Trion-induced negative photoconductivity in monolayer MoS2.

Optical excitation typically enhances electrical conduction and low-frequency radiation absorption in semiconductors. We, however, observe a pronounced transient decrease of conductivity in doped monolayer molybdenum disulfide (MoS(2)), a two-dimensional (2D) semiconductor, using ultrafast optical-pump terahertz-probe spectroscopy. In particular, the conductivity is reduced to only 30% of its equilibrium value at high pump fluence. This anomalous phenomenon arises from the strong many-body interactions in the 2D system, where photoexcited electron-hole pairs join the doping-induced charges to form trions, bound states of two electrons and one hole. The resultant increase of the carrier effective mass substantially diminishes the conductivity.

Spin-induced optical conductivity in the spin-liquid candidate herbertsmithite.

We report a direct measurement of the low-frequency optical conductivity of large-area single-crystal herbertsmithite, a promising spin-liquid candidate material, by means of terahertz time-domain spectroscopy. In the spectral range below 1.4 THz, we observe a contribution to the real part of the in-plane conductivity σ(ab)(ω) from the spin degree of freedom. This spin-induced conductivity exhibits a power-law dependence on frequency σ(ab)(ω) ~ ω(ß) with ß ≈ 1.4. Our observation is consistent with the theoretically predicted low-frequency conductivity arising from an emergent gauge field of a gapless U(1) Dirac spin liquid.

Observation of a warped helical spin texture in Bi2Se3 from circular dichroism angle-resolved photoemission spectroscopy.

A differential coupling of topological surface states to left- versus right-circularly polarized light is the basis of many optospintronics applications of topological insulators. Here we report direct evidence of circular dichroism from the surface states of Bi(2)Se(3) using laser-based time-of-flight angle-resolved photoemission spectroscopy. By employing a novel sample rotational analysis, we resolve unusual modulations in the circular dichroism photoemission pattern as a function of both energy and momentum, which perfectly mimic the predicted but hitherto unobserved three-dimensional warped spin texture of the surface states. By developing a microscopic theory of photoemission from topological surface states, we show that this correlation is a natural consequence of spin-orbit coupling. These results suggest that our technique may be a powerful probe of the spin texture of spin-orbit coupled materials in general.

Estrogen replacement therapy: determinants of persistence with treatment.

OBJECTIVE: To evaluate the persistence rate for estrogen therapy and to identify its determinants. METHODS: From the Quebec health insurance database we chose a cohort of 4527 women 35 years and older who received social assistance and were new users of estrogen between January 1989 and December 1997. Incident use was defined by the absence of any dispensed prescription of estrogen in the 3 years before the index date (date of first dispensed prescription). We estimated the cumulative persistence rate of treatment by Kaplan-Meier failure time analysis and identified its determinants with the Cox proportional hazards model. RESULTS: From the initial cohort, 3395 women (75%) renewed their first dispensed prescription and 905 (20%) continued treatment after 4 years. The determinants measured at the index date and significantly associated with a better persistence rate (relative risk [RR]) were younger than 60 years (RR 1.15, 95% confidence interval [CI] 1.01, 1.30), low dosage (RR 1.49, 95% CI 1.32, 1.70), continuous progestin combination (RR 1.40, 95% CI 1.27, 1.54), and a gynecologist as the first prescribing physician (RR 1.15, 95% CI 1.03, 1.21). Also, coronary heart disease or at least one risk factor for it in the year before the index date was associated with a better persistence rate for estrogen replacement therapy (RR 1.15, 95% CI 1.05, 1.22). CONCLUSIONS: The persistence rate for estrogen therapy is poor, implying that few women take it long enough to benefit from it.

1,3-Butanediol-induced increases in ketone bodies and potentiation of CCl4 hepatotoxicity.

Evidence previously reported suggest that 1,3-butanediol (BD) enhances the hepatotoxic effect of a single small dose of carbon tetrachloride (CCl4) in a dose-related manner. The present study provides additional information concerning the quantitative relationship between the severity of the ketotic state produced by BD and the magnitude of the potentiation observed and emphasizes the use of ketone bodies (KB) to predict the potential hazard of the BD-CCl4 interaction. Liver damage was modulated in male Sprague-Dawley rats by varying the concentration of the BD solutions ingested prior to a CCl4 challenge (0.1 ml/kg, i.p.). These data were compared to ketone bodies in plasma, hepatic tissue and urine. BD produced a dose-dependent metabolic ketosis observable at dosages between 1.1 and 9.9 g/kg per day given for 7 days. Plasma and liver data correlated well together. Concomitantly, potentiation of the CCl4-induced liver injury was also dose-related for the same dosage range; the minimum effective dosage of BD for potentiation was estimated as 1.1 g/kg per day. The linear correlations between hepatic or plasma KB values and the indices of hepatic dysfunction (ALT, OCT) were highly significant. Using a semiquantitative method, a correlation was also found for the urinary KB data. These results suggest that plasma KB concentrations might be useful for predicting possible potentiation of the hepatonecrotic effect of CCl4 by BD.

Nasal airflow asymmetries and human performance.

Recent studies of the nasal cycle and forced uni-nostril breathing have demonstrated that integrated EEG amplitudes are greater over the hemisphere contralateral to the dominant (less congested) or unblocked nostril. Two experiments were designed to determine if asymmetries in nasal airflow, occurring naturally as a result of the nasal cycle or artificially as a result of forced uni-nostril breathing have consequences for human performance on verbal and spatial tasks that are preferentially performed by the left and right hemispheres respectively. A significant relationship was obtained between the pattern of nasal airflow with normal breathing and relative spatial vs verbal performance. Forced uni-nostril breathing had no effect on performance.

Effects of distance between objects and distance from the vertical axis on shape identity judgments.

In three experiments, we independently manipulated the angular disparity between objects to be compared and the angular distance between the central axis of the objects and the vertical axis in a mental rotation paradigm. There was a linear increase in reaction times that was attributable to both factors. This result held whether the objects were rotated (with respect to each other and to the upright) within the frontal-parallel plane (Experiment 1) or in depth (Experiment 2), although the effects of both factors were greater for objects rotated in depth than for objects rotated within the frontal-parallel plane (Experiment 3). In addition, the factors interacted when the subjects had to search for matching ends of the figures (Experiments 1 and 2), but they were additive when the ends that matched were evident (Experiment 3). These data may be interpreted to mean that subjects normalize or reference an object with respect to the vertical upright as well as compute the rotational transformations used to determine shape identity.

Sex differences in depression and the method of administering the Beck Depression Inventory.

Carried out four experiments in which male and female undergraduates (N = 384) completed the Beck Depression Inventory ( BDI ) under conditions ranging from absolute anonymity to a face-to-face interview. BDI interitem reliability was comparable across the two sexes and across different methods of test administration, and no evidence was found in any of the experiments or in all four combined that depression is more severe or common in females. We also found that for both sexes responses to the BDI did not vary with the sex of the examiner. It is suggested that sex differences in depression have more to do with the population sampled than with the method of administering tests such as the BDI . Indeed, responses to the BDI appear essentially unaffected by the method of administration.

Effect of glutathione depletion on the uptake of acrylonitrile vapors and on its irreversible association with tissue macromolecules.

Cellular GSH may influence the metabolism of the rodent brain and forestomach carcinogen acrylonitrile (ACN) and its subsequent binding to tissue macromolecules. To investigate the role of GSH in ACN metabolism and binding to macromolecules, we studied the effect of GSH depletion on the irreversible association of radiolabel with tissue macromolecules in male F-344 rats given a 4 mg/kg dose of [2,3-14C]ACN by inhalation. A combined phorone/buthionine sulfoximine treatment (300 mg/kg and 2 mmol/kg, respectively) was given 30 minutes prior to ACN exposure to deplete GSH. The uptake of ACN vapor by control rats was biphasic and characterized by a rapid phase lasting about 60 min and by a slower phase from 60 min to the end of exposure. The rate of uptake for both phases was linearly related to the initial concentration of ACN in the chamber. GSH depletion caused an increase in the rate of ACN uptake in both phases. It also caused a decrease in total radioactivity recovered in brain, stomach, liver, kidney, and blood and a concomitant decrease in the ACN-derived nondialyzable radioactivity in these organs. In control rats, accumulation of radiolabel was greatest in brain RNA, but no radioactivity was detected in DNA of any organ examined. In GSH-depleted rats, the radiolabel concentration was higher in brain RNA than in the liver or stomach RNA, but was also 50% lower than that observed in brain RNA of control rats. Urinary excretion of thiocyanate (SCN-), a metabolite derived from the epoxide pathway of ACN metabolism, was doubled in GSH-depleted rats. These results suggest that GSH might be involved in the distribution of ACN-derived reactive species and, therefore, might play a role in the binding of ACN-derived species to tissue macromolecules and nucleic acids.

Effect of glutathione depletion on the irreversible association of acrylonitrile with tissue macromolecules after oral administration to rats.

Binding of acrylonitrile and its reactive metabolites to tissue macromolecules, especially nucleic acids, may be responsible for its carcinogenicity in rats. Both acrylonitrile and its primary metabolite, 2-cyanoethylene oxide, also react with glutathione. To better understand the role of glutathione in the manifestation of acrylonitrile toxicity, the irreversible binding to tissue macromolecules was assessed in control and glutathione-depleted F-344 rats treated with a 4 mg/kg dose (po) of [2,3-14C]acrylonitrile. Glutathione was depleted in rat tissues by the administration of a combined intraperitoneal phorone/buthionine sulfoximine treatment (300 mg/kg and 2 mmol/kg, respectively) given 30 min prior to acrylonitrile administration. The amount of total radioactivity recovered from brain, stomach (target organs), liver, kidney, lung, and blood (nontarget organs) was similar between control and glutathione-depleted rats. However, stomach, lung, blood, and liver showed an increase in total radioactivity content after glutathione depletion by phorone/buthionine sulfoximine treatment. Glutathione depletion also caused an increase in acrylonitrile-derived non-dialysable radioactivity (MW greater than 3500 Da) in liver, lung, kidney, stomach, blood, and brain macromolecules between 6 and 24 hr after the dose. There was no organ-specific accumulation of radiolabel in RNA in control rats. However, an increase in the radiolabel associated with nucleic acids in the target organs but not in the nontarget organs was measured in glutathione-depleted rats. Urinary excretion of thiocyanate, a metabolite derived from the epoxide pathway, was also increased by 300% in glutathione-depleted rats. These results suggest that glutathione might play a role in the extent of 2-cyanoethylene oxide formation and in the distribution of the radiolabel among tissues.

Failure of phenobarbital or butanediol pretreatment to potentiate tienilic acid hepatotoxicity in vivo in the rat.

Tienilic acid, a uricosuric diuretic, has been associated with hepatocellular injury in humans as a low-incidence adverse reaction. This phenomenon suggests that a metabolic idiosyncrasy may be involved. In the present study, the effect of phenobarbital and 1,3-butanediol pretreatment, prior to tienilic acid challenge (50 or 100 mg/kg, i.v.) on rat hepatic function was studied in vivo. The following parameters were assessed: plasma alanine amino-transferase activity, plasma bilirubin concentration and bile flow. The results show that neither pretreatment would reveal that tienilic acid possesses hepatotoxic properties in the rat. The discrepancies between these results observed in vivo and those obtained by others in the isolated perfused rat liver suggest: a) that a metabolite formed (under normal conditions) via the phenobarbital- or butanediol-inducible forms of cytochrome P-450 is not a likely part of the hepatotoxic sequence of events; b) that the isolated perfused rat liver model in this case is not representative of the in vivo situation.

Metabolites and ketone body production following methyl n-butyl ketone exposure as possible indices of MnBK potentiation of carbon tetrachloride hepatotoxicity.

While the biotransformation of methyl n-butyl ketone (MnBK) in animals is well characterized, little is known about the quantitative relationship between hepatic and plasma MnBK concentrations. This study provides such information and emphasizes the usefulness of MnBK metabolite quantification, as well as MnBK-induced metabolic ketosis for the biological monitoring of MnBK exposure in rats. Elimination of MnBK was followed 24 hr after oral administration (0.95, 1.90, and 5.70 mmol/kg in corn oil) to male Sprague-Dawley rats. Two metabolites [2-hexanol (2HOL), and 2,5-hexanedione (2,5HD)] were also monitored and their kinetics determined. These data were compared to ketone body (KB) concentrations found in plasma and liver during the same period. Plasma concentrations of MnBK and 2,5HD correlated well with those in the liver. This was not the case for 2HOL. MnBK, 2HOL, and 2,5HD were no longer detected in plasma and liver 18 hr after dosing. Meanwhile, a marked ketosis was observed from 12 to 24 hr. This ketotic state was due to an increase in beta-hydroxybutyrate (BOHB), while acetoacetate remained at its basal levels. These data indicate that MnBK can induce ketosis in rats and suggest that the resulting BOHB might be used as an alternative biological monitor of MnBK exposures at high concentrations.

Potentiation of CCl4-induced liver injury by ketonic and ketogenic compounds: role of the CCl4 dose.

Potentiation of haloalkane hepatotoxicity by ketones and ketogenic agents is a well-known phenomenon. The importance of the CCl4 dosage in these combinations, however, has not been explored. Its influence was investigated in male Sprague-Dawley rats. Dose-effect curves for potentiation were generated using 1,3-butanediol, methyl n-butyl ketone or methyl isobutyl ketone as potentiation agents. Animals were orally treated with these compounds prior to a challenge of CCl4 (0 to 0.5 ml/kg, ip). Liver injury was assessed by monitoring plasma ALT activity and bilirubin concentrations after CCl4 treatment. The minimal effective dosage (MED) for each potentiator was used as the criterion of comparison for each combination. The MED values were determined from the plasma ALT data. Results showed that when the CCl4 dosage was increased from 0.01 to 0.10 ml/kg, the MED of each potentiator decreased 10-fold. For a given potentiator, the product of the CCl4 dosage (H, "hepatotoxicant") by the corresponding MED value (P, "potentiator") remained the same in this range of CCL4 dosages. The severity of the liver injury was similar. These findings suggest that a given level of liver injury induced by a ketone/haloalkane combination could be evaluated on the basis of the [P X H] product.

Metabolism of acrylonitrile to 2-cyanoethylene oxide in F-344 rat liver microsomes, lung microsomes, and lung cells.

The metabolism of acrylonitrile to the epoxide, 2-cyanoethylene oxide (ANO) was examined in rat liver microsomes, lung microsomes, and isolated enriched lung cell preparations. GC/high resolution MS was used to quantitate ANO in microsomal and cellular extracts by monitoring the fragment ion C2H3N (m/z 41.0265). The limit of detection was 0.05 pmol of ANO/0.5 microliter of standard solution, microsomal extract, or cellular extract injected onto the column, and the linear range of analysis was 0.05 to 12.5 pmol of ANO. Kinetic parameters of Vmax, V/K, and Km were calculated for microsomal ANO formation. Liver microsomes were quantitatively more active than lung microsomes on a mg of protein basis. The Vmax (pmol of ANO formed/min/mg of protein) was 666.61 for liver and 45.07 for lung microsomes. The V/K (pmol of ANO/min/mg of protein/microM) was 12.83 for liver and 0.02 for lung microsomes. The apparent Km was 51.93 microM and 1853.83 microM for liver and lung microsomes, respectively. When calculated as nmol of ANO formed/min/nmol of microsomal P-450, the Vmax for lung was equivalent to the Vmax for liver. ANO formation in the rat lung was cell specific. The rates of metabolism in the Clara cell-enriched fraction, the alveolar type II cell-enriched fraction, and the cell suspension were 2.55, 0.38, and 0.67 pmol of ANO formed/min/mg of protein, respectively. No metabolism was observed in the endothelial (small) cell-enriched fraction or in the alveolar macrophages. The results suggest that the lung contributes to the metabolism and disposition of inhaled acrylonitrile.

The physiological and histopathological response of dogs to exchange transfusion with polyethylene glycol-modified bovine hemoglobin (PEG-Hb).

The performance of polyethylene glycol-modified bovine hemoglobin (PEG-Hb) was evaluated in dogs following the replacement of 30% or 50% of their blood volume with PEG-Hb or lactated Ringer's solution (LRS). Dogs fully instrumented with catheters and blood pressure probes were transfused by simultaneous bleeding from the jugular vein and infusion of PEG-Hb or LRS via the cephalic vein. Animals were monitored for abnormal behavior and clinical signs for fourteen days. No mortalities, overt toxicity, changes in body weight, food consumption or ophthalmology, or discernable trends in hematology, blood chemistry coagulation, urinalysis or hemodynamic parameters that could be attributed to PEG-Hb were noted. Blood gas analyses were steady and within physiological ranges. Dose-related histopathological findings of vacuolated histiocytes in the femoral bone marrow, splenic parenchyma, the medulla of the mesenteric and mandibular lymph nodes, and vacuolated sinusoidal cells in the liver and the renal tubular epithelial cells were believed to be related to the phagocytosis and degradation of PEG-Hb by the reticulo-endothelial system. The maintenance of high oxygen levels in the circulation for the two-week treatment period, as well as the insignificant physiological and histopathological findings indicate that PEG-Hb could be a successful blood substitute.

Influence of food on the bioavailability of diltiazem and two of its metabolites following the administration of conventional tablets and slow-release capsules.

The influence of food on the bioavailability of a conventional tablet and of a slow-release capsule of diltiazem was investigated in two separate groups of 24 healthy volunteers in two open crossover studies. Diltiazem, as a conventional tablet (2 x 30 mg, first group) or as a slow-release capsule (120 mg SR, second group), was administered in a fasting condition and 30 min after a breakfast of 784 kcal (23 per cent proteins, 55 per cent lipids, and 22 per cent of carbohydrates). Multiple blood samples were withdrawn during the next 24 h and diltiazem, desmethyldiltiazem, and deacetyldiltiazem were assayed by HPLC. Neither the rate of absorption, assessed by the rate constant of absorption, the peak plasma concentration, and the time required to reach the peak, nor the amount of drug reaching the systemic circulation, assessed by the area under the plasma concentration time curve (AUC infinity) were influenced by food, and that independently of the formulation. Compared to the fasting experiment, food did not affect either the rate of formation or the AUC infinity of desmethyldiltiazem or deacetyldiltiazem. The results of the present study show that the relative bioavailability of the single dose of diltiazem administered as a slow-release capsule is significantly higher (69 per cent) than that estimated after the administration of diltiazem in a conventional tablet. It was concluded that food does not influence the bioavailability of diltiazem administered as a conventional tablet or as a slow-release formulation.

Multiple-dose propranolol administration does not influence the single dose pharmacokinetics of quinapril and its active metabolite (quinaprilat).

To evaluate the influence of multiple dose propranolol administration on the single dose pharmacokinetics of quinapril and its active metabolite, quinaprilat, a drug-drug interaction study was performed in ten healthy volunteers. Each subject received a single 20 mg quinapril oral dose on Days 1 and 16 of the study. Oral propranolol doses of 40 mg BID were initiated on Day 3, titrated gradually to 80 mg TID by Day 10, and continued at 80 mg TID through Day 17. Comparable mean quinapril pharmacokinetic parameter values as well as comparable mean quinaprilat pharmacokinetic parameter values determined following quinapril administered alone and following quinapril administered with propranolol, indicate that propranolol does not alter the single dose pharmacokinetics of quinapril or quinaprilat.