Neuro-ophthalmologic manifestations of cholangiocarcinoma: a case series.

PurposeTo describe the neuro-ophthalmologic findings of cholangiocarcinoma.MethodsWe report a retrospective chart review of cholangiocarcinoma patients presenting at two tertiary care centers in the Texas Medical Center.ResultsFive patients with neuro-ophthalmologic symptoms related to cholangiocarcinoma were identified. One patient presented with diplopia due to metastasis to the left medial rectus muscle, two patients had metastasis to the occipital lobe resulting in homonymous hemianopsia, one patient had involvement of the clivus resulting in sixth nerve palsy, and one presented with a hypercoagulable state-related stroke causing a homonymous hemianopsia and visual hallucinations.ConclusionsNeuro-ophthalmic manifestations of cholangiocarcinoma depend upon both mechanism and localization. We report five cases of cholangiocarcinoma with neuro-ophthalmologic findings. To our knowledge, this is the largest such series reported in the English language ophthalmic literature.

Biodistribution and dosimetry of 195mPt-cisplatin in normal volunteers. Imaging agent for single photon emission computed tomography.

UNLABELLED: 195mPt-cisplatin is regarded as a promising imaging agent for optimizing dosage in patients receiving cisplatin chemotherapy. METHODS: We investigated the whole-body distribution and radiation dosimetry of 195mPt-cisplatin in humans. Whole-body scans were obtained up to 144 h after intravenous injection of 112.4 MBq 195mPt-cisplatin in each of five subjects. Blood samples were taken at various times up to 144 h after injection. Urine was collected up to 114 h after injection for calculation of renal clearance and whole-body clearance. Time/activity curves were generated by fitting the organ-specific geometric mean counts, obtained from regions of interest, on the respective images as a function of the time after injection. OLINDA software package was applied to calculate the absorbed radiation dose for various organs. RESULTS: Most of the activity (32 ± 4%) was excreted in the urine during the first 5 h. The effective clearance half-life derived from extrapolation of the whole-body curve was 40 hours (1.7 days). On average, the highest dose was received by the kidneys (mean dose received 2.68 ± 1.5 mGy/MBq), followed by the spleen (mean dose received 1.6 ± 0.8 mGy/MBq) followed by the liver (mean dose received 1.45 ± 0.38 mGy/MBq). The estimated mean effective dose for the adult subject was 0.185 ± 0.034 mSv/MBq. CONCLUSION: 195mPt-cisplatin proved a safe radiopharmaceutical with a favourable biodistribution for early and delayed imaging of pathology above the diaphragm. The ED obtained was 0.185 ± 0.034 mSv/MBq. The highest organ dose was received by the kidneys (2.68 ± 1.5 mGy/MBq).

Radiometal complexes: characterization and relevant in vitro studies.

Radiometals are, and will continue to be, very important to diagnostic and therapeutic nuclear medicine applications as they predominantly possess the most suitable nuclear properties for these types of applications. This article attempts to give the reader an overview of key aspects that need to be considered in the design and synthesis of a radiopharmaceutical using the commonly known and employed radionuclides, such as technetium, rhenium, the lanthanides and copper. While it is important to understand each radiometal ion has its own specific coordination chemistry requirements, there are several issues that are critical to all radiometal ions for their incorporation into a radiopharmaceutical. 1) The route of production and the presence of long lived contaminating radionuclides and or of naturally occurring metal ions that will interfere with the efficient and optimum radiolabelling of their ligand of choice as well as the final specific activity of the product; 2) the significant differences between the chemistry at the macroscopic (mM and higher concentrations) and radiotracer levels (uM and lower concentrations for the high specific activity radionuclides); 3) the rate of complexation and of dissociation of the radiometal ion vs the competing reaction of radiometal hydrolysis; 4) natural biological pathway of the radio-metal ion and therefore the design of the appropriate and relevant in vitro tests to assess the stability of the radiometal complex. These are a selection of critical factors that need to be considered in the design of a successful radiopharmaceutical, whether it is used for imaging or therapy. However, one should consider tailoring their investigations to suit the radiometal under investigation, and to be mindful where the technology is to be applied (e.g. imaging organs or disease).

Sarar technology for the application of Copper-64 in biology and materials science.

This review provides an overview of the synthesis and metal complexation chemistry of the nitrogen and sulphur donor bicyclic ligands or cages, and the key criteria that led to the design of sarar for the application for (64)Cu(II). Aspects of the high yielding synthesis of sarar and strategies for its conjugation to a range of antibodies for targeting colorectal cancer, neuroblastoma and melanoma are described. Free and conjugated to proteins sarar can complex (64)Cu(II) rapidly at room temperature and quantitatively; the latter leading to products of high specific activity and purity. The full occupation of the (64)Cu(II) ions 6 coordination sites by the sarar cage prevents the ready exchange of the (64)Cu(II) from the cage and is the rational for the extraordinary thermodynamic and kinetic stability of (64)Cu(II) labelled sarar and its conjugates. It's in vivo stability is further highlighted by the low uptake and retention of (64)Cu-sarar-conjugated antibodies in the liver. Finally, the prospects for the use of the sarar technology in the materials science arena for probing solid liquid interfaces, in particular, the quantification of functional groups on microspheres and in the engineering of novel materials are discussed.

Soil erosion and significance for carbon fluxes in a mountainous Mediterranean-climate watershed.

In topographically complex terrains, downslope movement of soil organic carbon (OC) can influence local carbon balance. The primary purpose of the present analysis is to compare the magnitude of OC displacement by erosion with ecosystem metabolism in such a complex terrain. Does erosion matter in this ecosystem carbon balance? We have used the Revised Universal Soil Loss Equation (RUSLE) erosion model to estimate lateral fluxes of OC in a watershed in northwestern Mexico. The watershed (4900 km2) has an average slope of 10 degrees +/- 9 degrees (mean +/- SD); 45% is >10 degrees, and 3% is >30 degrees. Land cover is primarily shrublands (69%) and agricultural lands (22%). Estimated bulk soil erosion averages 1350 Mg x km(-2) x yr(-1). We estimate that there is insignificant erosion on slopes < 2 degrees and that 20% of the area can be considered depositional. Estimated OC erosion rates are 10 Mg x km(-2) x yr(-1) for areas steeper than 2 degrees. Over the entire area, erosion is approximately 50% higher on shrublands than on agricultural lands, but within slope classes, erosion rates are more rapid on agricultural areas. For the whole system, estimated OC erosion is approximately 2% of net primary production (NPP), increasing in high-slope areas to approximately 3% of NPP. Deposition of eroded OC in low-slope areas is approximately 10% of low-slope NPP. Soil OC movement from erosional slopes to alluvial fans alters the mosaic of OC metabolism and storage across the landscape.

Antibiograms of resistant Gram-negative bacteria from Scottish CF patients.

BACKGROUND: Over a 19-month pilot phase, 93 multiply resistant Gram-negative isolates from Scottish cystic fibrosis patients were sent to a referral laboratory for further investigation. METHODS: In common with the referring diagnostic laboratories, disc diffusion testing was carried out. Antibiotic susceptibility testing was also established by MIC methodology. NCCLS methods were used throughout. Twenty antibiotics were tested. RESULTS: Comparing disc diffusion results against MIC results, there were 167 (14%) major errors. By MIC, Pseudomonas aeruginosa (n = 59), Stenotrophomonas maltophilia (n = 16), Burkholderia cepacia (n = 10) and Alcaligenes xylosoxidans (n = 7) were susceptible to 18%, 11%, 4% and 35% of the antibiotics tested, respectively. Colistin and tobramycin were the most active agents against P. aeruginosa with 60% and 49%, respectively, testing susceptible. Minocycline and gentamicin were most active against S. maltophilia with 58% and 18%, respectively, testing susceptible. B. cepacia were most susceptible to co-trimoxazole (10%) and ciprofloxacin (10%). Five and six of the seven A. xylosoxidans isolates were susceptible to piperacillin and imipenem, respectively. CONCLUSIONS: Improved methods for susceptibility testing of such clinical isolates need to be employed in routine diagnostic laboratories. Levels of resistance in referred isolates were very high and similar to those described in the USA.

Reproductive health and human rights.

Reproductive health programs should adopt an approach based on human rights at the levels of clinical management as well as national policy, especially those programs responsible for abortion and post-abortion care. Resource-poor women face greater maternal mortality and morbidity, suffer continuous risk because of a lack of access to adequate reproductive health services, and are likelier than more affluent women to resort to unsafe, inaccessible, and/or unaffordable abortion services. The public health and medical communities are highly effective when providing safe abortion procedures and treatment in the event of complications. Efforts must be continued to develop strategies to prevent unwanted pregnancies, unsafe abortions, and abortion-related deaths; to treat abortion complications; to broaden the types of medical and health professionals who are allowed to perform abortions; and to enhance training for abortion providers.

Distribution and significance of small, artificial water bodies across the United States landscape.

At least 2.6 million small, artificial water bodies dot the landscape of the conterminous United States; most are in the eastern half of the country. These features account for approximately 20% of the standing water area across the United States, and their impact on hydrology, sedimentology, geochemistry, and ecology is apparently large in proportion to their area. These features locally elevate evaporation, divert and delay downstream water flow, and modify groundwater interactions. They apparently intercept about as much eroded soil as larger, better-documented reservoirs. Estimated vertical accretion rates are much higher, hence, inferred sedimentary chemical reactions must be different in the small features than in larger ones. Finally, these features substantially alter the characteristics of aquatic habitats across the landscape.

SGN-10. Seattle Genetics.

Seattle Genetics is developing SGN-10 (BR96-SCIT), a single-chain immunotoxin (SCIT) under license from Bristol-Myers Squibb (BMS), as both a monotherapy and in combination with Taxotere (Rhône-Poulenc Rorer) for the potential treatment for cancer [308773]. SGN-10 is currently in phase I clinical trials [308773], [369809], [382807], [408963], [410348]. The compound is a follow-up to SGN-15 (BR96-DOX; BMS) and is potentially more effective and cheaper to manufacture. It delivers a bacterial toxin which is 250-times more potent than BR96-DOX and is one third the size, hence enabling tumor penetration more easily. BMS submitted an IND for SGN-10 in the first quarter of 1996 [200849], [204704]. BMS licensed the SCA-protein (single-chain antigen-binding protein) technology from Enzon in 1993 [352743]. In April 1998, Seattle Genetics completed a licensing agreement with BMS to take over development of SGN-10 [308773].

Heme pocket disorder in myoglobin: reversal by acid-induced soft refolding.

The protein folding process of heme proteins entails generation of not only a correct global polypeptide structure, but also a correct, functionally competent heme environment. We employed a variety of spectroscopic approaches to probe the structure and dynamics of the heme pocket of a recombinant sperm whale myoglobin. The conformational characteristics were examined by circular dichroism, time-resolved fluorescence spectroscopy, FTIR spectroscopy, and optical absorption spectroscopy in the temperature range 300-20 K. Each of these spectroscopic probes detected modifications confined exclusively to the heme pocket of the expressed myoglobin relative to the native protein. The functional properties were examined by measuring the kinetics of CO binding after flash-photolysis. The kinetics of the expressed myoglobin were more heterogeneous than those of the native protein. Mild acid exposure of the ferric derivative of the recombinant protein resulted in a protein with "nativelike" spectroscopic properties and homogeneous CO binding kinetics. The heme pocket modifications observed in this recombinant myoglobin do not derive from inverted heme. In contrast, when native apomyoglobin is reconstituted with the heme in vitro, the heme pocket disorder could be attributed exclusively to 180 degrees rotation of the bound heme [La Mar, G. N., Toi, H., and Krishnamoorthi, R. (1984) J. Am. Chem. Soc. 106, 6395-6401; Light, W. R., Rohlfs, R. J., Palmer, G., and Olson, J. S. (1987) J. Biol. Chem. 262, 46-52]. We conclude that exposure to low pH decreases the affinity of globin for the heme and allows an extended conformational sampling or "soft refolding" to a nativelike conformation.

GABA(B) receptors mediate motility signals for migrating embryonic cortical cells.

During development, postmitotic neurons migrate from germinal regions into the cortical plate (cp), where lamination occurs. In rats, GABA is transiently expressed in the cp, near target destinations for migrating neurons. In vitro GABA stimulates neuronal motility, suggesting cp cells release GABA, which acts as a chemoattractant during corticogenesis. Pharmacological studies indicate GABA stimulates migration via GABA(B)-receptor (GABA(B)-R) activation. Using immunohistochemistry, RT-PCR and Western blotting, we examined embryonic cortical cell expression of GABA(B)-Rs in vivo. At E17, GABA(B)-R1(+) cells were identified in the ventricular zone (vz) and cp. RT-PCR and Western blotting demonstrated the presence of GABA(B)-R1a and GABA(B)-R1b mRNA and proteins. Using immuno- cytochemistry, GABA(B)-R expression was examined in vz and cp cell dissociates before and after migration to GABA in an in vitro chemotaxis assay. GABA-induced migration resulted in an increase of GABA(B)-R(+) cells in the migrated population. While <20% of each starting dissociate was GABA(B)-R(+), >70% of migrated cells were immunopositive. We used a microchemotaxis assay to analyze cp cell release of diffusible chemotropic factor(s). In vitro, cp dissociates induced vz cell migration in a cell density-dependent manner that was blocked by micromolar saclofen (a GABA(B)-R antagonist). HPLC demonstrated cp cells release micromolar levels of GABA and taurine in several hours. Micromolar levels of both molecules stimulated cell migration that was blocked by micromolar saclofen. Thus, migratory cortical cells express GABA(B)-Rs, cp cells release GABA and taurine, and both molecules stimulate cortical cell movement. Together these findings suggest GABA and/or taurine act as chemoattractants for neurons during rat cortical histogenesis via mechanisms involving GABA(B)-Rs.

Sustainability of coastal resource use in San Quintin, Mexico.

San Quintin, Mexico, provides a useful site for integrated analyses of material fluxes and socioeconomic constraints in a geographically isolated system. Natural resource utilization on the land is dominated by groundwater exploitation for cultivation of horticulture crops (primarily tomatoes). Irrigation exceeds water recharge minus export by a factor of 6. Resource utilization in the bay is dominated by oyster culture; food for the oysters is provided by tidal exchange of bay and ocean water. Consideration of oyster respiration and system respiration suggests that the present level of aquaculture is about 40% of the sustainable level. A "physical unsustainability index" (PhUI) was developed to measure the proportional departure of utilization of the most limiting resource for sustainability: 6 on land; 0.4 in the bay. Based on PhUI and measures of economic development, we conclude that aquaculture is more viable than agriculture.

Nitrate esters as nitric oxide donors: SS-nitrates.

[structure: see text]. The important biological secondary messenger NO can be generated from exogenous nitrovasodilators and NO donors. Nitrate esters are nitrovasodilators and NO mimetics, believed to be biotransformed to NO in vivo. On the basis of a mechanistic hypothesis, nitrates have been synthesized that release NO at significant rates in neutral aqueous solution in the presence only of added thiol. The novel masked beta-mercaptonitrates reported (SS-nitrates), provide information on possible sulfhydryl-dependent biotransformation mechanisms for nitrates in clinical use.

GABA expression dominates neuronal lineage progression in the embryonic rat neocortex and facilitates neurite outgrowth via GABA(A) autoreceptor/Cl- channels.

GABA emerges as a trophic signal during rat neocortical development in which it modulates proliferation of neuronal progenitors in the ventricular/subventricular zone (VZ/SVZ) and mediates radial migration of neurons from the VZ/SVZ to the cortical plate/subplate (CP/SP) region. In this study we investigated the role of GABA in the earliest phases of neuronal differentiation in the CP/SP. GABAergic-signaling components emerging during neuronal lineage progression were comprehensively characterized using flow cytometry and immunophenotyping together with physiological indicator dyes. During migration from the VZ/SVZ to the CP/SP, differentiating cortical neurons became predominantly GABAergic, and their dominant GABA(A) receptor subunit expression pattern changed from alpha4beta1gamma1 to alpha3beta3gamma2gamma3 coincident with an increasing potency of GABA on GABA(A) receptor-mediated depolarization. GABA(A) autoreceptor/Cl(-) channel activity in cultured CP/SP neurons dominated their baseline potential and indirectly their cytosolic Ca(2+) (Ca(2+)c) levels via Ca(2+) entry through L-type Ca(2+) channels. Block of this autocrine circuit at the level of GABA synthesis, GABA(A) receptor activation, intracellular Cl(-) ion homeostasis, or L-type Ca(2+) channels attenuated neurite outgrowth in most GABAergic CP/SP neurons. In the absence of autocrine GABAergic signaling, neuritogenesis could be preserved by depolarizing cells and elevating Ca(2+)c. These results reveal a morphogenic role for GABA during embryonic neocortical neuron development that involves GABA(A) autoreceptors and L-type Ca(2+) channels.

Synthetic peptide mimics of a predicted topographical interaction surface: the cytochrome P450 2B1 recognition domain for NADPH-cytochrome P450 reductase.

In order to identify the cytochrome P450-binding domain for NADPH-cytochrome P450 reductase, synthetic peptide mimics of predicted surface regions of rat cytochrome P450 2B 1 were constructed and evaluated for inhibition of the P450-reductase interaction. A peptide corresponding to residues 116-134, which includes the C helix, completely inhibited reductase-mediated benzphetamine demethylation by purified P450 2B1. Replacement of Arg-125 by Glu yielded a noninhibitory peptide, suggesting that this residue significantly contributes to the reductase-P450 interaction. Additional P450 peptides were prepared which correspond to combinations of regions distant in primary sequence, but predicted to be spatially proximate. A peptide derived from segments of the C and L helices was a more potent inhibitor than peptides derived from either segment alone. This topographically designed peptide not only inhibited P450 2B1 in its purified form, but also when membrane-bound in rat liver microsomes. The peptide also inhibited microsomal aryl hydrocarbon hydroxylase, aniline hydroxylase, and erythromycin demethylase activities derived from other P450s. These results indicate that the C and L helices contribute to a reductase-binding site common to multiple P450s, and present a peptide mimic for this region that is useful for inhibition of P450-mediated microsomal activities.