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This study evaluates the impact of a recent upgrade in the physics package of the regional atmospheric climate model RACMO2 on the simulated surface mass balance (SMB) of the Antarctic ice sheet. The modelled SMB increases, in particular over the grounded ice sheet of East Antarctica (+44Gt a-1), with a small change in West Antarctica. This mainly results from an increase in precipitation, which is explained by changes in the cloud microphysics, including a new parameterization for ice cloud supersaturation, and changes in large-scale circulation patterns, which alter topographically forced precipitation. The spatial changes in SMB are evaluated using 3234 in situ SMB observations and ice-balance velocities, and the temporal variability using GRACE satellite retrievals. The in situ observations and balance velocities show a clear improvement of the spatial representation of the SMB in the interior of East Antarctica, which has become considerably wetter. No improvements are seen for West Antarctica and the coastal regions. A comparison of model SMB temporal variability with GRACE satellite retrievals shows no significant change in performance.

High-resolution (∼11 km) regional climate modeling shows total annual precipitation on the Greenland ice sheet for 1958-2007 to be up to 24% and surface mass balance up to 63% higher than previously thought. The largest differences occur in coastal southeast Greenland, where the much higher resolution facilitates capturing snow accumulation peaks that past five-fold coarser resolution regional climate models missed. The surface mass balance trend over the full 1958-2007 period reveals the classic pattern expected in a warming climate, with increased snowfall in the interior and enhanced runoff from the marginal ablation zone. In the period 1990-2007, total runoff increased significantly, 3% per year. The absolute increase in runoff is especially pronounced in the southeast, where several outlet glaciers have recently accelerated. This detailed knowledge of Greenland's surface mass balance provides the foundation for estimating and predicting the overall mass balance and freshwater discharge of the ice sheet. Copyright 2009 by the American Geophysical Union.

Large uncertainties remain in the current and future contribution to sea level rise from Antarctica. Climate warming may increase snowfall in the continents interior, but enhance glacier discharge at the coast where warmer air and ocean temperatures erode the buttressing ice shelves. Here, we use satellite interferometric synthetic-aperture radar observations from 1992 to 2006 covering 85 of Antarcticas coastline to estimate the total mass flux into the ocean. We compare the mass fluxes from large drainage basin units with interior snow accumulation calculated from a regional atmospheric climate model for 1980 to 2004. In East Antarctica, small glacier losses in Wilkes Land and glacier gains at the mouths of the Filchner and Ross ice shelves combine to a near-zero loss of 4±61 Gt yr1. In West Antarctica, widespread losses along the Bellingshausen and Amundsen seas increased the ice sheet loss by 59 in 10 years to reach 132±60 Gt yr1 in 2006. In the Peninsula, losses increased by 140 to reach 60±46 Gt yr1 in 2006. Losses are concentrated along narrow channels occupied by outlet glaciers and are caused by ongoing and past glacier acceleration. Changes in glacier flow therefore have a significant, if not dominant impact on ice sheet mass balance. © 2008 Nature Publishing Group.

Compared to other Arctic ice masses, Svalbard glaciers are low-elevated with flat interior accumulation areas, resulting in a marked peak in their current hypsometry (area-elevation distribution) at  ~450 m above sea level. Since summer melt consistently exceeds winter snowfall, these low-lying glaciers can only survive by refreezing a considerable fraction of surface melt and rain in the porous firn layer covering their accumulation zones. We use a high-resolution climate model to show that modest atmospheric warming in the mid-1980s forced the firn zone to retreat upward by  ~100 m to coincide with the hypsometry peak. This led to a rapid areal reduction of firn cover available for refreezing, and strongly increased runoff from dark, bare ice areas, amplifying mass loss from all elevations. As the firn line fluctuates around the hypsometry peak in the current climate, Svalbard glaciers will continue to lose mass and show high sensitivity to temperature perturbations.

Since the early 1990s, the Greenland ice sheet (GrIS) has been losing mass at an accelerating rate, primarily due to enhanced meltwater runoff following atmospheric warming. Here, we show that a pronounced latitudinal contrast exists in the GrIS response to recent warming. The ablation area in north Greenland expanded by 46%, almost twice as much as in the south (+25%), significantly increasing the relative contribution of the north to total GrIS mass loss. This latitudinal contrast originates from a different response to the recent change in large-scale Arctic summertime atmospheric circulation, promoting southwesterly advection of warm air toward the GrIS. In the southwest, persistent high atmospheric pressure reduced cloudiness, increasing runoff through enhanced absorption of solar radiation; in contrast, increased early-summer cloudiness in north Greenland enhanced atmospheric warming through decreased longwave heat loss. This triggered a rapid snowline retreat, causing early bare ice exposure, amplifying northern runoff.

Meltwater runoff from the Greenland ice sheet surface influences surface mass balance (SMB), ice dynamics, and global sea level rise, but is estimated with climate models and thus difficult to validate. We present a way to measure ice surface runoff directly, from hourly in situ supraglacial river discharge measurements and simultaneous high-resolution satellite/drone remote sensing of upstream fluvial catchment area. A first 72-h trial for a 63.1-km 2 moulin-terminating internally drained catchment (IDC) on Greenland's midelevation (1,207-1,381 m above sea level) ablation zone is compared with melt and runoff simulations from HIRHAM5, MAR3.6, RACMO2.3, MERRA-2, and SEB climate/SMB models. Current models cannot reproduce peak discharges or timing of runoff entering moulins but are improved using synthetic unit hydrograph (SUH) theory. Retroactive SUH applications to two older field studies reproduce their findings, signifying that remotely sensed IDC area, shape, and supraglacial river length are useful for predicting delays in peak runoff delivery to moulins. Applying SUH to HIRHAM5, MAR3.6, and RACMO2.3 gridded melt products for 799 surrounding IDCs suggests their terminal moulins receive lower peak discharges, less diurnal variability, and asynchronous runoff timing relative to climate/SMB model output alone. Conversely, large IDCs produce high moulin discharges, even at high elevations where melt rates are low. During this particular field experiment, models overestimated runoff by +21 to +58%, linked to overestimated surface ablation and possible meltwater retention in bare, porous, low-density ice. Direct measurements of ice surface runoff will improve climate/SMB models, and incorporating remotely sensed IDCs will aid coupling of SMB with ice dynamics and subglacial systems., Competing Interests: The authors declare no conflict of interest., (Copyright © 2017 the Author(s). Published by PNAS.)

Melting of the Greenland ice sheet (GrIS) and its peripheral glaciers and ice caps (GICs) contributes about 43% to contemporary sea level rise. While patterns of GrIS mass loss are well studied, the spatial and temporal evolution of GICs mass loss and the acting processes have remained unclear. Here we use a novel, 1 km surface mass balance product, evaluated against in situ and remote sensing data, to identify 1997 (±5 years) as a tipping point for GICs mass balance. That year marks the onset of a rapid deterioration in the capacity of the GICs firn to refreeze meltwater. Consequently, GICs runoff increases 65% faster than meltwater production, tripling the post-1997 mass loss to 36±16 Gt -1 , or ∼14% of the Greenland total. In sharp contrast, the extensive inland firn of the GrIS retains most of its refreezing capacity for now, buffering 22% of the increased meltwater production. This underlines the very different response of the GICs and GrIS to atmospheric warming.

The regional climate model (RCM) RACMO2 has been a powerful tool for improving surface mass balance (SMB) estimates from GCMs or reanalyses. However, new yearly SMB observations for West Antarctica show that the modelled interannual variability in SMB is poorly simulated by RACMO2, in contrast to ERA-Interim, which resolves this variability well. In an attempt to remedy RACMO2 performance, we included additional upper air relaxation (UAR) in RACMO2. With UAR, the correlation to observations is similar for RACMO2 and ERA-Interim. The spatial SMB patterns and ice sheet integrated SMB modelled using UAR remain very similar to the estimates of RACMO2 without UAR. We only observe an upstream smoothing of precipitation in regions with very steep topography like the Antarctic Peninsula. We conclude that UAR is a useful improvement for RCM simulations, although results in regions with steep topography should be treated with care.

Predicting Greenland Ice Sheet mass loss due to ice dynamics requires a complete understanding of spatiotemporal velocity fluctuations and related control mechanisms. We present a 5 year record of seasonal velocity measurements for 55 marine-terminating glaciers distributed around the ice sheet margin, along with ice-front position and runoff data sets for each glacier. Among glaciers with substantial speed variations, we find three distinct seasonal velocity patterns. One pattern indicates relatively high glacier sensitivity to ice-front position. The other two patterns are more prevalent and appear to be meltwater controlled. These patterns reveal differences in which some subglacial systems likely transition seasonally from inefficient, distributed hydrologic networks to efficient, channelized drainage, while others do not. The difference may be determined by meltwater availability, which in some regions may be influenced by perennial firn aquifers. Our results highlight the need to understand subglacial meltwater availability on an ice sheet-wide scale to predict future dynamic changes., Key Points: First multi-region seasonal velocity measurements show regional differencesSeasonal velocity fluctuations on most glaciers appear meltwater controlledSeasonal development of efficient subglacial drainage geographically divided.

We combined an ensemble of satellite altimetry, interferometry, and gravimetry data sets using common geographical regions, time intervals, and models of surface mass balance and glacial isostatic adjustment to estimate the mass balance of Earth's polar ice sheets. We find that there is good agreement between different satellite methods--especially in Greenland and West Antarctica--and that combining satellite data sets leads to greater certainty. Between 1992 and 2011, the ice sheets of Greenland, East Antarctica, West Antarctica, and the Antarctic Peninsula changed in mass by -142 ± 49, +14 ± 43, -65 ± 26, and -20 ± 14 gigatonnes year(-1), respectively. Since 1992, the polar ice sheets have contributed, on average, 0.59 ± 0.20 millimeter year(-1) to the rate of global sea-level rise.

Mass budget calculations, validated with satellite gravity observations [from the Gravity Recovery and Climate Experiment (GRACE) satellites], enable us to quantify the individual components of recent Greenland mass loss. The total 2000-2008 mass loss of approximately 1500 gigatons, equivalent to 0.46 millimeters per year of global sea level rise, is equally split between surface processes (runoff and precipitation) and ice dynamics. Without the moderating effects of increased snowfall and refreezing, post-1996 Greenland ice sheet mass losses would have been 100% higher. Since 2006, high summer melt rates have increased Greenland ice sheet mass loss to 273 gigatons per year (0.75 millimeters per year of equivalent sea level rise). The seasonal cycle in surface mass balance fully accounts for detrended GRACE mass variations, confirming insignificant subannual variation in ice sheet discharge.

The mammalian target of rapamycin (mTOR) is an intracellular serine/threonine protein kinase positioned at a central point in a variety of cellular signaling cascades. The established involvement of mTOR activity in the cellular processes that contribute to the development and progression of cancer has identified mTOR as a major link in tumorigenesis. Consequently, inhibitors of mTOR, including temsirolimus, everolimus, and ridaforolimus (formerly deforolimus) have been developed and assessed for their safety and efficacy in patients with cancer. Temsirolimus is an intravenously administered agent approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) for the treatment of advanced renal cell carcinoma (RCC). Everolimus is an oral agent that has recently obtained US FDA and EMEA approval for the treatment of advanced RCC after failure of treatment with sunitinib or sorafenib. Ridaforolimus is not yet approved for any indication. The use of mTOR inhibitors, either alone or in combination with other anticancer agents, has the potential to provide anticancer activity in numerous tumor types. Cancer types in which these agents are under evaluation include neuroendocrine tumors, breast cancer, leukemia, lymphoma, hepatocellular carcinoma, gastric cancer, pancreatic cancer, sarcoma, endometrial cancer, and non-small-cell lung cancer. The results of ongoing clinical trials with mTOR inhibitors, as single agents and in combination regimens, will better define their activity in cancer.

Background: The impact of reducing door-to-balloon time on hospital revenues, costs, and net income is unknown., Methods: We prospectively determined the impact on hospital finances of (1) emergency department physician activation of the catheterization lab and (2) immediate transfer of the patient to an immediately available catheterization lab by an in-house transfer team consisting of an emergency department nurse, a critical care unit nurse, and a chest pain unit nurse. We collected financial data for 52 consecutive ST-elevation myocardial infarction patients undergoing emergency percutaneous intervention from October 1, 2004-August 31, 2005 and compared this group to 80 consecutive ST-elevation myocardial infarction patients from September 1, 2005-June 26, 2006 after protocol implementation., Results: Per hospital admission, insurance payments (hospital revenue) decreased ($35,043 +/- $36,670 vs. $25,329 +/- $16,185, P = 0.039) along with total hospital costs ($28,082 +/- $31,453 vs. $18,195 +/- $9,242, P = 0.009). Hospital net income per admission was unchanged ($6962 vs. $7134, P = 0.95) as the drop in hospital revenue equaled the drop in costs. For every $1000 reduction in total hospital costs, insurance payments (hospital revenue) dropped $1077 for private payers and $1199 for Medicare/Medicaid. A decrease in hospital charges ($70,430 +/- $74,033 vs. $53,514 +/- $23,378, P = 0.059), diagnosis related group relative weight (3.7479 +/- 2.6731 vs. 2.9729 +/- 0.8545, P = 0.017) and outlier payments with hospital revenue>$100,000 (7.7% vs. 0%, P = 0.022) all contributed to decreasing ST-elevation myocardial infarction hospitalization revenue. One-year post-discharge financial follow-up revealed similar results: Insurance payments: $49,959 +/- $53,741 vs. $35,937 +/- $23,125, P = 0.044; Total hospital costs: $39,974 +/- $37,434 vs. $26,778 +/- $15,561, P = 0.007; Net Income: $9984 vs. $9159, P = 0.855., Conclusion: All of the financial benefits of reducing door-to-balloon time in ST-elevation myocardial infarction go to payers both during initial hospitalization and after one-year follow-up., Trial Registration: ClinicalTrials.gov ID: NCT00800163.

Antarctic Ice Sheet elevation changes, which are used to estimate changes in the mass of the interior regions, are caused by variations in the depth of the firn layer. We quantified the effects of temperature and accumulation variability on firn layer thickness by simulating the 1980-2004 Antarctic firn depth variability. For most of Antarctica, the magnitudes of firn depth changes were comparable to those of observed ice sheet elevation changes. The current satellite observational period ( approximately 15 years) is too short to neglect these fluctuations in firn depth when computing recent ice sheet mass changes. The amount of surface lowering in the Amundsen Sea Embayment revealed by satellite radar altimetry (1995-2003) was increased by including firn depth fluctuations, while a large area of the East Antarctic Ice Sheet slowly grew as a result of increased accumulation.

Diarrhea is a well-recognized side effect of chemotherapy and can result in chemotherapy delay and/or dose reduction, potentially reducing the therapeutic benefit of treatment. Octreotide has been shown to be effective in controlling chemotherapy-induced diarrhea (CID). In this open-label, randomized, multicenter study, designed to asses the effects of two dose levels of octreotide long-acting release (LAR), patients with active or prior CID and scheduled for chemotherapy were randomized to receive up to six doses of either 30 or 40 mg of octreotide LAR. The primary endpoint was the proportion of patients experiencing severe diarrhea during the trial. Secondary endpoints included the proportion of patients requiring IV fluids due to diarrhea, unscheduled visits to healthcare professionals due to diarrhea, and changes in primary therapy, as well as treatment satisfaction and quality of life. In total, 147 patients were randomized and received at least 1 dose; 124 patients were efficacy-evaluable. Baseline characters were balanced in the 30-mg and 40-mg groups with the exception of gender. Fewer patients in the 40-mg group compared with those in the 30-mg group experienced severe diarrhea (61.7% vs 48.4%; P = 0.14), required IV fluid (31.7% vs 18.8%; P = 0.10), and had diarrhea-related unscheduled healthcare visits (41.7% vs. 28.1 %; P = 0.11); however, these differences were not statistically significant. No significant differences were observed between the treatment groups in either measured quality of life or treatment satisfaction. Adverse events were balanced between the two groups. No specific recommendations can be made from this trial regarding the use of 30 mg versus 40 mg of octreotide LAR for CID.

Recombinant human interleukin-12 (rHuIL-12) is a pleiotropic cytokine with anticancer activity against renal cell carcinoma (RCC) in preclinical models and in a phase I trial. A randomized phase II study of rHuIL-12 compared with interferon-alpha (IFN-alpha) evaluated clinical response for patients with previously untreated, advanced RCC. Patients were randomly assigned 2:1 to receive either rHuIL-12 or IFN-alpha2a. rHuIL-12 was administered by subcutaneous (s.c.) injection on days 1, 8, and 15 of each 28-day cycle. The dose of IL-12 was escalated during cycle 1 to a maintenance dose of 1.25 microg/kg. IFN was administered at 9 million units by s.c. injection three times per week. Serum concentrations of IL-12, IFN-gamma, IL-10, and neopterin were obtained in 10 patients treated with rHuIL-12 after the first full dose of 1.25 microg/kg given on day 15 (dose 3) of cycle 1 and again after multiple doses on day 15 (dose 6) of cycle 2. Thirty patients were treated with rHuIL-12, and 16 patients were treated with IFN-alpha. Two (7%) of 30 patients treated with rHuIL-12 achieved a partial response, and the trial was closed to accrual based on the low response proportion. IL-12 was absorbed rapidly after s.c. drug administration, with the peak serum concentration appearing at approximately 12 h in both cycles. Serum IL-12 concentrations remained stable on multiple dosing. Levels of IFN-gamma, IL-10, and neopterin increased with rHuIL-12 and were maintained in cycle 2. rHuIL-12 is a novel cytokine with unique pharmacologic and pharmacodynamic features under study for the treatment of malignancy and other medical conditions. The low response proportion associated with rHuIL-12 single-agent therapy against metastatic RCC was disappointing, given the preclinical data. Further study of rHuIL-12 for other medical conditions is underway. For RCC, the study of new cytokines is of the highest priority.

We report the first measurements of the electron-beam microbunching z dependence in a self-amplified spontaneous-emission (SASE) free-electron laser (FEL) experiment by the observation of visible wavelength coherent transition radiation (CTR). In this case the fundamental SASE wavelength was at 537 nm, and the CTR exhibited an exponential intensity growth similar to the SASE radiation. In addition, we observed for the first time structure in the CTR angular distribution patterns that may be useful for optimizing SASE FEL performance.

The aim of this study was to determine the antitumor activity of irofulven (6-hydroxymethylacylfulvene) in patients with advanced renal cell carcinoma (RCC). Eligible patients had advanced renal cell carcinoma with bidimensionally measurable disease, a Karnofsky performance status of at least 70, life expectancy of greater than three months, no prior treatment with chemotherapy, and no evidence of brain metastases. Irofulven was administered at a dose of 11 mg/m2 by 5-min intravenous infusion, on 5 consecutive days. Cycles were repeated every 28 days. Thirteen patients were enrolled in this study and 12 were evaluable for response. Of the twelve evaluable patients, no major responses were achieved. Eight patients had stable disease as best response. Toxicity included myelosuppression and gastrointestinal side effects. At the dose and schedule used in this trial, irofulven did not produce clinical response in RCC.

Purpose: To evaluate the relationship between treatment with cytokine therapy and survival, investigate the effect of nephrectomy on survival, and identify long-term survivors among a cohort of 670 patients with advanced renal cell carcinoma (RCC)., Patients and Methods: A total of 670 patients with advanced RCC treated on 24 clinical trials of systemic chemotherapy or cytokine therapy were the subjects of this retrospective analysis. Treatment was categorized as cytokine (containing interferon alfa and/or interleukin-2) in 396 patients (59%) and as chemotherapy (cytotoxic or hormonal therapy) in 274 (41%). Among the 670 patients, those with survival times of greater than 5 years were identified as long-term survivors., Results: Patients treated with cytokine therapy had a longer survival time than did those treated with chemotherapy, regardless of the year of treatment or risk category based on pretreatment features. The median survival times for favorable-, intermediate-, and poor-risk patients were 27, 12, and 6 months for those treated with cytokines and 15, 7, and 3 months for those treated with chemotherapy, respectively. The magnitude of difference in median survival was greater in the favorable- and intermediate-risk groups. The median survival time was less than 6 months in the poor-risk group for both treatment programs. Median survival time was 14 months among patients with prior nephrectomy plus time from diagnosis to treatment greater than 1 year versus 8 months among those with time from diagnosis to treatment less than 1 year, regardless of pretreatment nephrectomy status. Thirty patients (4.5%) among the 670 patients were identified as long-term survivors; 12 were free of disease after nephrectomy and treatment with interferon alfa, interleukin-2, or surgical resection of metastasis., Conclusion: The low proportion of patients with advanced RCC who achieve long-term survival emphasizes the need for clinical investigation to identify more effective therapy.

Metastatic renal cell carcinoma remains one of the most treatment-resistant malignancies in humans. As such, long-term survival is limited to a minority of patients. Interferon-alpha and interleukin-2 induced major responses in some patients with renal cell carcinoma, and in so doing generated a great deal of interest and hope. However, clinical benefit is limited to relatively few patients. Here, we briefly discuss the management of metastatic renal cell carcinoma, and then elaborate on several novel treatment approaches in development, including retinoids, monoclonal antibodies, and antiangiogenesis strategies.

A persisting paradox in cytoskeletal regulation of cell motility is the loss of the actin filament fragmenting protein, gelsolin, in transformed epithelial cells that have gained the ability to migrate. Either actin filament severing does not occur during motility of carcinoma cells or a novel fragmentation protein is expressed during transformation. Using an antibody specific for severin, the Mr 40,000 actin filament severing protein from Dictyostelium discoideum amoebae, we have identified a mammalian form of severin in murine LL/2 carcinoma cells lacking gelsolin. Mammalian severin (M-severin) isolated from LL/2-derived Lewis lung carcinoma tumors severed F-actin in a calcium-dependent manner, mimicking the function of Dictyostelium severin. M-severin preferentially localized to the cleavage furrow of dividing LL/2 cells and to the actin-rich cortex of migratory LL/2 cells, known sites of active actin cytoskeleton rearrangement. The mammalian severing protein was fully expressed in transformed LL/2 epithelial cells but went undetected in normal mouse muscle, liver, spleen, or kidney. Normal mouse lung tissue contained minute amounts of M-severin, attributed to motile cells in pulmonary connective tissue. In striking contrast to M-severin, gelsolin was highly expressed in normal lung but disappeared in transformed LL/2 carcinoma cells. Based on prior observations of a functional role for actin filament fragmentation in cell migration, the simultaneous induction of M-severin and loss of gelsolin during epithelial transformation suggests that replacement of gelsolin by M-severin may function to achieve actin filament rearrangements necessary for active cell migration in invasive or metastatic carcinoma. Induction of M-severin in an invasive tumor was directly observed in human colon adenocarcinoma by cytoimmunohistochemistry with antibodies directed against severin isolated from both Dictyostelium amoebae and Lewis lung carcinoma cells. Because normal colon epithelium from the same patient did not express M-severin, it may serve as a sensitive marker for detection and staging of epithelial tumors.

Retinoic acid receptor-beta (RAR-beta) mRNA is not expressed by retinoid-resistant renal cancer cell lines but is present in retinoid-sensitive SK-RC-06 renal cancer cells and increases following incubation with retinoic acid (RA), suggesting that the antitumor action of RA is mediated through RAR-beta (A. D. Hoffman et al., Clin. Cancer Res., 2: 1077-1082, 2996). To determine whether RAR-beta expression correlates in vivo with major clinical response to patients with renal cell carcinoma (RCC) who were treated with retinoid-based therapy, we used in situ hybridization to analyze RAR-beta expression in tumor specimens obtained from patients who were treated on a clinical trial with 13-cis-RA and IFN-alpha. Thirty-three tissue specimens were analyzed (23 pretreatment and 10 on-treatment). mRNA expression was based on staining intensity, with scores within tumor cells ranging from 0 to 2, where a score of 0 indicated absence of staining, a score of 1 indicated weak staining, and a score of 2 indicated strong staining. RAR-beta expression was present in 22 of 23 (96%) pretreatment and 9 of 10 (90%) on-treatment specimens. Pretreatment levels of expression did not associate with the site of biopsy and did not predict for major clinical response to RA plus IFN-alpha therapy (two-sided Fisher's exact test, P = 0.826). However, an increase in the intensity of RAR-beta mRNA expression was detected in four of five (80%) patients who achieved a major response but in none of the five patients with progressive disease in whom sequential biopsies were available (two-sided Fisher's exact test, P = 0.048). These data show that RAR-beta transcripts increase in tumor cells of RCC patients who clinically respond to retinoid-based therapy. Retinoids that potently induce RAR-beta expression should be evaluated in the treatment of advanced RCC.

Bacillus Calmette-Guerin was administered through the ileal conduit of a 63-year-old man with upper tract recurrence of transitional cell carcinoma. Subsequent computed tomography showed bilateral renal masses, which were granulomatous at pathologic examination. The bacilli likely reached the kidneys via proven ileoureteral reflux. Patients with reflux may benefit from antituberculous prophylaxis.

The aim of this study was to determine the antitumor activity of pyrazoloacridine in patients with renal cell carcinoma. Eligible patients had advanced renal cell carcinoma with bidimensionally measurable disease, a Karnofsky performance status of at least 70, life expectancy of greater than three months, no prior treatment with chemotherapy, and no evidence of brain metastases. Patients were treated intravenously with 750 mg/m2 every three weeks. Twelve patients were enrolled in this study and all were evaluable for response and toxicity. Of the twelve patients, no major responses were achieved. Toxicity was mild, with three patients requiring a 20% dose reduction. At the dose and schedule used in this trial, pyrazoloacridine is inactive in renal cell carcinoma.

Renal cell carcinoma (RCC) is characterized by (a) lack of early warning signs, which results in a high proportion of patients with metastases at the time of diagnosis; (b) protean clinical manifestations; and (c) resistance to radiotherapy and chemotherapy. The estimates of new diagnoses and deaths from kidney cancer in the United States during 1996 are 30,600 and 12,000, respectively. RCC occurs nearly twice as often in men as in women. The age at diagnosis is generally older than 40 years; the median age is in the midsixties. The incidence of RCC has been rising steadily. Between 1974 and 1990, there was a 38% increase in the number of patients who had a diagnosis of RCC. This increase was accompanied by a significant improvement in 5-year survival. Both trends are likely the result of improved diagnostic capability. Newer radiographic techniques, including ultrasonography, computed tomography, and magnetic resonance imaging, are detecting kidney tumors more frequently and at a lower disease stage, when tumors can be resected for cure. Surgical treatment is the only curative therapy for localized RCC. Radical nephrectomy remains the mainstay of surgical management, but techniques are being modified. These modifications include partial nephrectomy and resection of vena caval thrombi. In highly selected cases, surgical resection of locally recurrent RCC or of disease at a solitary metastatic site is associated with long-term survival. Metastatic RCC is highly resistant to the many systemic therapies that have been extensively investigated. A minority of patients achieve complete or partial response to interferon, interleukin-2, or both. Response can be dramatic but is rarely durable. Because most patients do not achieve response, these agents are not considered effective treatments for RCC, but the response in some patients indicates the need for continued research on their use. Identification of new agents with better antitumor activity against metastases remains a high priority in clinical investigation of therapy for this refractory disease.

The aim of this study was to determine the antitumor activity of 13-cis-retinoic acid as a single agent in patients with advanced renal cell carcinoma. Eligible patients had advanced renal cell carcinoma with bi-dimensionally measurable disease, a Karnofsky performance status of at least 70, life expectancy of greater than three months, no evidence of brain metastases, and treatment with no more than one chemotherapy regimen. Patients were treated with one mg/kg/day of 13-cis-retinoic acid orally. Twenty-six patients were enrolled in this study and 25 were evaluable for response and toxicity. Of the twenty-five evaluable patients, no major responses were achieved. Toxicity was mild, with no patient requiring a dose reduction. At the dose administered in this trial, 13-cis-retinoic acid is inactive as a single agent in renal cell carcinoma.

Heart rate (HR) variability has long been recognized as a sign of cardiac health. In the presence of heart disease, HR variability decreases, an observation that has been associated with poor prognosis in a number of recent studies. HR variability is particularly altered in congestive heart failure (CHF), a condition associated with a number of typical functional hemodynamic and neurohumoral alterations. The relation of measurements of HR variability to these abnormalities in patients with heart failure has not been carefully examined. Twenty-three patients (19 men, 4 women, mean age 49 years) with New York Heart Association class II to IV CHF were studied prospectively without cardiac medications; radionuclide ventriculography, right-sided heart catheterization, peroneal microneurography, plasma norepinephrine and 24- to 48-hour ambulatory electrocardiography were performed. Average RR interval and its standard deviation, and HR power spectrum (0 to 0.5, 0.05 to 0.15 and 0.2 to 0.5 Hz) were derived from the ambulatory electrocardiographic recordings and compared with left ventricular ejection fraction, thermodilution cardiac output, pulmonary arterial wedge pressure, New York Heart Association class, age, muscle sympathetic nerve activity (peroneal nerve) and norepinephrine level by linear regression. None of the measures of HR variability were significantly related to age, left ventricular ejection fraction, cardiac output or functional classification, whereas the 0.05 to 0.15 and 0.20 to 0.50 Hz components were weakly but significantly related to cardiac output (r = 0.49 and 0.42, p = 0.02 and 0.045, respectively). In contrast, a generally stronger and negative relation was demonstrated between spectral and nonspectral measurements of HR variability, and indicators of sympathoexcitation, muscle sympathetic nerve activity and plasma norepinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)

Baroreflex control of heart rate, vascular resistance and norepinephrine is impaired in patients with heart failure, but recent animal studies demonstrate preserved baroreflex control of sympathetic nerve activity in this disorder. Studies were therefore performed to compare baroreflex control of efferent sympathetic nerve activity to muscle in 10 normal subjects (age mean +/- SEM 21 +/- 1 years) and in 11 patients with moderate to severe heart failure (age 48 +/- 5 years, New York Heart Association class II to IV, left ventricular ejection fraction 19 +/- 2%, pulmonary capillary wedge pressure 27 +/- 2 mm Hg, cardiac index 2.04 +/- 0.22 liters/min/m2). Baroreflex activation was produced by intravenous infusion of phenylephrine (0.5 to 2.0 micrograms/kg/min) and deactivation by infusion of nitroprusside (0.4 to 2.5 micrograms/kg/min). During phenylephrine infusion, comparable increases in mean arterial pressure were produced in normal subjects (89 +/- 2 to 99 +/- 3 mm Hg, p less than 0.01) and in patients with heart failure (90 +/- 2 to 99 +/- 3 mm Hg, p less than 0.01). The patients with heart failure exhibited significantly attenuated (p less than 0.01 for normal vs heart failure) decreases in heart rate (93 +/- 5 to 90 +/- 6 beats/min, p = not significant [NS]) compared with normal subjects (67 +/- 3 to 58 +/- 4 beats/min, p less than 0.01) and tended to demonstrate attenuated sympathoinhibitory responses to this pressor stimulus. More strikingly, patients with heart failure demonstrated significant impairment of baroreflex responses during nitroprusside-induced baroreceptor deactivation. In normal subjects, nitroprusside produced a decrease in mean arterial (90 +/- 2 to 80 +/- 3 mm Hg, p less than 0.001) and right atrial (4 +/- 1 to 2 +/- 1 mm Hg, p less than 0.01) pressures with a resultant reflex increase in heart rate (68 +/- 3 to 81 +/- 4 beats/min, p less than 0.001) and muscle sympathetic nerve activity (326 +/- 74 to 746 +/- 147 U/min, p less than 0.01). In patients with heart failure (n = 10), nitroprusside produced comparable (p = NS for normal vs heart failure) decreases in mean arterial (89 +/- 2 to 77 +/- 2 mm Hg, p less than 0.001) and right atrial (6 +/- 1 to 1 +/- 1 mm Hg, p less than 0.001) pressures, but did not significantly alter heart rate (91 +/- 6 to 97 +/- 4 beats/min, p = NS) or sympathetic nerve activity (936 +/- 155 to 1179 +/- 275 U/min, p = NS).(ABSTRACT TRUNCATED AT 400 WORDS)

Studies in patients with congestive heart failure (CHF) demonstrate blunting of sympathoexcitatory responses to baroreflex perturbation. Whereas experimental and limited clinical evidence suggests impairment of baroreflex mechanisms as the etiology of these attenuated responses, an alternative mechanism would be an inability of patients with CHF to increase sympathetic neural outflow above markedly elevated baseline levels. Hemodynamic and sympathetic neural responses (peroneal microneurography) were therefore compared of normal subjects (n = 10) and patients with CHF (n = 10) during the non-baroreflex sympathoexcitatory stimulus of the cold pressor test. The cold pressor stimulus produced increases in arterial pressure and heart rate in both groups. During hand immersion in ice water, normal subjects demonstrated significant increases in muscle sympathetic nerve activity expressed as burst frequency (20 +/- 2 to 28 +/- 3 bursts/min, p less than 0.01), total integrated nerve activity (224 +/- 41 to 342 +/- 62 U/min, p less than 0.05), and total activity corrected for accompanying changes in heart rate (375 +/- 81 to 538 +/- 118 U/100 heart beats, p less than 0.05). Similarly, despite elevated control levels of sympathetic activity, patients with CHF also demonstrated significant sympathoexcitatory responses to the cold pressor stimulus, with increases in muscle sympathetic nerve burst frequency (60 +/- 7 to 67 +/- 7 bursts/min, p less than 0.01) total integrated nerve activity (818 +/- 159 to 1,015 +/- 191 U, p less than 0.001), and total activity corrected for accompanying changes in heart rate (1,008 +/- 178 to 1,173 +/- 201 U/100 heart beats, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

To characterize the neural excitatory state of heart failure, simultaneous measurements of efferent sympathetic nerve activity to muscle (by microneurography) and rest hemodynamics were obtained in 10 normal subjects (age 25 +/- 2 years, mean +/- SEM) and 29 patients with heart failure (age 49 +/- 2 years; New York Heart Association functional class II to IV; left ventricular ejection fraction 21 +/- 1%; cardiac index = 2.16 +/- 0.13 liters/min per m2; pulmonary capillary wedge pressure 23 +/- 2 mm Hg). Sympathetic nerve activity was significantly higher in the patients with heart failure (54.7 +/- 4.5 bursts/min) than in normal subjects (16.7 +/- 2.2 bursts/min, p less than 0.001). Multiple linear regression analyses indicated that sympathetic activity in these human subjects was most strongly and inversely correlated with left ventricular stroke work index (r = -0.86, p less than 0.0001) and stroke volume index (r = -0.85, p less than 0.0001). There was a strong positive correlation between sympathetic nerve activity and pulmonary artery diastolic (r = 0.82, p less than 0.0001) and mean (r = 0.81, p less than 0.0001) pressures. Similar correlations were seen when patients with heart failure were analyzed separately. There was no significant correlation between sympathetic nerve activity and mean arterial pressure, left ventricular ejection fraction (by radionuclide ventriculography), cardiac chamber size (by echocardiography) or arterial oxygen tension in the patients with heart failure. Direct measurements of sympathetic nerve activity correlated closely with plasma norepinephrine (r = 0.72, p less than 0.0001) in patients with heart failure. Thus, sympathetic nerve activity at rest parallels impairment of cardiac performance in patients with heart failure.

To determine if circulating levels of atrial natriuretic factor comparable with those seen in pathophysiologic states alter autonomic control of the circulation, direct recordings of hemodynamic variables and efferent sympathetic nerve activity to muscle (microneurography) were obtained during two separate protocols in a total of 21 normal men (age 25 +/- 1 years). In protocol 1, the responses of 10 men were compared during incremental mechanical unloading of cardiopulmonary baroreceptors with lower body negative pressure versus responses to comparable unloading during infusion of alpha-human atrial natriuretic factor. Lower body negative pressure decreased pulmonary artery diastolic and right atrial pressures, did not alter arterial pressure or heart rate and increased muscle sympathetic nerve activity from 205.2 +/- 36.3 to 438.7 +/- 100.2 units/min (p less than 0.01). Intravenous infusion of atrial natriuretic factor (25 ng/kg per min) increased plasma levels of the hormone from 24 +/- 4 to 322 +/- 34 pg/ml (p less than 0.01, n = 6), produced similar decreases in pulmonary artery diastolic and right atrial pressures, did not alter arterial pressure, increased heart rate and increased sympathetic nerve activity from 233.1 +/- 35.6 to 387.2 +/- 64.9 units/min (p less than 0.05). Thus, during similar hemodynamic perturbations produced by lower body negative pressure or infusion of atrial natriuretic factor at the dose used in this study, these subjects exhibited comparable sympathoexcitatory responses, with a 109 +/- 23% increase in sympathetic activity during lower body negative pressure and a 76 +/- 19% increase during atrial natriuretic factor infusion (p = NS). In protocol 2, the responses of 11 additional men were examined during lower body negative pressure performed before and again during infusion of atrial natriuretic factor (12.5 ng/kg per min). During baseline (prehormone) trials, lower body negative pressure (-14.5 +/- 1.6 mm Hg) decreased central venous pressure, did not change arterial pressure or heart rate and increased sympathetic nerve activity from 215 +/- 47.7 to 372.3 +/- 64.3 units/min (p less than 0.001). Infusion of atrial natriuretic factor increased plasma levels of the hormone from 39 +/- 8 to 313 +/- 18 pg/ml (p less than 0.01, n = 7); central venous pressure was held constant during hormone infusion by intravenous infusion of saline solution.(ABSTRACT TRUNCATED AT 400 WORDS)

Tissue extracts of skeletal muscle, heart, eye, brain, liver, kidney, gill and stomach were electrophoretically examined for glucose dehydrogenase (EC 1.1.1.47) activity in 21 species of marine teleost fishes. Glucose dehydrogenase expression was detected only in liver extracts. Considerable interordinal variation was found in levels of enzymatic activity. Available data support the hypothesis that glucose dehydrogenase provides NADPH for the mixed-function oxidase system in teleosts.

Digitalis glycosides exert both excitatory and inhibitory autonomic actions in animals and produce vasoconstriction in normal humans but produce vasodilation in heart failure patients. To determine whether or not these contrasting vascular responses are due to differing autonomic actions of the drug, we compared the responses to intravenous administration of Cedilanid-D (0.02 mg/kg) in eight normal subjects (mean age, 23 +/- 1 years) and eight patients with moderate-to-severe heart failure (mean age, 52 +/- 5 years, NYHA Class III-IV). Hemodynamics and efferent sympathetic nerve activity to muscle (MSNA) were measured during 5-minute periods before (control) and 20 minutes after drug administration. In the heart failure patients, Cedilanid-D significantly increased systolic and pulse pressures, whereas mean arterial pressure was unchanged. There was a decrease in right atrial pressure and a tendency for a decrease in pulmonary artery diastolic pressure with a slowing of heart rate. Cardiac index increased by 24 +/- 7%. Short-term administration of digitalis in these heart failure patients produced a fall in forearm vascular resistance (from 37.6 +/- 8.2 to 31.8 +/- 8.1 units, p less than 0.05) and an early, profound, and sustained decrease in MSNA (from 831.0 +/- 118.4 to 474.4 +/- 103.6 units/100 heart beats, p less than 0.01). Digitalis glycosides produced different vascular and MSNA responses in the normal subjects. In the normal volunteers, the drug significantly increased systolic, mean, and pulse pressures and decreased central venous pressure and heart rate. Despite the significant increase in arterial pressure, there was no change in forearm vascular resistance (from 11.7 +/- 1.0 to 12.7 +/- 1.0 units, p = NS) or MSNA (from 494.8 +/- 88.5 to 369.1 +/- 60.5 units/100 heart beats, p = NS), suggesting a sympathoexcitatory response in normal subjects. To determine whether or not the digitalis-induced sympathoinhibition in the heart failure patients was simply due to an inotropic effect (stimulation of inhibitory cardiac mechanoreceptors), we studied the responses of seven additional patients with heart failure before and during administration of dobutamine (3.4 +/- 0.4 micrograms/kg/min). Dobutamine produced a 34 +/- 3% increase in cardiac index, no significant change in systemic arterial pressures, a decrease in pulmonary artery diastolic and right atrial pressures, and no change in heart rate or forearm vascular resistance (from 30.2 +/- 4.3 to 26.5 +/- 4.7 units, p = NS).(ABSTRACT TRUNCATED AT 400 WORDS)