Tropospheric Emissions: Monitoring of Pollution (TEMPO).

TEMPO was selected in 2012 by NASA as the first Earth Venture Instrument, for launch between 2018 and 2021. It will measure atmospheric pollution for greater North America from space using ultraviolet and visible spectroscopy. TEMPO observes from Mexico City, Cuba, and the Bahamas to the Canadian oil sands, and from the Atlantic to the Pacific, hourly and at high spatial resolution (~2.1 km N/S×4.4 km E/W at 36.5°N, 100°W). TEMPO provides a tropospheric measurement suite that includes the key elements of tropospheric air pollution chemistry, as well as contributing to carbon cycle knowledge. Measurements are made hourly from geostationary (GEO) orbit, to capture the high variability present in the diurnal cycle of emissions and chemistry that are unobservable from current low-Earth orbit (LEO) satellites that measure once per day. The small product spatial footprint resolves pollution sources at sub-urban scale. Together, this temporal and spatial resolution improves emission inventories, monitors population exposure, and enables effective emission-control strategies. TEMPO takes advantage of a commercial GEO host spacecraft to provide a modest cost mission that measures the spectra required to retrieve ozone (O3), nitrogen dioxide (NO2), sulfur dioxide (SO2), formaldehyde (H2CO), glyoxal (C2H2O2), bromine monoxide (BrO), IO (iodine monoxide),water vapor, aerosols, cloud parameters, ultraviolet radiation, and foliage properties. TEMPO thus measures the major elements, directly or by proxy, in the tropospheric O3 chemistry cycle. Multi-spectral observations provide sensitivity to O3 in the lowermost troposphere, substantially reducing uncertainty in air quality predictions. TEMPO quantifies and tracks the evolution of aerosol loading. It provides these near-real-time air quality products that will be made publicly available. TEMPO will launch at a prime time to be the North American component of the global geostationary constellation of pollution monitoring together with the European Sentinel-4 (S4) and Korean Geostationary Environment Monitoring Spectrometer (GEMS) instruments.

Tropical tropospheric ozone and biomass burning.

New methods for retrieving tropospheric ozone column depth and absorbing aerosol (smoke and dust) from the Earth Probe-Total Ozone Mapping Spectrometer (EP/TOMS) are used to follow pollution and to determine interannual variability and trends. During intense fires over Indonesia (August to November 1997), ozone plumes, decoupled from the smoke below, extended as far as India. This ozone overlay a regional ozone increase triggered by atmospheric responses to the El Niño and Indian Ocean Dipole. Tropospheric ozone and smoke aerosol measurements from the Nimbus 7 TOMS instrument show El Niño signals but no tropospheric ozone trend in the 1980s. Offsets between smoke and ozone seasonal maxima point to multiple factors determining tropical tropospheric ozone variability.

Record low global ozone in 1992.

The 1992 global average total ozone, measured by the Total Ozone Mapping Spectrometer (TOMS) on the Nimbus-7 satellite, was 2 to 3 percent lower than any earlier year observed by TOMS (1979 to 1991). Ozone amounts were low in a wide range of latitudes in both the Northern and Southern hemispheres, and the largest decreases were in the regions from 10 degrees S to 20 degrees S and 100N to 60 degrees N. Global ozone in 1992 is at least 1.5 percent lower than would be predicted by a statistical model that includes a linear trend and accounts for solar cycle variation and the quasi-biennial oscillation. These results are confirmed by comparisons with data from other ozone monitoring instruments: the SBUV/2 instrument on the NOAA-11 satellite, the TOMS instrument on the Russian Meteor-3 satellite, the World Standard Dobson Instrument 83, and a collection of 22 ground-based Dobson instruments.

Membrane changes in lipopolysaccharide-stimulated murine B lymphocytes associated with cell activation.

The lateral diffusion of the fluorescent lipid analog 3,3'-dioctadecylindocarbocyanine iodide (DiI) was measured in the membranes of murine B lymphocytes treated with the B cell mitogen lipopolysaccharide (LPS). The mobility of DiI, as measured by fluorescence photobleaching recovery (FPR) techniques, was temperature-dependent with a value of 6.1.10(-9) cm2 s-1 at 37 degrees C. Untreated cells exhibited this diffusion coefficient over 72 h in culture. In contrast, DiI mobility decreased to 2.0.10(-9) cm2 s-1 at 37 degrees C in membranes of LPS-stimulated lymphocytes 24 h following LPS exposure. Interestingly, this decreased lipid lateral diffusion was not accompanied by any change in surface immunoglobulin lateral diffusion which remained essentially unchanged at 3.6-4.3.10(-11) cm2 s-1 over 72 h. To determine whether LPS effects on lipid lateral diffusion were due to insertion of LPS into the cell plasma membrane, we examined TRITC-LPS diffusion in B lymphocytes from LPS-responsive Balb/c and C3Heb/FeJ mice and from hypo-responsive C3H/HeJ mice. DiI and TRITC-LPS mobility decreased more than 50% in LPS-stimulated Balb/c and C3Heb/FeJ cells by 72 h. On C3H/HeJ lymphocytes, there was no change in DiI or TRITC-LPS lateral diffusion throughout the incubation period. These data indicate that B lymphocyte membrane composition is altered in LPS-activated lymphoblasts and that the decreased lateral diffusion of lipid probes does not result from membrane perturbation by LPS insertion into the lipid bilayer. Further, similarities between TRITC-LPS and DiI lateral diffusion suggest that most LPS molecules interact non-specifically with B cell membranes, presumably by acyl chain insertion of the lipid A moiety.

In situ gene therapy for adenocarcinoma of the prostate: a phase I clinical trial.

For patients with local recurrence of prostate cancer after definitive irradiation therapy there is no treatment widely considered safe and effective. After extensive preclinical testing of prodrug gene therapy in vitro and in vivo, we conducted a phase I dose escalation clinical trial of intraprostatic injection of a replication-deficient adenovirus (ADV) containing the herpes simplex virus thymidine kinase gene (HSV-tk) injected directly into the prostate, followed by intravenous administration of the prodrug ganciclovir (GCV). Our goal was to determine safe dose levels of the vector for future trials of efficacy. Patients with a rising serum prostate-specific antigen (PSA) level and biopsy confirmation of local recurrence of prostate cancer without evidence of metastases one or more years after definitive irradiation therapy were eligible for the trial. After giving informed consent, patients received injections of increasing concentrations of ADV/HSA-tk in 1 ml into the prostate under ultrasound guidance. Ganciclovir was then given intravenously for 14 days (5 mg/kg every 12 hr). Patients were monitored closely for evidence of toxicity and for response to therapy. Eighteen patients were treated at 4 escalating doses: group 1 (n = 4) received 1 x 10(8) infectious units (IU); group 2 (n = 5) received 1 x 10(9) IU; group 3 (n = 4) received 1 x 10(10) IU; group 4 (n = 5) received 1 x 10(11) IU. Vector was detected by PCR of urine samples after treatment, increasing in frequency and duration (up to 32 days) as the dose increased. All cultures of blood and urine specimens were negative for growth of adenovirus. Minimal toxicity (grade 1-2) was encountered in four patients. One patient at the highest dose level developed spontaneously reversible grade 4 thrombocytopenia and grade 3 hepatotoxicity. Three patients achieved an objective response, one each at the three highest dose levels, documented by a fall in serum PSA levels by 50% or more, sustained for 6 weeks to 1 year. This study is the first to demonstrate the safety of ADV/HSV-tk plus GCV gene therapy in human prostate cancer and the first to demonstrate anticancer activity of gene therapy in patients with prostate cancer. Further trials are underway to identify the optimal distribution of vector within the prostate and to explore the safety of repeat courses of gene therapy.

Rodent carcinogenicity with the thiazolidinedione antidiabetic agent troglitazone.

Carcinogenic potential of the thiazolidinedione antidiabetic troglitazone was assessed in 104-week studies in mice and rats. Mice were given 50, 400, or 800 mg/kg, male rats 100, 400, or 800 mg/kg, and female rats 25, 50, or 200 mg/kg. Vehicle and placebo controls were included. Survival was significantly decreased in both sexes of both species at high doses, but was adequate for valid evaluation of carcinogenicity. Hypertrophy and hyperplasia of brown adipose tissue was observed in both species at all doses, and fatty change and hypocellularity of bone marrow was noted in mice at all doses and in female rats at 50 and 200 mg/kg. Hepatocellular vacuolation was observed in mice at 400 and 800 mg/kg, and centrilobular hepatocellular hypertrophy occurred in rats at > or = 200 mg/kg. Ventricular dilatation, myocardial fibrosis, and atrial myocyte karyomegaly in male rats at 400 and 800 mg/kg and female rats at all doses were morphologically similar to spontaneous lesions, but incidence and severity were increased compared with controls. In mice, the incidence of hemangiosarcoma was increased in females at 400 mg/kg and in both sexes at 800 mg/kg. The incidence of hepatocellular carcinoma was increased in female mice at 800 mg/kg. Troglitazone exposure [AUC((0-24))] at the lowest dose associated with increased tumor incidence in mice was 16 times human therapeutic exposure at 400 mg daily. No tumors of any type were increased in rats at exposures up to 47 times therapeutic exposure.

Kaposi's sarcoma of scrotum.

A rare case is presented of Kaposi's sarcoma localized to the scrotum with history, and physical and laboratory findings. Excision of the scrotum with bilateral orchiectomy was performed, with uneventful recovery. Literature is reviewed of Kaposi's sarcoma originating in the male external genitalia.

Differentiation between myenteric plexus and longitudinal muscle of the rat jejunum as the site of action of putative enteric neurotransmitters.

The contribution of the myenteric plexus in the mechanical responses of rat jejunal longitudinal muscle produced by several enteric nerve substances was evaluated. The myenteric plexus of a segment of rat jejunum was destroyed by serosal application of benzalkonium chloride (BAC). Fifteen days after BAC treatment, both the BAC-treated and an orad control jejunal segment were removed and the mechanical responses of the longitudinal muscle produced by the following substances were examined: substance P, acetylcholine (ACh), 5-hydroxytryptamine (5-HT), cholecystokinin octapeptide (CCK-8), norepinephrine, vasoactive intestinal peptide (VIP), bombesin, [Leu5]enkephalin and somatostatin. Our results indicate that: substance P and norepinephrine produce their mechanical responses by acting predominantly on the longitudinal smooth muscle; 5-HT, CCK-8, ATP, VIP and neurotensin act predominantly through the myenteric plexus; ACh possesses both direct and indirect actions; and because the responses to [Leu5]enkephalin, bombesin and somatostatin were equivocal, a conclusion as to their site of action could not be made with this preparation.

Preclinical toxicology studies with the angiotensin-converting enzyme inhibitor quinapril hydrochloride (Accupril).

Acute, subacute, and chronic toxicity studies, carcinogenicity bioassays, and reproductive and genetic toxicology studies were performed with quinapril, an ACE inhibitor used in the treatment of hypertension. Acute toxicity is minimal in rodents, and repeated dosing elicits gastric irritation, juxtaglomerular apparatus (JGA) hypertrophy and hyperplasia and tubular degenerative changes in the kidney, and reduced red cell parameters and heart weights in rodents and/or dogs. Other manifestations of toxicity, including hepatic lesions in dogs, reduced offspring weights in rats, marked sensitivity of the rabbit, and clastogenic effects at cytotoxic doses in the in vitro V79 chromosome aberration assay, have been reported with other drugs of this class.