, and desholothurin A) were secreted when the animals were stressed. In addition, two new congeners (detected at m/z 1301 and 1317) were also present in the immediate surroundings of stressed holothuroids. These new saponins do not originate from the epidermis and could come from an internal organ. Quantities of secreted saponins were very low compared with the body wall and Cuvierian tubules concentrations. At natural concentrations, saponins do not represent a threat to the health of predatory fish. The deterrent effect of saponins seems therefore to act as an aposematic signal, warning potential predators of the unpalatability of the holothuroid tissues.
Effects of temperature on responses to anoxia and oxygen reperfusion in Drosophila melanogaster
Authors: Schilman Pablo E. , Waters James S. , Harrison Jon F. , Lighton John R. B.
Published: March 2011

Insects in general, and Drosophila in particular, are much more capable of surviving anoxia than vertebrates, and the mechanisms involved are of considerable biomedical and ecological interest. Temperature is likely to strongly affect both the rates of damage occurring in anoxia and the recovery processes in normoxia, but as yet there is no information on the effect of this crucial variable on recovery rates from anoxia in any animal. We studied the effects of temperature, and thus indirectly of metabolic flux rates, on survival and recovery times of individual male Drosophila melanogaster following anoxia and O2 reperfusion. Individual flies were reared at 25°C and exposed to an anoxic period of 7.5, 25, 42.5 or 60 min at 20, 25 or 30°C. Before, during and after anoxic exposure the flies' metabolic rates (MRs), rates of water loss and activity indices were recorded. Temperature strongly affected the MR of the flies, with a Q10 of 2.21. Temperature did not affect the slope of the relationship between time to recovery and duration of anoxic exposure, suggesting that thermal effects on damage and repair rates were similar. However, the intercept of that relationship was significantly lower (i.e. recovery was most rapid) at 25°C, which was the rearing temperature. When temperatures during exposure to anoxia and during recovery were switched, recovery times matched those predicted from a model in which the accumulation and clearance of metabolic end-products share a similar dependence on temperature.
Cortisol response to stress is associated with myocardial remodeling in salmonid fishes
Authors: Johansen Ida B. , Lunde Ida G. , Røsjø Helge , Christensen Geir , Nilsson Göran E. , Bakken Morten , Øverli Øyvind
Published: March 2011

Cardiac disease is frequently reported in farmed animals, and stress has been implicated as a factor for myocardial dysfunction in commercial fish rearing. Cortisol is a major stress hormone in teleosts, and this hormone has adverse effects on the myocardium. Strains of rainbow trout (Oncorhynchus mykiss) selected for divergent post-stress cortisol levels [high responsive (HR) and low responsive (LR)] have been established as a comparative model to examine how fish with contrasting stress-coping styles differ in their physiological and behavioral profiles. We show that the mean cardiosomatic index (CSI) of adult HR fish was 34% higher than in LR fish, mainly because of hypertrophy of the compact myocardium. To characterize the hypertrophy as physiological or pathological, we investigated specific cardiac markers at the transcriptional level. HR hearts had higher mRNA levels of cortisol receptors (MR, GR1 and GR2), increased RCAN1 levels [suggesting enhanced pro-hypertrophic nuclear factor of activated T-cell (NFAT) signaling] and increased VEGF gene expression (reflecting increased angiogenesis). Elevated collagen (Col1a2) expression and deposition in HR hearts supported enhanced fibrosis, whereas the heart failure markers ANP and BNP were not upregulated in HR hearts. To confirm our results outside the selection model, we investigated the effect of acute confinement stress in wild-type European brown trout, Salmo trutta. A positive correlation between post-stress cortisol levels and CSI was observed, supporting an association between enhanced cortisol response and myocardial remodeling. In conclusion, post-stress cortisol production correlates with myocardial remodeling, and coincides with several indicators of heart pathology, well-known from mammalian cardiology.
The Squam Lake Report: Commentary
Authors: Goodhart Charles A. E
Published: March 2011

The idea of the Squam Lake Report was to bring together some fifteen leading U.S. financial economists to see what regulatory changes they could jointly agree and thereby influence policy discussions. Seeking to find a consensus, however, meant that many issues were not mentioned in the Report, e.g., structural limitations, Pigovian taxes, procyclicality, and boundary problems between banks and nonbanks. But what is presented is generally, though not invariably, admirable, and the book is beautifully written in good, easily accessible English. (JEL E44, E52, G01, G21, G28, L51)
Genital shedding of HIV after scheduled treatment interruption
Authors: Ananworanich J , Kerr S J , Vernazza P , Mangclaviraj S , Chaithongwongwatthana S , Chotnopparatpattara P , Mahanontharit A , Ubolyam S , Jupimai T , Cooper D A , Ruxrungtham K , Hirschel B
Published: March 2011

This study assessed genital shedding of HIV in patients on intermittent combination antiretroviral therapy (cART) and assessed predictors of having detectable genital HIV RNA in 156 Thai patients with CD4 > 350 cells/μL and HIV RNA ≤50 copies/mL who were randomized to continuous therapy (CT, n = 65) or CD4-guided cART ( n = 91). There were 383 matched genital and plasma HIV RNA samples (CT: 158, CD4 guided: 225). In 14 samples collected within eight weeks of treatment interruption, detectable HIV RNA was present in 29% of genital samples and 71% of plasma samples. In 55 samples collected after eight weeks of treatment interruption, detectable HIV RNA was present in 60% of genital samples and 98% of plasma samples. In 110 samples collected up to 96 weeks after treatment re-initiation, detectable genital HIV RNA was found in 8% of samples and all of these were within the first 17 weeks. Independent predictors of detectable genital HIV RNA were increasing age and increasing concentrations of HIV RNA in plasma. These findings support the role of cART in maintaining undetectable HIV RNA in genital secretions.
Menopause and HIV infection: age at onset and associated factors, ANRS CO3 Aquitaine cohort
Authors: de Pommerol M , Hessamfar M , Lawson-Ayayi S , Neau D , Geffard S , Farbos S , Uwamaliya B , Vandenhende M-A , Pellegrin J-L , Blancpain S , Dabis F , Morlat P
Published: March 2011

The aim of the paper is to describe the characteristics of postmenopausal HIV-infected women and to investigate the factors associated with an earlier onset of menopause in a hospital-based cohort. Information was collected using a self-administered questionnaire. A Cox model was used to determine factors associated with menopause. Among the 404 women who completed the questionnaire, 69 were naturally postmenopausal at the time of the study (median age at onset: 49 years, premature menopause <40 years: 12%). The onset of menopause was studied among the 41 women still menstruating at the enrolment in the cohort, and who experienced menopause during follow-up. African origin (hazard ratio [HR] = 8.16; 95% confidence interval [CI] = 2.23–29.89) and history of injecting drug use (IDU) (HR = 2.46; 95% CI = 1.03–5.85) were associated with an increased risk of earlier menopause. Women with a CD4 cell count <200 cells/mm3 tended to reach menopause earlier (HR = 2.25; 95% CI = 0.94–5.39). Earlier occurrence of menopause seems to be associated with factors already reported in HIV-negative women (IDU, ethnicity) and with HIV-related immunodeficiency.
HIV infection, sexual risk behaviour and condom use in the Belize defense force
Authors: Anastario M , Manzanero R , Blanco R , Reyes E , Jaramillo R , Black L , Dann G E , Leonard E , Boryc K , Chun H
Published: March 2011

This study is the first Biological and Behavioral Surveillance Survey to be conducted among personnel in the Belize Defense Force. The purpose of the study was to understand the prevalence of HIV infection and risk behaviours, and to identify key correlates of sexual risk behaviours. A representative sample of personnel underwent serological testing and an Audio Computer-Assisted Self Interview. Of those sampled, 351 completed a blood test and 334 completed a behavioural interview. The prevalence of HIV was 1.14%. Twelve percent had ever reported being diagnosed with a sexually transmitted infection (STI) or screened positive for HIV infection. The odds of ever having an STI/HIV were higher among those who had less education, those who had sex with a commercial sex worker (CSW), those who ever engaged in receptive anal sex and those with post-traumatic stress disorder (PTSD). Alcohol abuse and PTSD were prevalent and associated with HIV risk behaviours. These results are being used to inform current prevention efforts.
An unusual cause of acute obstructive jaundice in an HIV-infected patient
Authors: Gupta N , Wright J G , Bowman C A
Published: March 2011

We describe the case of an HIV-1-infected patient presenting with acute obstructive jaundice as the initial manifestation of primary small bowel Burkitt's lymphoma. The biliary obstruction resolved rapidly following chemotherapy without the need for surgical intervention. The prognosis is favourable with appropriate timely treatment.
Burkitt's non-Hodgkins lymphoma presenting as facial nerve palsy in HIV-positive patients
Authors: Woodcock H , Nelson M
Published: March 2011

An isolated facial nerve palsy is rare as the presentation of a central nervous system lymphoma. In this case series, we present the clinical features of three HIV-positive patients presenting with facial nerve palsies due to HIV-associated Burkitt's lymphoma. These patients had a non-resolving facial paralysis, which occurred during a late stage of HIV. Magnetic resonance imaging (MRI) did not show leptomeningeal enhancement. Cerebrospinal fluid revealed a lymphocytosis with elevated protein and low glucose levels. The diagnosis of Burkitt's lymphoma was made on histology which showed the characteristic ‘starry sky’ appearance due to scattered tangible body-laden macrophages. The patients were commenced on the intensive chemotherapy regimen of CODOX-M/IVAC. Two patients died of disease progression and the third patient died of chemotherapy toxicity. This case series highlights the need for a high index of suspicion for underlying malignancy when a patient presents with a persistent facial paralysis in the later stages of HIV infection.
Short-term estrogen replacement therapy reduces platelet marker levels in Malaysian postmenopausal women
Authors: Sheikh Shabbir Ahmad , Roshan Tariq Mahmood , Khattak Muhammad Naeem , Baig Atif Amin , Noor Shahreza Johan , Hassan Rosline , Zaki Nik Mohamed
Published: March 2011

Objectives

In healthy postmenopausal women (PMW) increased platelet activation has been associated with adverse cardiovascular events. There is much debate about the relationship between platelet function and serum estradiol level in PMW. This study assessed the effect of short-term oral estrogen replacement therapy (ERT) on platelet activation markers (CD62P and PAC-1) and its correlation with age and body mass index (BMI) among healthy PMW.

Methods

A prospective intervention study was conducted at Hospital University Sains Malaysia, involving 48 healthy PMW who were evaluated for platelet activation marker levels as determined by flow cytometry, before and after two weeks of oral ERT with 0.625 mg of conjugated equine estrogen once daily. The pre- and post-ERT platelets activation markers difference was analysed by paired t-test.

Results

The pre-ERT, mean ± SD percentage levels of CD62P and PAC-1 were significantly reduced from 7.00 ± 5.91 and 41.75 ± 26.85 to 3.05 ± 2.47 and 20.86 ± 19.02, respectively, after two weeks of ERT ( P value < 0.001). The correlation of platelet activation markers was significant with estradiol but not with age and BMI.

Conclusion

Short-term ERT leads to reduction in platelet activity, which might contribute to protection against cardiovascular diseases in healthy PMW.
Insulin resistance and management of the menopause: a clinical hypothesis in practice
Authors: Whitcroft Sovra , Herriot Anne
Published: March 2011

Insulin resistance (IR) is associated with a number of metabolic abnormalities including glucose intolerance, dyslipidemia and central obesity (the metabolic syndrome), which predispose to cardiovascular disease, diabetes mellitus and some cancers. The incidence of many of these conditions increases after the menopause, a time when IR also increases. Medical intervention to help alleviate menopausal symptoms, frequently vasomotor in origin, usually involves hormone replacement therapy (HRT), but some women may only experience partial symptom relief. We have hypothesized that this may be due to concurrent IR. Our approach is therefore to manage menopausal symptoms in conjunction with the treatment of any concurrent IR, achieved through a combination of hormone replacement, dietary intervention and, if necessary, an insulin sensitizer. We suggest that this approach may not only improve symptom relief but may also reduce the risk of developing more serious health complaints in the future.
Vitamin K, osteoporosis and degenerative diseases of ageing
Authors: Vermeer Cees , Theuwissen Elke
Published: March 2011

The function of vitamin K is to serve as a co-factor during the post-translational carboxylation of glutamate (Glu) residues into γ-carboxyglutamate (Gla) residues. The vital importance of the Gla-proteins essential for normal haemostasis is well recognized. During recent years, new Gla-containing proteins have been discovered and the vitamin K-dependent carboxylation is also essential for their function. It seems, however, that our dietary vitamin K intake is too low to support the carboxylation of at least some of these Gla-proteins. According to the triage theory, long-term vitamin K inadequacy is an independent, but modifiable risk factor for the development of degenerative diseases of ageing including osteoporosis and atherosclerosis.
Pregnancy with Gitelman's syndrome
Authors: Raffi F , Fairlie F M , Madhuvrata P , Bennet W M
Published: March 2011

Gitelman's syndrome is a rare genetic disease associated with chronic hypokalaemia, hypomagnesaemia and hypocalciuria. It requires lifelong supplementation with potassium and magnesium. Pregnancy management can be difficult and there are few published reports. Our case adds to the literature and illustrates some of the potential problems.
Appendicitis in pregnancy mimicking haemolysis, elevated liver enzymes and low platelets syndrome
Authors: Sikka Pooja , Aggarwal Neelam , Chopra Seema , Suri Vanita
Published: March 2011

We report a patient with pregnancy at term in whom appendicitis mimicked haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome. A high index of suspicion of appendicitis should be kept in patients with abdominal pain and biochemical evidence of HELLP.
The impact of positive acquired thrombophilia serology on ultrasound, obstetric outcome and the placenta in a low-risk primigravid population
Authors: Cooley Sharon M , Donnelly Jennifer C , Walsh Thomas , Collins Claire , McMahon Corrina , Gillan John , Geary Michael P
Published: March 2011

Our aim was to determine the prevalence and sequelae of positive acquired thrombophilia serology in the asymptomatic low-risk primigravid population. We undertook a prospective blinded study of 1011 primigravid patients screening for lupus anticoagulant, anticardiolipin antibody, anti- β2 glycoprotein-1 and antinuclear antibody assessment at booking and 36 weeks gestation. Serial ultrasounds of the fetus with uterine and umbilical Dopplers and placental evaluation were performed at 24 and 36 weeks gestation. Antenatal course, labour and delivery outcome and placental histology were reviewed. The incidence of positive acquired thrombophilia serology was 27.4%. Overall, there was no difference in rates of fetal loss or maternal disease between women with positive acquired thrombophilia serology and the control population. Routine testing for acquired thrombophilic traits is therefore not warranted.
Use of imaging for investigation of suspected pulmonary embolism during pregnancy and the postpartum period
Authors: Scott Katherine , Rutherford Natalie , Fagermo Narelle , Lust Karin
Published: March 2011

Pulmonary embolism (PE) is recognized as a leading cause of maternal mortality in the developed world; however, it is a very difficult diagnosis to make on clinical grounds, and in most cases imaging is required. Pregnancy is a recognized risk factor for venous thromboembolism, and symptoms of normal pregnancy including shortness of breath, tachycardia and leg swelling are included in clinical tools for risk stratification for PE in the non-pregnant population. This results in a very low threshold for imaging, despite concerns regarding the risk of exposure to ionizing radiation both for the fetus and the maternal breast. We reviewed the results of all ventilation/perfusion scans and computed tomography pulmonary angiograms performed in pregnant women at a single institution to identify how many of these tests were positive for PE, and which clinical features may identify a low-risk group. A total of 386 scans were performed to investigate 375 episodes of suspected PE, representing 1.3–1.5% of pregnant women. Fifteen patients were diagnosed with PE, giving an incidence of one in 2000 maternities. The only statistically significant factors associated with PE were smoking or the presence of multiple risk factors. Clinical features of tachycardia and leg swelling did not provide significant diagnostic value; however, the absence of pleuritic chest pain had a negative predictive value of 97.8%. Arterial blood gas and D-dimer were statistically different between those with and without PE but not to a clinically useful degree. Currently available clinical and laboratory tools are not adequate to exclude a diagnosis of PE in a pregnant patient, thus imaging is justified to exclude PE. Further longitudinal studies to identify a low-risk group who do not require imaging is vital.
The effect of warfarin dosage on maternal and fetal outcomes in pregnant women with prosthetic heart valves
Authors: Soma-Pillay P , Nene Z , Mathivha T M , Macdonald A P
Published: March 2011

There are several challenges in the management of pregnant women with mechanical heart valves. Pregnancy increases the risk of thromboembolism and there is currently no consensus on the safest anticoagulation method during pregnancy. The objective of the study was to determine the correlation between the warfarin dose and pregnancy outcome in pregnant women with prosthetic heart valves. Warfarin in pregnancy was associated with a low risk of valve thrombosis or maternal death. The risk for fetal abnormalities was not related to the maternal warfarin dosage. However, the risk for stillbirth was significantly increased with increasing doses of warfarin.
Generic Optimality Conditions for Semialgebraic Convex Programs
Authors: Bolte Jérôme , Daniilidis Aris , Lewis Adrian S.
Published: March 2011

We consider linear optimization over a nonempty convex semialgebraic feasible region F. Semidefinite programming is an example. If F is compact, then for almost every linear objective there is a unique optimal solution, lying on a unique “active” manifold, around which F is “partly smooth,” and the second-order sufficient conditions hold. Perturbing the objective results in smooth variation of the optimal solution. The active manifold consists, locally, of these perturbed optimal solutions; it is independent of the representation of F and is eventually identified by a variety of iterative algorithms such as proximal and projected gradient schemes. These results extend to unbounded sets F.
Inhibition of AP-1 suppresses cervical cancer cell proliferation and is associated with p21 expression
Authors: Maritz Michelle F. , van der Watt Pauline J. , Holderness Nina , Birrer Michael J. , Leaner Virna D.
Published: March 2011

AP-1, a transcription factor comprised primarily of Jun and Fos family proteins, regulates genes involved in proliferation, differentiation and oncogenesis. Previous studies demonstrated that elevated expression of Jun and Fos family member proteins is associated with numerous human cancers and in cancer-relevant biological processes. In this study we used a dominant-negative mutant of c-Jun, Tam67, which interferes with the functional activity of all AP-1 complexes, to investigate the requirement of AP-1 in the proliferation and cell cycle progression of cervical cancer cells. Transient and stable expression of Tam67 in CaSki cervical cancer cells resulted in decreased AP-1 activity that correlated with a significant inhibition of cell proliferation and anchorage-independent colony formation. Inhibiting AP-1 activity resulted in a two-fold increase in cells located in the G2/M phase of the cell cycle and an accompanying increase in the expression of the cell cycle regulatory protein, p21. The increase in p21 was associated with a decrease in HPV E6 expression and an increase in p53. Importantly, blocking the induction of p21 in CaSki-Tam67-expressing cells accelerated their proliferation rate to that of CaSki, implicating p21 as a key player in the growth arrest induced by Tam67. Our results suggest a role for AP-1 in the proliferation, G2/M progression and inhibition of p21 expression in cervical cancer.
Recent insights into regulation of transcription by RNA polymerase III and the cellular functions of its transcripts
Authors: Nikitina Tatyana V. , Tischenko Lyudmila I. , Schulz Wolfgang A.
Published: March 2011

The products of transcription by the multisubunit enzyme RNA polymerase III (Pol III), such as 5S rRNA, tRNAs, U6 snRNA, are important for cell growth, proliferation and differentiation. The known range of the Pol III transcriptome has expanded over recent years, and novel functions of the newly discovered and already well known transcripts have been identified, including regulation of stress responses and apoptosis. Furthermore, transcription by Pol III has turned out to be strongly regulated, differing between diverse class III genes, among cell types and under stress conditions. The mechanisms involved in regulation of Pol III transcription are being elucidated and disturbances in that regulation have been implicated in various diseases, including cancer. This review summarizes the novel data on the regulation of RNA polymerase III transcription, including epigenetic and gene specific mechanisms and outlines recent insights into the cellular functions of the Pol III transcriptome, in particular of SINE RNAs.
Grafted Neural Progenitors Integrate and Restore Synaptic Connectivity across the Injured Spinal Cord
Authors: Bonner Joseph F. , Connors Theresa M. , Silverman William F. , Kowalski David P. , Lemay Michel A. , Fischer Itzhak
Published: March 2011

Transplantation of neural progenitor cells (NPC) is a promising therapeutic strategy for replacing neurons lost after spinal cord injury, but significant challenges remain regarding neuronal integration and functional connectivity. Here we tested the ability of graft-derived neurons to reestablish connectivity by forming neuronal relays between injured dorsal column (DC) sensory axons and the denervated dorsal column nuclei (DCN). A mixed population of neuronal and glial restricted precursors (NRP/GRP) derived from the embryonic spinal cord of alkaline phosphatase (AP) transgenic rats were grafted acutely into a DC lesion at C1. One week later, BDNF-expressing lentivirus was injected into the DCN to guide graft axons to the intended target. Six weeks later, we observed anterogradely traced sensory axons regenerating into the graft and robust growth of graft-derived AP-positive axons along the neurotrophin gradient into the DCN. Immunoelectron microscopy revealed excitatory synaptic connections between regenerating host axons and graft-derived neurons at C1 as well as between graft axons and DCN neurons in the brainstem. Functional analysis by stimulus-evoked c-Fos expression and electrophysiological recording showed that host axons formed active synapses with graft neurons at the injury site with the signal propagating by graft axons to the DCN. We observed reproducible electrophysiological activity at the DCN with a temporal delay predicted by our relay model. These findings provide the first evidence for the ability of NPC to form a neuronal relay by extending active axons across the injured spinal cord to the intended target establishing a critical step for neural repair with stem cells.
Rules of the Road: The Traveling Films of Hiroshi Shimizu
Authors: Cook Ryan
Published: March 2011

A review of four films made on location by Hiroshi Shimizu from 1933–41 which considers the director's fondness for the road and his stylistic openness in relation to his use of formal motifs evoking travel.
The Dislike Button
Authors: Tyree J. M.
Published: March 2011

A study of David Fincher's film about the founding of Facebook, The Social Network, in terms of its continuity with the director's previous work; its depiction of U.S. institutions; and its complex, disturbing account of the cultural consequences of the Internet.