Instruments to assess appropriateness of hip and knee arthroplasty: a systematic review.

OBJECTIVE: To assess criteria and psychometric properties of instruments for assessing appropriateness of elective joint arthroplasty (JA) for adults with primary hip and knee osteoarthritis (OA). METHODS: A systematic review guided by Cochrane methods and PRISMA guidelines. Studies were searched in five databases. Eligible articles include all study designs developing, testing, and/or using an instrument to assess JA appropriateness. Two independent reviewers screened and extracted data. Instruments were compared with Hawker et al. JA consensus criteria. Psychometric properties of instruments were described and appraised guided by Fitzpatrick's and COSMIN approaches. RESULTS: Of 55 instruments included, none met all Hawker et al. JA consensus criteria. Criteria the most met were pain (n = 50), function (n = 49), quality of life (n = 33), and radiography (n = 24). Criteria the least met were clinical evidence of OA (n = 18), expectations (n = 15), readiness for surgery (n = 11), conservative treatments (n = 8), and patient/surgeon agree benefits outweigh risks (n = 0). Instrument by Arden et al. met the most criteria (6 of 9). The most tested psychometric properties were appropriateness (n = 55), face/content validity (n = 55), predictive validity (n = 29), construct validity and feasibility (n = 24). The least tested psychometric properties were intra-rater reliability (n = 3), internal consistency (n = 5), and inter-rater reliability (n = 13). Instruments by Gutacker et al. and Osborne et al. met the most psychometric properties (4 of 10). CONCLUSION: Most instruments included traditional criteria for assessing JA appropriateness but did not include a trial of conservative treatments or shared decision-making elements. There was limited evidence on psychometric properties.

Effectiveness of patient decision aids for total hip and knee arthroplasty decision-making: a systematic review.

OBJECTIVES: To determine the effectiveness of patient decision aids (PtDAs) compared to alternative interventions (including usual care) on decision quality and quality of the decision-making process for adults with hip and knee osteoarthritis considering primary elective total joint arthroplasty. METHODS: A systematic review guided by Cochrane methods and PRISMA reporting guidelines. Studies were searched in five databases. Included studies were RCTs evaluating the effect of PtDAs on total joint arthroplasty decision-making. Study quality was appraised with Cochrane's risk of bias tool. Quality and strength of recommendations were appraised with GRADE. RESULTS: Ten included studies were conducted in North American using the same PtDA. Compared to usual care, PtDA groups demonstrated increased decision quality (e.g., higher knowledge, more informed values-based choices) and quality of the decision making process (e.g., decreased decisional conflict) (6 trials). Secondary outcomes showed increased surgeon satisfaction within the consultation and no difference in patient satisfaction or uptake of the chosen option (surgery: RR 1.03, 95% CI = 0.84 to 1.25; I2 = 66%; 4 trials). When PtDAs formtats were compared, there were similar effects but no difference between PtDAs (4 trials). CONCLUSIONS: There was low to very low GRADE certainty of evidence for the effect of PtDAs on decision quality and quality of the decision-making process compared to usual care. No differences were found when different formats of PtDAs were compared (moderate to very low GRADE certainty of evidence).

Nutrient-rich submarine groundwater discharge fuels the largest green tide in the world.

One of the largest "green tide" (Ulva prolifera) outbreaks in the world has occurred every year from 2007 to present in the Southern Yellow Sea, China. Currently, the coastal area around Jiangsu Province (Subei Shoal region) is thought to be the origination point of these giant green tide blooms. The combination of high nutrient demand but low river discharge and other inputs suggests that there is a significant flux of submarine groundwater discharge (SGD) in this area. By using a radium mass balance model, we estimated the SGD flux in the area to be (0.7-1.4) × 109 m3 d-1 (6.1-12 cm d-1), at the high end of SGD fluxes worldwide. Geographically, Subei Shoal is less than 5% of the entire Southern Yellow Sea area, while our calculated SGD flux just for the shoal area is ~3 times larger than previously documented for the whole Southern Yellow Sea. Therefore, Subei Shoal may be considered a SGD hotspot that plays an important role in SGD associated material fluxes. Compared to inputs from local rivers, atmospheric deposition, and anthropogenic activities, SGD-derived nutrients are the main source term that can support the growth of macroalgae. We specifically highlight that this type of areas that are shallow, intensively mixed, anthropogenically polluted, sandy or muddy with heavy bio-irrigation, may have a higher risk of suffering harmful ecological problems, even with limited terrestrial runoff.

Risk of relapse after anti-PD1 discontinuation in patients with Hodgkin lymphoma.

INTRODUCTION: Patients with relapsed/refractory Hodgkin lymphoma (R/R HL) experience high response rates upon anti-PD1 therapy. In these patients, the optimal duration of treatment and the risk of relapse after anti-PD1 discontinuation are unknown. METHODS: We retrospectively analyzed patients with R/R HL who responded to anti-PD1 monotherapy and discontinued the treatment either because of unacceptable toxicity or prolonged remission. A machine learning algorithm based on 17 candidate variables was trained and validated to predict progression-free survival (PFS) landmarked at the time of discontinuation of anti-PD1 therapy. RESULTS: Forty patients from 14 centers were randomly assigned to training (n = 25) and validation (n = 15) sets. At the time of anti-PD1 discontinuation, patients had received treatment for a median duration of 11.2 (range, 0-time to best response was not statistically significant in discriminating patients with PFS lesser or greater than 12 months). Considering PFS status as a binary variable (alive or dead) at a specific time point (12 months) is convenient, intuitive and allows for comparing the value of potential predicting variables in these two groups of patients. Nonetheless, this approach has two drawbacks: first, it binarizes outcome; second, it excludes patients alive with a time to last follow up lesser 12 months. Therefore, it is less powerful to demonstrate statistically significant association with PFS even if it exists 5 months. Patients discontinued anti-PD1 treatment either because of prolonged remission (N = 27, 67.5%) or unacceptable toxicity (N = 13, 32.5%). Most patients were in CR (N = 35, 87.5%) at the time of anti-PD1 discontinuation. In the training set, the machine learning algorithm identified that the most important variables to predict PFS were patients' age, time to best response, and presence or absence of CR. The performance observed in the training set was validated in the validation set. CONCLUSION: In this pilot, proof of concept study using a machine learning algorithm, we identified biomarkers capable of predicting the risk of relapse after anti-PD1 discontinuation (age, time to best response, quality of response). Once confirmed, these simple biomarkers will represent useful tools to guide the management of these patients.

Current and historical rates of input of mercury to the Penobscot River, Maine, from a chlor-alkali plant.

Mercury inputs by surface and ground water sources to Penobscot River from a defunct Hg-cell chlor-alkali plant were measured in 2009-10 and estimated for the entire period of operation of this facility. Over the measured interval (422 days) approximately 2.3 kg (5.4 g day-1) of mercury was discharged to the Penobscot River by the two surface streams that drain the site, with most of the combined loading (1.8 kg Hg, 78%) associated with a single storm with rainfall in excess of 100 mm. Groundwater seepage rates from the site, as estimated from both a radon tracer and seepage meter methods were in the range of 3 to 4 cm day-1 and, when combined with a best estimate of the area of groundwater discharge (11,000 m2) and average seepage/porewater mercury concentration (242 ng L-1, UCL95), yielded a loading of 0.11 g day-1 for site groundwater. None of the municipal or other industrial point sources of mercury to the river between Veazie and Bucksport, Maine exceeded 1 g day-1 individually, nor was the aggregate loading of all such sources >3 g day-1 (based on State of Maine data). Mercury loadings for the three largest tributaries downstream of Veazie Dam were estimated to contribute 4.2, 3.7 and 2.5 g day-1, respectively, to the Penobscot River. Based on sampling (total Hg ~ 2 to 4 ng L-1) and historical mean discharge data (340-460 m3 s-1), the Penobscot River upstream of the plant site contributes as much as 160 g day-1 to the downstream reach depending on river discharge. Estimates of historical (1967-2012) mercury loading using both generic emission factors and measured releases ranged from 2.6 to 27 MT while the mass of mercury found in downstream sediments amounted to 9 MT.

Isotopic, geophysical and biogeochemical investigation of submarine groundwater discharge: IAEA-UNESCO intercomparison exercise at Mauritius Island.

Submarine groundwater discharge (SGD) into a shallow lagoon on the west coast of Mauritius Island (Flic-en-Flac) was investigated using radioactive ((3)H, (222)Rn, (223)Ra, (224)Ra, (226)Ra, (228)Ra) and stable ((2)H, (18)O) isotopes and nutrients. SGD intercomparison exercises were carried out to validate the various approaches used to measure SGD including radium and radon measurements, seepage rate measurements using manual and automated meters, sediment bulk conductivity and salinity surveys. SGD measurements using benthic chambers placed on the floor of the Flic-en-Flac Lagoon showed discharge rates up to 500 cm/day. Large variability in SGD was observed over distances of a few meters, which were attributed to different geomorphological features. Deployments of automated seepage meters captured the spatial and temporal variability of SGD with a mean seepage rate of 10 cm/day. The stable isotopic composition of submarine waters was characterized by significant variability and heavy isotope enrichment and was used to predict the contribution of fresh terrestrially derived groundwater to SGD (range from a few % to almost 100%). The integrated SGD flux, estimated from seepage meters placed parallel to the shoreline, was 35 m(3)/m day, which was in reasonable agreement with results obtained from a hydrologic water balance calculation (26 m(3)/m day). SGD calculated from the radon inventory method using in situ radon measurements were between 5 and 56 m(3)/m per day. Low concentrations of radium isotopes observed in the lagoon water reflected the low abundance of U and Th in the basalt that makes up the island. High SGD rates contribute to high nutrients loading to the lagoon, potentially leading to eutrophication. Each of the applied methods yielded unique information about the character and magnitude of SGD. The results of the intercomparison studies have resulted a better understanding of groundwater-seawater interactions in coastal regions. Such information is an important pre-requisite for the protection and management of coastal freshwater resources.

Isotope tracing of submarine groundwater discharge offshore Ubatuba, Brazil: results of the IAEA-UNESCO SGD project.

Results of groundwater and seawater analyses for radioactive (3H, 222Rn, 223Ra, 224Ra, 226Ra, and 228Ra) and stable (D and 18O) isotopes are presented together with in situ spatial mapping and time series 222Rn measurements in seawater, direct seepage measurements using manual and automated seepage meters, pore water investigations using different tracers and piezometric techniques, and geoelectric surveys probing the coast. This study represents first time that such a new complex arsenal of radioactive and non-radioactive tracer techniques and geophysical methods have been used for simultaneous submarine groundwater discharge (SGD) investigations. Large fluctuations of SGD fluxes were observed at sites situated only a few meters apart (from 0 cm d(-1) to 360 cm d(-1); the unit represents cm3/cm2/day), as well as during a few hours (from 0 cm d(-1) to 110 cm d(-1)), strongly depending on the tidal fluctuations. The average SGD flux estimated from continuous 222Rn measurements is 17+/-10 cm d(-1). Integrated coastal SGD flux estimated for the Ubatuba coast using radium isotopes is about 7x10(3) m3 d(-1) per km of the coast. The isotopic composition (deltaD and delta18O) of submarine waters was characterised by significant variability and heavy isotope enrichment, indicating that the contribution of groundwater in submarine waters varied from a small percentage to 20%. However, this contribution with increasing offshore distance became negligible. Automated seepage meters and time series measurements of 222Rn activity concentration showed a negative correlation between the SGD rates and tidal stage. This is likely caused by sea level changes as tidal effects induce variations of hydraulic gradients. The geoelectric probing and piezometric measurements contributed to better understanding of the spatial distribution of different water masses present along the coast. The radium isotope data showed scattered distributions with offshore distance, which imply that seawater in a complex coast with many small bays and islands was influenced by local currents and groundwater/seawater mixing. This has also been confirmed by a relatively short residence time of 1-2 weeks for water within 25 km offshore, as obtained by short-lived radium isotopes. The irregular distribution of SGD seen at Ubatuba is a characteristic of fractured rock aquifers, fed by coastal groundwater and recirculated seawater with small admixtures of groundwater, which is of potential environmental concern and has implications on the management of freshwater resources in the region.

Biochemotherapy for the treatment of metastatic malignant melanoma: a clinical practice guideline.

QUESTIONS: What is the role of biochemotherapy in the treatment of metastatic malignant melanoma?What are the adverse effects and effects on quality of life of biochemotherapy as a treatment option?For the purposes of this report, "biochemotherapy" is defined as a therapeutic regimen that includes, at a minimum, chemotherapy (either single-agent or combination) and interleukin-2. PERSPECTIVES: Although early detection, appropriate surgery, and in some cases adjuvant therapy have improved outcomes, at least one third of patients with early-stage melanoma will develop metastases. Recently, in an effort to potentially maximize outcomes, the combination of chemotherapy and immunotherapy (biochemotherapy) was evaluated. The level of interest that this approach has generated, particularly with regard to the apparently high response rates seen in this otherwise devastating illness, was sufficient to merit closer examination by the Melanoma Disease Site Group (dsg) of Cancer Care Ontario's Program in Evidence-based Care (pebc). OUTCOMES: Outcomes of interest include response rate, diseasefree survival, overall survival, quality of life, and incidence of grades 3 and 4 toxicities. METHODOLOGY: Evidence was selected and reviewed by three members of the pebc's Melanoma dsg and by two methodologists. The present practice guideline report was reviewed and approved by the Melanoma dsg, which comprises medical and radiation oncologists, surgeons, and dermatologists. External review by Ontario practitioners was obtained through a mailed survey, the results of which were incorporated into the practice guideline. Final approval of the original guideline report was obtained from the pebc's Report Approval Panel. RESULTS: Clinical recommendations were drafted based on the evidence identified through a systematic review. The practice guideline report with draft recommendations was mailed to Ontario practitioners for external review and to the Report Approval Panel. Feedback from both groups was incorporated into this report to create the final practice guideline. PRACTICE GUIDELINE: The recommendations that follow apply to adult patients with metastatic malignant melanoma. Because of the inconsistent results of the available studies with regard to benefit (response, time to progression, and survival) and consistently high toxicity rates, biochemotherapy is not recommended for the treatment of metastatic melanoma.

Single-agent interleukin-2 in the treatment of metastatic melanoma.

QUESTIONS: What is the role of single-agent interleukin-2 (il-2) in the treatment of adults with metastatic melanoma? If there is a role for single-agent il-2, what patient population can appropriately be considered for treatment? If there is a role for single-agent il-2, what dose and schedule are appropriate? What are the toxicities associated with il-2? PERSPECTIVES: Many agents have been investigated for antitumour activity in melanoma, but few have shown promising response rates. Early detection, appropriate surgery, and adjuvant therapy have all improved outcomes, but approximately one third of patients with early-stage disease will nevertheless develop metastases. Single-agent il-2 has attracted much attention over the past several years. A number of randomized trials and many phase ii trials investigating single-agent il-2 suggest that this systemic treatment produces durable responses in melanoma patients. Given the dismal survival of patients with meta-static melanoma and the limited availability of effective treatments, the Melanoma Disease Site Group (dsg) of Cancer Care Ontario's Program in Evidence-Based Care (pebc) felt that the durable responses seen with il-2 treatment warranted closer examination. OUTCOMES: Primary outcomes of interest included objective response rate, complete response rate, duration of response, toxicity, and quality of life. Secondary outcomes of interest included progression-free survival and overall survival. METHODOLOGY: A systematic review was developed, and clinical recommendations relevant to patients in Ontario were drafted. The practice guideline report was reviewed and approved by the Melanoma dsg, which comprises medical oncologists, surgeons, and dermatologists. External review by Ontario practitioners was obtained through a mailed survey, the results of which were incorporated into the practice guideline. Final review and approval of the practice guideline was obtained from the pebc's Report Approval Panel. RESULTS: The present practice guideline reflects the integration of the draft recommendations based on a systematic review of the available evidence with the feedback obtained from external review by practitioners and the Report Approval Panel. PRACTICE GUIDELINE: No studies have compared il-2 to the current standard of care-dacarbazine (dtic)-or to placebo in the treatment of metastatic melanoma. After reviewing and weighing the evidence that does exist, the opinion of the Melanoma dsg is that high-dose il-2 is a reasonable treatment option for a select group of patients with metastatic melanoma: Patients should have a good performance status (Eastern Cooperative Oncology Group 0-1) and a normal lactate dehydrogenase level.Patients should have fewer than three organs involved or have cutaneous and/or subcutaneous metastases only, and no evidence of central nervous system metastases should be present.In this select group of patients, il-2 treatment can produce durable complete remissions. High-dose il-2 is recommended to be given at 600,000 IU/kg per dose, delivered intravenously over 15 minutes, every 8 hours, for a maximum of 14 doses. High-dose il-2 delivery is recommended to be done in a tertiary-care facility by staff trained in the provision of this treatment and with appropriate monitoring. To facilitate treatment and to develop expertise in this therapeutic modality, the dsg recommends that high-dose il-2 programs be established in one or two centres in Ontario. QUALIFYING STATEMENTS: High-dose il-2 has response rates that are similar to those seen with standard chemotherapy. However, unlike chemotherapy, il-2 demonstrates low but durable complete response rates that may lead to years of benefit for patients with metastatic melanoma. Based on the available data assessing prognostic factors and patient selection, patients with non-visceral metastases and fewer metastatic sites have a much higher response rate. In these select patients, high dose il-2 may be considered for first-line therapy. The lack of large randomized trials comparing il-2 to dtic or other chemotherapy means that recommendations for this guideline are based largely on phase ii data and limited phase iii data. Further randomized data will not soon become available, because no randomized trials are currently ongoing or planned. Interleukin-2 is currently widely used in the United States, and it is an approved therapy in both Canada and the United States.

Temozolomide for the treatment of metastatic melanoma.

QUESTIONS: What is the role of single-agent temozolomide in the treatment of patients with metastatic melanoma? In comparison with single-agent temozolomide, does the addition of interferon-alpha to temozolomide improve disease-free survival, overall survival, or response rates? In comparison with single-agent temozolomide, does the addition of thalidomide to temozolomide improve disease-free survival, overall survival, or response rates? PERSPECTIVES: Because of its oral route of administration and its ability to cross the blood-brain barrier, temozolomide is a potentially attractive chemotherapy agent for adult patients with unresectable metastatic malignant melanoma. To provide treatment recommendations for this new agent, the Melanoma Disease Site Group (dsg) of Cancer Care Ontario's Program in Evidence-Based Care (pebc) decided to review the available literature on single-agent temozolomide and on temozolomide in combination with interferon-alpha or thalidomide. OUTCOMES: Outcomes of interest included response rates, disease-free survival, overall survival, quality of life, and adverse effects. METHODOLOGY: Evidence was selected and reviewed by two members of the Melanoma dsg and by methodologists. The present practice guideline report was reviewed and approved by the Melanoma dsg, which comprises medical and radiation oncologists, surgeons, and dermatologists. External review was obtained through a mailed survey of Ontario practitioners, the results of which were reflected in revisions to the practice guideline. Final approval of the guideline report was obtained from the Report Approval Panel of the pbec. PRACTICE GUIDELINE: These recommendations apply to adult patients with unresectable metastatic malignant melanoma. It is reasonable to use temozolomide at a dose of 200 mg/m(2) orally for 5 days every 4 weeks as initial systemic treatment for patients with unresectable metastatic malignant melanoma. The addition of moderate-dose interferon-alpha 2b has produced a significantly higher response rate than has single-agent temozolomide in a large randomized phase iii study. However, overall survival was not altered, and grades 3 and 4 hematologic toxicities were higher with the combined treatment. At the present time, the addition of interferon-alpha to temozolomide is not recommended. One randomized phase ii study and six other phase ii studies showed encouraging response rates when thalidomide was combined with temozolomide. However, the doses and schedules of temozolomide in those studies differed from the conventionally prescribed doses and schedules. It is not clear whether the improved response rates were attributable to the small number of patients in the studies, the different temozolomide doses and schedules, or the addition of thalidomide. Further phase iii studies are required to confirm whether a benefit is associated with the combination of temozolomide and thalidomide. Therefore, at this time, it is not recommended that thalidomide be combined with temozolomide. QUALIFYING STATEMENTS: Dacarbazine is the only chemotherapy drug currently approved for the treatment of metastatic malignant melanoma. In large randomized trials, response rates with dacarbazine ranged from 6% to 15%. Almost all responses were partial, with a median response duration of only 7-8 months. Given these disappointing overall results, the consensus among most physicians who are treating patients with metastatic malignant melanoma is that recommending more convenient treatment or experimental treatment to these patients is appropriate. Because of oral dosing, temozolomide is a reasonable choice, particularly for patients who would have difficulty traveling to cancer centres for intravenous chemotherapy. Temozolomide has demonstrated efficacy equal to that of dacarbazine in a randomized phase iii trial. However, unlike dacarbazine, temozolomide is a convenient oral treatment that penetrates the blood-brain barrier and that has shown activity against brain metastases. Although surgery is the preferred treatment modality for patients with solitary brain metastases from melanoma, temozolomide is the preferred chemotherapy for patients with brain metastases who require systemic treatment.

Quantifying submarine groundwater discharge in the coastal zone via multiple methods.

Submarine groundwater discharge (SGD) is now recognized as an important pathway between land and sea. As such, this flow may contribute to the biogeochemical and other marine budgets of near-shore waters. These discharges typically display significant spatial and temporal variability making assessments difficult. Groundwater seepage is patchy, diffuse, temporally variable, and may involve multiple aquifers. Thus, the measurement of its magnitude and associated chemical fluxes is a challenging enterprise. A joint project of UNESCO and the International Atomic Energy Agency (IAEA) has examined several methods of SGD assessment and carried out a series of five intercomparison experiments in different hydrogeologic environments (coastal plain, karst, glacial till, fractured crystalline rock, and volcanic terrains). This report reviews the scientific and management significance of SGD, measurement approaches, and the results of the intercomparison experiments. We conclude that while the process is essentially ubiquitous in coastal areas, the assessment of its magnitude at any one location is subject to enough variability that measurements should be made by a variety of techniques and over large enough spatial and temporal scales to capture the majority of these changing conditions. We feel that all the measurement techniques described here are valid although they each have their own advantages and disadvantages. It is recommended that multiple approaches be applied whenever possible. In addition, a continuing effort is required in order to capture long-period tidal fluctuations, storm effects, and seasonal variations.

Doxorubicin-based chemotherapy for the palliative treatment of adult patients with locally advanced or metastatic soft tissue sarcoma.

BACKGROUND: Considerable controversy exists as to whether any benefit of doxorubicin-based combination chemotherapy outweighs increased toxic effects, inconvenience, and additional costs, compared to single-agent doxorubicin. There is substantial variation in clinical practice in the treatment of patients with locally advanced and metastatic soft tissue sarcoma (STS). OBJECTIVES: To determine:1) the effect, if any on response rate or survival, by using doxorubicin-based combination chemotherapy compared with single-agent doxorubicin for the treatment of patients with incurable locally advanced or metastatic STS2)if combination chemotherapy is associated with increased adverse effects compared with single-agent doxorubicin in this setting. SEARCH STRATEGY: We searched CENTRAL (Cochrane Library, issue 4, 2002), MEDLINE (1966 to October 2002), CANCER LIT (1975 to October 2002), reference lists, the Physician Data Query (PDQ) clinical trials database, and the American Society of Clinical Oncology (ASCO) Annual Meeting Proceedings (1995 to 2002). SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing single-agent doxorubicin with doxorubicin-based combination chemotherapy in adults with locally advanced or metastatic STS requiring palliative chemotherapy. Abstracts and full reports published in English were eligible. DATA COLLECTION AND ANALYSIS: Data were abstracted and assessed by two reviewers. Response and survival data were pooled. Data on adverse effects was tabulated. MAIN RESULTS: Data on 2281 participants from eight RCTs were available from reports of single-agent doxorubicin versus doxorubicin-based combination chemotherapy. Meta-analysis using the fixed effect model detected a higher tumour response rate with combination chemotherapy compared with single-agent chemotherapy (odds ratio [OR= 1.29; 95% confidence interval [CI], 1.03 to 1.60; p = 0.03), but the OR from a pooled analysis using the random effects model and the same data did not achieve statistical significance (OR= 1.26; 95% CI, 0.96 to 1.67; p = 0.10). No significant difference between the two regimens was detected in the pooled one-year mortality rate (OR = 0.87; 95% CI, 0.73 to 1.05; p=0.14) or two-year mortality rate (OR = 0.84; 95% CI, 0.67 to 1.06; p=0.13) (N=2097). Although reporting of adverse effects was limited and inconsistent among trials (making pooling of data for this outcome impossible), adverse effects such as nausea/vomiting and hematologic toxic effects were consistently reported as being worse with combination chemotherapy across the eight eligible studies. REVIEWER'S CONCLUSIONS: Compared to single-agent doxorubicin, the combination chemotherapy regimens evaluated, given in conventional doses, produced only marginal increases in response rates, at the expense of increased toxic effects and with no improvements in overall survival.

A mesoscale phytoplankton bloom in the polar Southern Ocean stimulated by iron fertilization.

Changes in iron supply to oceanic plankton are thought to have a significant effect on concentrations of atmospheric carbon dioxide by altering rates of carbon sequestration, a theory known as the 'iron hypothesis'. For this reason, it is important to understand the response of pelagic biota to increased iron supply. Here we report the results of a mesoscale iron fertilization experiment in the polar Southern Ocean, where the potential to sequester iron-elevated algal carbon is probably greatest. Increased iron supply led to elevated phytoplankton biomass and rates of photosynthesis in surface waters, causing a large drawdown of carbon dioxide and macronutrients, and elevated dimethyl sulphide levels after 13 days. This drawdown was mostly due to the proliferation of diatom stocks. But downward export of biogenic carbon was not increased. Moreover, satellite observations of this massive bloom 30 days later, suggest that a sufficient proportion of the added iron was retained in surface waters. Our findings demonstrate that iron supply controls phytoplankton growth and community composition during summer in these polar Southern Ocean waters, but the fate of algal carbon remains unknown and depends on the interplay between the processes controlling export, remineralisation and timescales of water mass subduction.

Pseudouridine in RNA: what, where, how, and why.

Pseudouridine (5-ribosyluracil) is a ubiquitous yet enigmatic constituent of structural RNAs (transfer, ribosomal, small nuclear, and small nucleolar). Although pseudouridine (psi) was the first modified nucleoside to be discovered in RNA, and is the most abundant, its biosynthesis and biological roles have remained poorly understood since its identification as a "fifth nucleoside" in RNA. Recently, a combination of biochemical, biophysical, and genetic approaches has helped to illuminate the structural consequences of psi in polyribonucleotides, the biochemical mechanism of U-->psi isomerization in RNA, and the role of modification enzymes (psi synthases) and box H/ACA snoRNAs, a class of eukaryotic small nucleolar RNAs, in the site-specific biosynthesis of psi. Through its unique ability to coordinate a structural water molecule via its free N1-H, psi exerts a subtle but significant "rigidifying" influence on the nearby sugar-phosphate backbone and also enhances base stacking. These effects may underlie the biological role of most (but perhaps not all) of the psi residues in RNA. Certain genetic mutants lacking specific psi residues in tRNA or rRNA exhibit difficulties in translation, display slow growth rates, and fail to compete effectively with wild-type strains in mixed culture. In particular, normal growth is severely compromised in an Escherichia coli mutant deficient in a pseudouridine synthase responsible for the formation of three closely spaced psi residues in the mRNA decoding region of the 23S rRNA. Such studies demonstrate that pseudouridylation of RNA confers an important selective advantage in a natural biological context.

Time window of intracisternal osteogenic protein-1 in enhancing functional recovery after stroke.

Osteogenic protein-1 (OP-1, BMP-7) is a member of the bone morphogenetic protein subfamily of the TGF-ss superfamily that selectively stimulates dendritic neuronal outgrowth. In previous studies, we found that the intracisternal injection of OP-1, starting at one day after stroke, enhanced sensorimotor recovery of the contralateral limbs following unilateral cerebral infarction in rats. In the current study, we further explored the time window during which intracisternal OP-1 enhances sensorimotor recovery, as assessed by limb placing tests. We found that intracisternal OP-1 (10 microg) given 1 and 3 days, or 3 and 5 days, but not 7 and 9 days after stroke, significantly enhanced recovery of forelimb and hindlimb placing. There was no difference in infarct volume between vehicle- and OP-1-treated animals. The mechanism of OP-1 action might be stimulation of new dendritic sprouting in the remaining uninjured brain.

Bone morphogenetic protein-7 enhances dendritic growth and receptivity to innervation in cultured hippocampal neurons.

Members of the bone morphogenetic protein (BMP) family of growth factors are present in the central nervous system during development and throughout life. They are known to play an important regulatory role in cell differentiation, but their function in postmitotic telencephalic neurons has not been investigated. To address this question, we examined cultured hippocampal neurons following treatment with bone morphogenetic protein-7 (BMP-7, also referred to as osteogenic protein-1). When added at the time of plating, BMP-7 markedly stimulated the rate of dendritic development. Within 1 day, the dendritic length of BMP-7-treated neurons was more than twice that of controls. By three days the dendritic arbors of BMP-7-treated neurons had attained a level of branching similar to that of 2-week-old neurons cultured under standard conditions. Several findings indicate that BMP-7 selectively enhances dendritic development. While dendritic length was significantly increased in BMP-7-treated neurons, the length of the axon was not. In addition, the mRNA encoding the dendritic protein MAP2 was significantly increased by BMP-7 treatment, but the mRNA for tubulin was not. Finally, BMP-7 did not enhance cell survival. Because dendritic maturation is a rate-limiting step in synapse formation in hippocampal cultures, we examined whether BMP-7 accelerated the rate at which neurons became receptive to innervation. Using two separate experimental paradigms, we found that the rate of synapse formation (assessed by counting synapsin I-positive presynaptic vesicle clusters) was increased significantly in neurons that had been exposed previously to BMP-7. Because BMP-7 and related BMPs are expressed in the hippocampus in situ, these factors may play a role in regulating dendritic branching and synapse formation in both development and plasticity.