A carbon monoxide laser-based specialty optical fiber preform fabrication system.

We report the development of a specialty optical fiber preform fabrication system based on carbon monoxide (CO) laser heating. The laser heating is accomplished via a single-beam optical arrangement integrated into a rotating glass lathe. The CO laser output power and its beam quality are affected by absorption of the laser radiation by water vapor present in the surrounding air. This is addressed by construction of an enclosed and fully motorized system to enable preform processing in a dry air environment. The performance of the system is evaluated, and the ability to maintain a desired preform processing temperature is demonstrated. Relevant aspects of preform manufacturing, such as glass cutting, splicing, tapering, and overcladding, are described in detail. The process of using these aspects to fabricate optical fiber preforms made of highly dissimilar materials and of various core-to-cladding ratios is discussed. Specialty fibers drawn from these preforms exhibit low-loss and show good optical performance.

Temperature dynamics in silicon core fibers during CO2 laser processing.

Silicon core fibers are a promising candidate for optoelectronic and photonic applications. Fabrication and post-processing of those fibers is thus far done without precise knowledge of the processing temperatures. Here, a simple technique is presented that allows for in-situ temperature monitoring during thermal processing of silicon core fibers. The temperature was probed across the silicon melting point and cooling rates above 3500 °C s-1 were measured. The silicon core was found to be molten at a temperature of 1281 °C, more than 100 °C below the bulk silicon melting point. This is attributed to stress inbuilt to silicon core fibers during the fabrication process.

In-situ non-contact high-temperature measurement of an optical fiber up to the glass softening point.

The optical fiber itself can function as a partially reflecting concentric cavity interferometer when transversely probed by a focused laser beam. In this study, the thermal response of the fiber heated by a CO2-laser beam was characterized by monitoring the back-scattered interference pattern. Simultaneous measurement of the Bragg wavelength shift of an inscribed, high-temperature stable fiber Bragg grating allowed for calibration of the temperature-dependent phase response of the interferometer. The presented technique allows for in-situ non-contact temperature measurements up to the glass softening point.

EBV-associated post-transplant lymphoproliferative disorder following in vivo T-cell-depleted allogeneic transplantation: clinical features, viral load correlates and prognostic factors in the rituximab era.

EBV-associated post-transplant lymphoproliferative disease (PTLD) following Alemtuzumab-based allo-SCT is a relatively uncommon and challenging clinical problem but has not received detailed study in a large cohort. Quantitative-PCR (qPCR) monitoring for EBV reactivation post allo-SCT is now commonplace but its diagnostic and predictive value remains unclear. Sixty-nine patients with PTLD following Alemtuzumab-based allo-SCT were studied. Marked clinicopathological heterogeneity was evident; lymphadenopathy was frequently absent, whereas advanced extranodal disease was common. The median viral load at clinical presentation was 49 300 copies/mL (50-65 200 000 copies/mL) and, notably, 23% and 45% of cases, respectively, had 10 000 and 40 000 copies/mL. The overall response rate to rituximab as first-line therapy was 70%. For rituximab failures, chemotherapy was ineffectual but DLIs were successful. A four-parameter prognostic index predicted response to therapy (OR 0.30 (0.12-0.74); P=0.009] and PTLD mortality (hazard ratio (HR) 1.81 (1.12-2.93) P=0.02) on multivariate analysis. This is the largest detailed series of EBV-associated PTLD after allo-SCT. At clinical presentation, EBV-qPCR values are frequently below customary thresholds for pre-emptive therapy, challenging current paradigms for monitoring and intervention. A four-point score identifies a proportion of patients at risk of rituximab-refractory disease for whom alternative therapy is needed.

Equity, efficiency, uncertainty, and the mitigation of global climate change.

Policies to mitigate potential damages from global climate change impose costs on the current generation to provide benefits to future generations. This article examines how comparisons among three stylized policies-business-as-usual, mitigation of climate change, and compensation for climate damages-depend on social preferences with respect to risk and intertemporal equity. Also examined is the opportunity-cost criterion, which asserts that mitigation should not be chosen if its net present value is smaller than that of business-as-usual. Analysis reveals that the discount factor used to evaluate whether mitigation satisfies this criterion depends on preferences regarding risk and intertemporal inequality of consumption, and on the risk of the compensation policy. Risk aversion favors mitigation over business-as-usual. If society is neutral to inequality, risk aversion disfavors compensation, but if society is inequality averse, the effect of risk aversion on preferences between compensation and business-as-usual is ambiguous. Inequality aversion tends to favor business-as-usual over both alternative policies provided that, roughly speaking, the anticipated future improvements in welfare exceed the anticipated climate damages.

Disposition of valproic acid in a case of fatal intoxication.

The case history and toxicological findings of a fatal suicidal valproic acid overdose are presented. Valproic acid concentrations were determined in body tissues and fluids by gas-liquid chromatography (GLC) following both direct extraction and the method of standards addition and quantitative fluorescence polarization immunoassay. The quantitative results obtained by the three procedures were in good agreement. Qualitative identification of valproic acid as its methylated derivative was by ion-trap gas chromatography-mass spectrometry. Toxicological analysis by direct extraction GLC yielded the following valproate concentrations (mg/mL or mg/kg): blood, 1050; bile, 713; brain, 510; heart, 670; kidney, 1580; liver, 985; and vitreous, 516. A total of 15.1 g of valproate was recovered in the stomach contents. These findings far exceed those associated with valproate therapy and are similar to the limited valproate disposition data reported in prior fatal overdoses.

Fatal fentanyl intoxication following excessive transdermal application.

The case history and toxicological findings of a fatal fentanyl intoxication due to the application of multiple transdermal patches are presented. An 83 year-old white female with terminal cancer was found dead with three 100 mg/h fentanyl patches on her chest. The autopsy and subsequent histological studies revealed extensive areas of gastric carcinoma, a large atrial tumor, ulceration of esophagus, metastasis of peripancreatic lymph nodes and a recent surgical removal of part of the lower lobe of the left lung. Toxicological analysis by GC/MS yielded fentanyl concentrations of blood, 25 ng/mL; brain, 54 ng/g; heart 94 ng/g; kidney 69 ng/g; and liver 104 ng/g. The cause of death was determined to be fentanyl overdose and the manner of death was ruled undetermined as the investigation was unable to conclusively establish whether this was an accidental overdose, a suicide, an assisted suicide, or possible a homicide. This case demonstrates the need for caution in self-administration of transdermal fentanyl patches, in particular, the dangers inherent in the application of multiple patches which can result in the release of potentially toxic or lethal doses.

Fatal ephedrine intoxication.

A 28-year-old white female with a history of two prior suicide attempts was found dead in her home by her common law husband. Autopsy findings were unremarkable except for partially dissolved ephedrine tablets in the stomach contents. Quantitation of ephedrine was by gas chromatography/mass spectrometry (GC/MS) following liquid/liquid extraction from alkaline samples and pentafluoropropionic acid derivatization. Significant toxicological finding included ephedrine; blood, 11 mg/L; liver, 24 mg/kg; kidney, 14 mg/kg; brain, 8.9 mg/kg; and amitriptyline; blood, 0.33 mg/kg; liver 7.8 mg/kg. The ephedrine values found far exceed those associated with therapeutic administration and are consistent with the few reported cases of severe ephedrine intoxication. The cause of death was determined to be fatal ephedrine intoxication and manner of death suicide.

Functional expression of the nitrobenzylthioinosine-sensitive nucleoside transporter of human choriocarcinoma (BeWo) cells in isolated oocytes of Xenopus laevis.

Cultured human choriocarcinoma (BeWo) cells have previously been shown to exhibit, in comparison with other cultured cell types, elevated nitrobenzylthioinosine (NBMPR)-sensitive transport activity and large numbers (> 10(7)/cell) of high-affinity NBMPR-binding sites [Boumah, Hogue and Cass (1992) Biochem. J. 288, 987-996]. The present study investigates whether NBMPR-sensitive nucleoside transport activity could be induced in Xenopus laevis oocytes by microinjection of poly(A)+ RNA isolated from proliferating cultures of BeWo cells. Expression of uridine transport activity was assayed by comparing rates of uptake (22 degrees C) of 100 microM [3H]uridine by RNA-injected oocytes with uptake by water-injected or uninjected oocytes. A 4-fold stimulation of uridine uptake (2.0 versus 0.5 pmol/90 min per oocyte) was seen when oocytes were injected with 50 ng of BeWo poly(A)+ RNA, and this stimulation was abolished when the RNA-injected oocytes were assayed in the presence of 10 microM NBMPR. The expressed uridine transport activity in oocytes was highly sensitive to NBMPR, with a 50% reduction seen at 1.1 nM NBMPR (IC50 value). The IC50 value for NBMPR inhibition of uptake of 100 microM [3H]uridine by intact BeWo cells was 1.4 nM. Inward fluxes of [3H]uridine in the RNA-injected oocytes were greatly reduced in the presence of high concentrations (2 mM) of non-radioactive nucleosides (adenosine, thymidine, inosine) that are known permeants of NBMPR-sensitive nucleoside transport processes. These results establish that the abundance of NBMPR-sensitive nucleoside transporter mRNA in poly(A)+ RNA preparations from BeWo cells is sufficient to achieve production of functionally active transporter protein in Xenopus oocytes and that, when expressed in Xenopus oocytes, the transporters exhibit NBMPR sensitivity and permeant selectively similar to that of the native transporters.

Blows to the maternal abdomen causing fetal demise: report of three cases and a review of the literature.

Traumatic abruption results in 6% of third-trimester gravidas who are hit or kicked in the abdomen during assaults. Three cases are presented in which blows inflicted to the abdomen of pregnant women in their third trimester resulted in the death of the fetus due to abruptio placentae. Two cases were domestic altercations while one was a third-party criminal assault. In all cases the gravida herself escaped significant intra-abdominal injury, and external abdominal findings were minimal. The clinical signs were a history of loss of fetal movements shortly after the assault and loss of fetal heart tones within hours after the assault. One patient had vaginal bleeding; one had uterine contractions. In the cases of domestic abuse, both women initially gave false histories of how the injury occurred.

Functional expression of Na(+)-dependent nucleoside transport systems of rat intestine in isolated oocytes of Xenopus laevis. Demonstration that rat jejunum expresses the purine-selective system N1 (cif) and a second, novel system N3 having broad specificity for purine and pyrimidine nucleosides.

Isolated stage VI oocytes from Xenopus laevis expressed uridine transport activity after microinjection of mRNA from rat jejunum. Uridine uptake during 30 min (10 microM, 20 degrees C) by mRNA-injected oocytes reached 2.5 pmol/oocyte, compared with endogenous uptake by water-injected oocytes of about 0.05 pmol/oocyte. The expressed transport activity was 96% Na(+)-dependent, saturable (apparent Km = 15 microM) and inhibited by phloridzin (IC50 = 100 microM). Nucleoside inhibition studies resolved the expressed transport activity into two components: 1) a novel Na(+)-dependent system of broad purine and pyrimidine specificity that was inhibited by low concentrations of guanosine, inosine, adenosine, uridine, thymidine, and cytidine and 2) a Na(+)-dependent system of narrower specificity that was inhibited by low concentrations of guanosine, inosine, adenosine, and uridine and by high concentrations of thymidine and cytidine. The characteristics of the latter system are consistent with those of the Na(+)-dependent nucleoside transport system N1 (cif), previously identified in a number of cell types and tissues, including intestinal epithelia and cultured cells of intestinal origin. The broad specificity system, which was also detected in mRNA-injected oocytes using thymidine as permeant, has been given the provisional designation N3 to distinguish it from the previously described N1 (purine-selective) and N2 (pyrimidine-selective) Na(+)-linked nucleoside transporters. Rat jejunal transporters N1 and N3 were both expressed maximally by the same mRNA size fraction (1.6-3.0 kb, peak 2.3 kb).

Expression of rat intestinal L-lysine transport systems in isolated oocytes of Xenopus laevis.

The mechanisms by which cationic amino acids are transported across the intestinal epithelium are poorly understood. We show that isolated stage VI oocytes of Xenopus laevis can express lysine transport activity, which is due to the microinjection of mRNA from rat small intestine. L-Lysine transport activity (0.2 mM, 20 degrees C) reaches 400 pmol.oocyte-1.h-1, compared with a typical endogenous rate of 85 pmol.oocyte-1.h-1. Na(+)-dependence and amino acid inhibition studies resolved the expressed transport activity into three components: 1) a Na(+)-dependent transport system that can be inhibited by leucine with high affinity and also by alanine; 2) a Na(+)-independent system that can be inhibited by leucine with high affinity when Na+ is present, but this affinity is reduced in its absence; 3) a Na(+)-independent system that is inhibited by leucine with high affinity only when Na+ is present. Peak arginine-inhibitable lysine influx was found in a mRNA size fraction of 1.5-2.25 (median 2.0) kb.

Cation and harmaline interactions with Na(+)-independent dibasic amino acid transport system y+ in human erythrocytes and in erythrocytes from a primitive vertebrate the pacific hagfish (Eptatretus stouti).

Transport systems y+, asc and ASC exhibit dual interactions with dibasic and neutral amino acids. For conventional Na(+)-dependent neutral amino acid system ASC, side chain amino and guanido groups bind to the Na+ site on the transporter. The topographically equivalent recognition site on related system asc binds harmaline (a Na(+)-site inhibitor) with the same affinity as asc (apparent Ki range 1-4 mM), but exhibits no detectable affinity for Ha. Although also classified as Na(+)-independent, dibasic amino acid transport system y+ accepts neutral amino acids when Na+ or another acceptable cation is also present. This latter observation implies that the y+ translocation site binds Na+ and suggests possible functional and structural similarities with ASC/asc. In the present series of experiments with human erythrocytes, system y(+)-mediated lysine uptake (5 microM, 20 degrees C) was found to be 3-fold higher in isotonic sucrose medium than in normal 150 mM NaCl medium. This difference was not a secondary consequence of changes in membrane potential, but resulted from Na+ functioning as a competitive inhibitor of transport. Apparent Km and Vmax values for lysine transport at 20 degrees C were 15.2 microM and 183 mumol/l cells per h, respectively, in sucrose medium and 59.4 microM and 228 mumol/l cells per h in Na+ medium. Similar results were obtained with y+ in erythrocytes of a primitive vertebrate, the Pacific hagfish (Eptatretus stouti), indicating that Na(+)-inhibition is a general property of this class of amino acid transporter. At a permeant concentration of 5 microM, the IC50 value for Na(+)-inhibition of lysine uptake by human erythrocytes was 27 mM. Other inorganic and organic cations, including K+ and guanidinium+, also inhibited transport. In parallel with its actions on ASC/asc harmaline competitively inhibited lysine uptake by human cells in sucrose medium. As predicted from mutually competitive binding to the y+ translocation site, the presence of 150 mM Na+ increased the harmaline inhibition constant (Ki) from 0.23 mM in sucrose medium to 0.75 mM in NaCl medium. We interpret these observations as further evidence that y+, asc and ASC represent a family of closely related transporters with a common evolutionary origin.

Heart failure augments the cardiovascular and renal effects of neutral endopeptidase inhibition in rats.

We compared the cardiovascular and renal actions of the neutral endopeptidase (NEP) inhibitor, SQ 28,603, in normal rats and in rats with healed myocardial infarcts. The infarcted rats were studied in the conscious state 8 weeks after ligation of the left main coronary artery and 4 h after placement of cardiovascular and renal catheters. Infarct size was 39 +/- 1.2% of left ventricle circumference; right ventricle and lung weight to body weight ratios were twice those of normal rats. These postmortem values were shown to be associated with elevated left ventricular end diastolic pressure and high plasma atrial natriuretic peptide (ANP) concentration in separate groups of rats. SQ 28,603 at 100 mumol/kg intravenously (i.v.) caused urine volume and sodium excretion to increase by 79 +/- 11 microliters/min and 8.2 +/- 1.4 microEq/min, respectively, 20 min after injection in infarcted rats; these changes were significantly greater than those in normal rats (12 +/- 5 microliters/min and 1.6 microEq/min, respectively). Thoracic venous pressure decreased by 1.9 +/- 0.4 mm Hg 80 min after SQ 28,603 in infarcted rats and by only 0.1 +/- 0.1 mm Hg in normal rats (p less than 0.05 vs. infarcted rats). SQ 28,603 had no effects on mean arterial pressure (MAP), cardiac output (CO), or glomerular filtration rate (GFR). The observation that NEP inhibition has more pronounced effects in animals with high ambient ANP level than in those with normal ANP is consistent with previous studies in a variety of animal models and supports the concept that NEP inhibition potentiates endogenous ANP.

Increased lysine transport capacity in erythrocytes from patients with chronic renal failure.

1. The initial rate of L-lysine influx into erythrocytes from 13 patients with chronic renal failure has been measured using 14C-labelled lysine. Ten patients were on maintenance haemodialysis and three had never been dialysed. The results are compared with data obtained from 12 normal individuals. 2. The rate of lysine influx into washed cells from buffered saline containing 0.02-0.5 mmol of L-lysine/l has been calculated. The results can be fitted with a model in which influx has a single saturable component obeying Michaelis-Menten kinetics, and a linear non-saturable component. 3. In uraemic erythrocytes the saturable component had a mean Vmax. of 0.762 mmol h-1 litre-1 of cells (n = 13, SEM 0.072) and a mean Km of 68.2 mumol/l (SEM 5.7). These values in normal erythrocytes were 0.566 mmol h-1 litre-1 of cells (n = 12, SEM 0.033) and 70.5 mumol/l (SEM 4.1), respectively. The mean apparent diffusion constant (KD) for the linear component of influx was 0.224 h-1 (SEM 0.039) in uraemic cells and 0.178 h-1 (SEM 0.028) in normals. 4. The 35% increase in mean Vmax seen in uraemic erythrocytes was statistically significant (P = 0.02). A similar increase in Vmax. in uraemic cells compared with controls was seen in erythrocytes which were studied in zero-trans conditions after depletion of intracellular amino acids. The mean values of Km and KD were not significantly different in uraemia. The origins of this increased membrane transport capacity for lysine in uraemia are discussed.

Differentiation of angiotensin-converting enzyme (ACE) inhibitors by their selective inhibition of ACE in physiologically important target organs.

Seven ACE inhibitors were studied for possible differences in distribution to aorta, brain, heart, lung, and kidney after administration of single oral doses to spontaneously hypertensive rats (SHR). Doses, normalized for differences in inhibitory potency and molecular weight, were expected to deliver equivalent levels of ACE-inhibitory activity to the circulation, and this was confirmed by preliminary dose-response studies. The relative potencies of the active moieties of the seven drugs and the normalized oral doses used were: SQ 29,852 (1.0), 100 mg/kg; captopril (3.5), 30 mg/kg; enalapril (12), 20 mg/kg; fosinopril (13), 25 mg/kg; zofenopril (20), 10 mg/kg; lisinopril (24), 10 mg/kg; and ramipril (51), 5 mg/kg. In these ex vivo studies, ACE activities were determined fluorometrically in SHR sera and in uncentrifuged homogenates of the solid tissues at various times after oral dosing with the ACE inhibitors. As expected, the normalized oral doses of the seven inhibitors had equivalent effects on serum ACE. In lung, where ACE has a vascular endothelial localization, and in aorta, where ACE inhibition correlates with antihypertensive action, ramipril, lisinopril, and zofenopril were distinguished by the magnitude and duration (three to four days) of their effects. In the brain, where ACE may affect central regulation of blood pressure and participate in the degradation of certain neuropeptides, ramipril and enalapril had no effect; captopril and zofenopril had modest, short-lasting effects, and fosinopril, lisinopril, and SQ 29,852 had delayed but long-lasting inhibitory actions. In the kidney, where ACE inhibition may have positive or negative effects on renal function, ramipril and fosinopril could be distinguished by their weak actions, perhaps associated with biliary routes of excretion. In the heart, where ACE inhibitors may prevent ischemic damage to the myocardium, single oral doses of captopril, fosinopril, and particularly zofenopril produced striking and long-lasting inhibition, whereas equivalent doses of ramipril and enalapril produced barely detectable inhibition.