STM imaging, spectroscopy and manipulation of a self-assembled PTCDI monolayer on epitaxial graphene.

Scanning Tunneling Microscopy (STM), Scanning Tunneling Spectroscopy (STS), and manipulation studies were performed on an ordered self-assembled monolayer (SAM) of N,N'-bis(1-hexylheptyl)perylene-3,4:9,10-bis(dicarboximide) molecules on epitaxial graphene on hexagonal silicon carbide - SiC(0001). Four novel aspects of the molecular SAM on graphene are presented. Molecules adsorb in both armchair and zig-zag configurations, giving rise to six orientations of the molecular layer with respect to the underlying substrate. The interaction between the molecules and the graphene surface shifts the LUMO towards the Fermi level, inducing a charge transfer and the opening of a band gap in the graphene, with the LUMO inside. This decouples the LUMO from the surface rendering it invisible in the dI/dV spectroscopy. The HOMO only becomes visible at short tip-surface distances, as its energy lies within the band gap of the SiC substrate. Finally, the observed molecular defects are very particular, being composed exclusively of molecular dimers. These molecular dimers have a stronger interaction with the graphene than other molecules.

The paradox of an insulating contact between a chemisorbed molecule and a wide band gap semiconductor surface.

Controlling the intrinsic optical and electronic properties of a single molecule adsorbed on a surface requires electronic decoupling of some molecular orbitals from the surface states. Scanning tunneling microscopy experiments and density functional theory calculations are used to study a perylene molecule derivative (DHH-PTCDI), adsorbed on the clean 3 × 3 reconstructed wide band gap silicon carbide surface (SiC(0001)-3 × 3). We find that the LUMO of the adsorbed molecule is invisible in I(V) spectra due to the absence of any surface or bulk states and that the HOMO has a very low saturation current in I(z) spectra. These results present a paradox that the molecular orbitals are electronically isolated from the surface of the wide band gap semiconductor even though strong chemical bonds are formed.

Nonlocal activation of a bistable atom through a surface state charge-transfer process on Si(100)-(2×1):H.

The reversible hopping of a bistable atom on the Si(100)-(2×1):H surface is activated nonlocally by hole injection into Si-Si bond surface states with a low temperature (5 K) scanning tunneling microscope. In the contact region, at short distances (<1.5 nm) between the hole injection site and the bistable atom, the hopping yield of the bistable atom exhibits remarkable variations as a function of the hole injection site. It is explained by the density of state distribution along the silicon bond network that shows charge-transfer pathways between the injection sites and the bistable atom.

Theoretical simulations of the tip-induced configuration changes of the 4,4(')-diacetyl-p-terphenyl molecule chemisorbed on Si(001).

We have investigated from a theoretical point of view modifications of the 4,4(')-diacetyl-p-terphenyl molecule chemisorbed on Si(001) induced by the scanning tunneling microscope (STM). In previous experiments, these modifications were observed to occur preferentially at the end of the molecule after a +4.0 V voltage pulse and at the center after a +4.5 V voltage pulse. In the framework of ab initio simulations, we have realized a systematic energetic study of the dissociative chemisorption of one, two, or three phenyl rings of the substituted p-terphenyl molecule. Charge densities were then calculated for the investigated configurations and compared to the STM topographies. Before manipulation with the STM tip, the substituted p-terphenyl molecule is preferentially adsorbed without phenyl ring dissociation, allowing a partial rotation of the central phenyl ring. Our results show that the STM induced modifications observed at the end of the molecule might originate from the dissociation of two phenyl rings (one central and one external ring), while the modifications occurring at the central part of the molecule can be interpreted as a dissociation of the two external rings.

Mastering the molecular dynamics of a bistable molecule by single atom manipulation.

At low temperature (5 K), a single biphenyl molecule adsorbed on a Si(100) surface behaves as a bistable device which can be reversibly switched by electronic excitation with the scanning tunneling microscope tip. Density functional theory suggests that the biphenyl molecule is adsorbed with one dissociated hydrogen atom bonded to a neighbor surface silicon atom. By desorbing this hydrogen atom with the STM tip, the interaction of the molecule with the surface is modified such that it becomes transformed into a multistable device with four stable states having switching yields increased by almost 2 orders of magnitude.

Famotidine for infant gastro-oesophageal reflux: a multi-centre, randomized, placebo-controlled, withdrawal trial.

BACKGROUND: Gastro-oesophageal reflux afflicts up to 7% of all infants. Histamine-2 receptor antagonists are the most commonly prescribed medications for this disorder, but few controlled studies support this practice. AIM: To evaluate the safety and efficacy of famotidine for infant gastro-oesophageal reflux disease. METHODS: Thirty-five infants, 1.3-10.5 months of age, entered an 8-week, multi-centre, randomized, placebo-controlled, two-phase trial: first 4 weeks, observer-blind comparison of famotidine 0.5 mg/kg and famotidine 1.0 mg/kg; second 4 weeks, double-blind withdrawal comparison (safety and efficacy) of each dose with placebo. RESULTS: No serious adverse events were reported. Eleven patients had 16 non-serious, possibly drug-related adverse experiences: 6 patients with agitation or irritability (manifested as head-rubbing in two), 3 patients with somnolence, 2 patients with anorexia, 2 with headache, 1 patient with vomiting, 1 patient with hiccups, and 1 patient with candidiasis. Of the 35 infants, 27 completed Part I. There were significant score improvements for famotidine 0.5 mg/kg in regurgitation frequency (P = 0.04), and for famotidine 1.0 mg/kg in crying time (P = 0.027) and regurgitation frequency (P = 0.004) and volume (P = 0.01). Eight infants completed Part II on double-blind treatment, which was insufficient for meaningful comparisons. CONCLUSIONS: Histamine-2 receptor antagonists may cause agitation and headache in infants. A possibly efficacious famotidine dose for infants is 0.5 mg/kg (frequency adjusted for age). As 1.0 mg/kg may be more efficacious in some, the dosage may require individualization based on response. Further sizeable placebo-controlled evaluations of histamine-2 receptor antagonists in infants with gastro-oesophageal reflux disease are warranted.

Comparative efficacies of supportive and cognitive behavioral group therapies for young children who have been sexually abused and their nonoffending mothers.

The differential efficacies of supportive and cognitive behavioral group therapy models designed for young children (ages 2 to 8) who have experienced sexual abuse and their nonoffending mothers were compared. Forty-four mothers and their respective children participated in either supportive or cognitive behavioral therapy groups with the group format being randomly determined. Repeated measures MANOVAs indicated that compared to mothers who participated in the support groups, the mothers who participated in cognitive behavioral groups reported greater reductions at posttest in (a) their intrusive thoughts and (b) their negative parental emotional reactions regarding the sexual abuse. The children treated with cognitive behavioral therapy demonstrated greater improvement in their knowledge regarding body safety skills at posttest than did the children who received supportive therapy.

Efficient beam shaping of linear, high-power diode lasers by use of micro-optics.

We have designed, fabricated, and characterized a micro-optical beam-shaping device that is intended to optimize the coupling of an incoherent, linearly extended high-power diode laser into a multimode fiber. The device uses two aligned diffractive optical elements (DOEs) in combination with conventional optics. With a first prototype, we achieved an overall efficiency of 28%. Straightforward improvements, such as antireflective coatings and the use of gray-tone elements, are expected to lead to an efficiency of approximately 50%. The device is compact, and its fabrication is suited for mass production at low cost. This micro-optical device, used in a range-finder measurement system, will extend the measurement range. In addition to the direct laser writing technique, which was used for fabrication of the DOEs of the prototype, we applied two other technologies for the fabrication of the micro-optical elements and compared their performance. The technologies were multiple-projection photolithography in combination with reactive-ion etching in fused silica and high-energy beam-sensitive glass gray-tone lithography in photoresist. We found that refractive-type elements (gray tone) yield better efficiency for large deflection angles, whereas diffractive elements (multilevel or laser written) give intrinsically accurate deflection angles.

ADL performance of black Americans and white Americans on the assessment of motor and process skills.

OBJECTIVE: The purpose of this study was to examine whether the Assessment of Motor and Process Skills (AMPS), an assessment of personal and domestic activities of daily living (ADL) performance, can be used as a valid, nonbiased tool when assessing black Americans. METHOD: The participants were 466 blacks and 466 whites drawn from the entire sample of blacks and whites contained in the AMPS database who met the following criteria: (a) were 16 years of age and older; (b) had a notable history of a neurological, musculoskeletal, medical, developmental, cognitive, or psychiatric disorders or were healthy older persons; and (c) resided in North America. The participants were matched according to functional level, gender, diagnosis, and age. Examination for bias included between-group comparison of (a) item difficulty and task challenge hierarchies of the AMPS, (b) goodness-of-fit of the participants to the many-faceted Rasch (MFR) model, and (c) mean ADL motor and ADL process abilities. RESULTS: Both the item difficulty and the task challenge hierarchies remained stable between the two groups. On the ADL Motor scale, 95.3% of the black participants and 92.4% of the white participants demonstrated acceptable goodness-of-fit (MS < or = 1.4, z < 2) to the MFR model. On the ADL Process scale, 91.2% of the black participants and 90.1% of the white participants demonstrated acceptable goodness-of-fit. A significant difference, t(2, 930) = 3.56, p < .01, between the two groups was found in mean ADL process ability, but no significant difference, t(2, 930) = .69, p = .49) was found in mean ADL motor ability. CONCLUSION: The results of this study support the validity of the AMPS when applied to black Americans.

The gcvB gene encodes a small untranslated RNA involved in expression of the dipeptide and oligopeptide transport systems in Escherichia coli.

The Escherichia coli gcvB gene encodes a small RNA transcript that is not translated in vivo. Transcription from the gcvB promoter is activated by the GcvA protein and repressed by the GcvR protein, the transcriptional regulators of the gcvTHP operon encoding the enzymes of the glycine cleavage system. A strain carrying a chromosomal deletion of gcvB exhibits normal regulation of gcvTHP expression and glycine cleavage enzyme activity. However, this mutant has high constitutive synthesis of OppA and DppA, the periplasmic-binding protein components of the two major peptide transport systems normally repressed in cells growing in rich medium. The altered regulation of oppA and dppA was also demonstrated using oppA-phoA and dppA-lacZ gene fusions. Although the mechanism(s) involving gcvB in the repression of these two genes is not known, oppA regulation appears to be at the translational level, whereas dppA regulation occurs at the mRNA level.

The effects of a histidine residue on the C-terminal side of an asparaginyl residue on the rate of deamidation using model pentapeptides.

The effects of a histidine (His) residue located on the C-terminal side of an asparaginyl (Asn) residue on the rate of deamidation were studied using Gly-Gln-Asn-X-His pentapeptides. The rates of deamidation of the pentapeptides were determined at 37 degrees C (I = 0.5) as function of pH, buffer species, and buffer concentration. A capillary electrophoresis stability-indicating assay was developed to monitor simultaneously the disappearance of the starting peptides and the appearance of the degradation products. The rates of degradation of the peptides were pH dependent, increasing with pH, and followed apparent first-order kinetics. At pH values <6.5, Gly-Gln-Asn-His-His degraded faster than Gly-Gln-Asn-Gly-His, suggesting that the N+1 His residue is catalyzing the deamidation of the Asn residue. The His side chain at these pH values could function as a general acid catalyst, stabilizing the oxyanionic transition state of the cyclic imide intermediate formation. In contrast, at pH values >6.5, Gly-Gln-Asn-Gly-His deamidates more rapidly than Gly-Gln-Asn-His-His. The bulk of the side chain of the N+1 His residue versus the N+1 Gly residue apparently inhibits the flexibility of the peptide around the reaction site and, consequently, reduces the rate of the reaction. The significance of this steric hindrance effect of the N+1 His residue on the rate of deamidation was examined further. It was observed that at pH >6.0, Gly-Gln-Asn-His-His undergoes deamidation faster than Gly-Gln-Asn-Val-His. This observation indicated that, at the higher pH values, the N+1 His residue is also acting as a catalyst. Thus, at basic pH, the N+1 His residue influences the rate of deamidation via two opposing effects; that is, general base catalysis and steric interference. The pentapeptide Gly-Gln-Asn-His-His, in addition to undergoing the deamidation reaction, also undergoes bond cleavage at the Asn-His peptide bond. The enhanced rate of Asn-His peptide bond cleavage can be attributed to the general base behavior of the His residue, leading to increased nucleophilicity of the Asn side-chain amide group. Finally, we have shown that the His residue that is two amino acids removed from the Asn, the N+2 position, has little or no effect on the rate of deamidation.

Nocturnal intragastric acidity after over-the-counter doses of famotidine, ranitidine or placebo.

AIM: To compare the inhibitory effects of over-the-counter doses of famotidine or ranitidine on nocturnal intragastric acidity in a placebo-controlled study. METHODS: Twelve-hour intragastric acidity was measured simultaneously in 24 healthy subjects who ate a standard meal at 18.30 h and were dosed (at 19.30 h) with either famotidine 10 mg, ranitidine 75 mg or placebo in a balanced three-period crossover design. Five-millilitre aliquots of gastric juice were aspirated half-hourly 0-3 h post-dose, and then hourly until the end of the study. pH was measured with a glass electrode. Integrated pH (area under the curve (AUC) of the pH-time curve) was calculated for the intervals 0-12 h and 9-12 h post-dose. Statistical analysis was by ANOVA. RESULTS: In the 0-12 h post-dose period, when the 24 subjects were dosed with placebo, mean AUC was 2.12, increasing by 75% to 3.70 with famotidine (P < 0.001) and by 81% to 3.83 with ranitidine (P < 0.001). In the 9-12 h post-dose period, when the subjects were dosed with placebo, mean AUC was 2.13, increasing by 91% to 4.07 with famotidine (P < 0.001) and by 79% to 3.82 with ranitidine (P < 0.001). There was no significant difference between the pH-raising effects of famotidine and ranitidine in both periods. CONCLUSIONS: Famotidine and ranitidine in over-the-counter doses have a similar, sustained, effect on post-prandial nocturnal intragastric acidity in healthy subjects lasting up to 12 h after oral dosing.

Prevention of heartburn relapse by low-dose famotidine: a test meal model for duration of symptom control.

AIM: To establish whether patients taking famotidine 10 mg to treat an episode of heartburn were protected from a recurrence of symptoms after a subsequent test meal. METHODS: Frequent heartburn sufferers (n = 366) were randomized to receive double blind treatment with famotidine 10 mg or 2 x 250 mg chewable alginate tablets within 30 min of a spontaneous episode of heartburn. After 4 h, patients with no or slight residual symptoms consumed a meal likely to induce heartburn. Over the next 4 h patients recorded the severity of heartburn and any consumption of 'rescue' antacids. At the end of this time they rated the global efficacy of their treatment in controlling meal-induced symptoms. RESULTS: Study groups were well matched for all baseline characteristics. Of the 366 randomized patients, 276 took study medication and data from 269 patients (132 famotidine, 137 alginate) were analysed for efficacy. Compared to the alginate control group famotidine treated patients reported better global efficacy following the test meal (P < 0.001; relative odds for a more favourable response: 2.26 [95% CI: 1.45-3.53]). Fewer patients receiving famotidine resorted to antacid rescue (P = 0.038; relative odds for a more favourable response: 2.24 [95% CI: 1.04-4.79]) and peak heartburn was significantly less severe with famotidine treatment (P < 0.001: relative odds for a more favourable response: 2.90 [95% CI: 1.85-4.53]). Eleven famotidine-treated patients (8%) and 13 alginate patients (9%) reported adverse events. CONCLUSION: Compared to patients receiving an alginate preparation, patients self medicating with famotidine 10 mg for heartburn are better protected against a recurrence of their symptoms when they next eat. This suggests that the duration of acid control (9 h) previously demonstrated with this dose translates into a similar duration of measurable symptom control during the day.

Early and late effects of low-dose famotidine, ranitidine or placebo on pentagastrin-stimulated gastric acid secretion in man.

BACKGROUND: There are no published comparative studies on the effect of low-dose H2-antagonists on pentagastrin-stimulated gastric acid secretion. METHODS: Twenty-four healthy subjects were dosed with either famotidine 10 mg, ranitidine 75 mg or placebo in a balanced three-period cross-over design. The subjects were studied in groups of 12, simultaneously, under identical controlled environmental conditions. Gastric juice was aspirated in 15-min aliquots during sub-maximal (0.6 microgram.h/kg) intravenous pentagastrin stimulation in the third and fourth hours (early period) and the eighth and ninth hours (late period) after oral dosing. The hydrogen ion (H+) content of gastric juice was measured ex vivo, by titrating to pH7 known volumes of gastric aspirate against 0.1 M sodium hydroxide, using a versatile microprocessor-controlled auto-titration unit. Gastric acid output during the period of interest was calculated by adding the hydrogen ion content of 15-min aliquots collected during that period. The geometric mean of the cumulative pentagastrin-stimulated gastric acid output during the early and late periods was determined for the subjects dosed with either famotidine, ranitidine or placebo. Comparisons were performed by ANOVA. RESULTS: During the early period (2-4 h post-dose), When the subjects were given placebo, mean gastric acid output was 46.6 mmol, decreasing by 76% to 11.3 mmol (P < 0.001) when treated with famotidine and by 76% to 11.1 mmol (P < 0.001) when treated with ranitidine. During the late period (7-9 h post-dose), when the subjects were dosed with placebo, mean gastric acid output was 41.2 mmol, decreasing by 38% to 25.7 mmol (P < 0.001) when treated with famotidine and by 27% to 30.0 mmol (P = 0.007) when treated with ranitidine. The difference between the inhibitory effects of famotidine and ranitidine on gastric acid output were non-significant during either period. CONCLUSIONS: Low-dose famotidine and ranitidine, intended for over-the-counter use, inhibit stimulated gastric acid secretion profoundly in the third and fourth hours after an oral dose. Modest effects are still detectable up to 9 h after dosing.

Low-dose famotidine and ranitidine as single post-prandial doses: a three-period placebo-controlled comparative trial.

BACKGROUND: Low-dose H2-receptor antagonists are available without prescription for the self-medication of dyspepsia. METHODS: To investigate the relative abilities of low doses of famotidine and ranitidine to raise intragastric pH after a single post-prandial evening dose, 25 healthy volunteers completed a three-period cross-over trial of famotidine 10 mg, ranitidine elixir 75 mg and placebo. A standard meal was given at 18.30 h and drug or placebo at 19.30 h to subjects fasted for 5.5 h. Intragastric pH was recorded with nasogastric electrodes from 18.00 to 07.30 h by GastrograpH II recorder. RESULTS: The geometric mean area under the pH-time curve for the 5-9 h post-dose period was 1.49 pH units/h following placebo, 3.43 pH units/h following famotidine 10 mg (agent/placebo ratio 2.3; P < 0.001, ANOVA) and 2.6 pH units/h following ranitidine 75 mg (1.75; P < 0.001). The geometric mean area under the pH-time curve ratio of famotidine 10 mg to ranitidine 75 mg was 1.32 (P < 0.016). Median pH over the 5-9 h period was 1.1 following placebo, 2.7 following famotidine 10 mg (P < 0.05 by comparison with placebo) and 1.9 following ranitidine 75 mg (P < 0.05); comparison of median pH showed no significant difference between the active drugs. The percentage of pH values greater than 3.0 for the period 0-12 h post-dose was 9.7% following placebo, 30.0% following famotidine 10 mg (P < 0.05) and 24.9% following ranitidine 75 mg (P < 0.05); there was no significant difference between the active drugs. CONCLUSIONS: We conclude that both famotidine 10 mg and ranitidine 75 mg significantly raise intragastric pH when given as single post-prandial doses. Famotidine 10 mg may have a greater effect than ranitidine elixir 75 mg over the 5-9-h period after dosing.

Novel oral medication delivery system for famotidine.

A famotidine wafer that rapidly disperses on the tongue without water is a novel alternative to other histamine2 (H2)-antagonist dosage forms. Benefits associated with such a dosage form include convenience and potentially improved compliance for patients who dislike or have difficulty taking tablets and capsules. This report describes the research of three studies on the famotidine wafer dosage form. In the first trial, the bioequivalence and tolerability of the new 40-mg famotidine wafer and the marketed 40-mg famotidine tablet were studied in a 2-period crossover study (n = 18). The two formulations were bioequivalent as assessed by area under the plasma concentration versus time curve and maximum plasma concentration of famotidine. The plasma concentration of famotidine associated with 50% inhibition of pentagastrin stimulated gastric acid secretion (EC50; 10 ng/mL) was attained on average within 0.5 hours post-dose for the wafer and tablet. In a second trial, the tolerability of the famotidine 20-mg and 40-mg wafers or placebo given twice daily (bid) for 14 days were evaluated (n = 192). Both wafer strengths were well and equally tolerated. In a third trial of 450 subjects, the 40-mg wafer was preferred over tablets by 75% of the subjects, when they were asked to consider the method of administration and flavor. When used as an alternative to tablets and other conventional dosage forms, the wafers have the potential therapeutic benefit of improved compliance. It is concluded that similar systemic exposure, excellent tolerability, palatability, and preference make the famotidine wafer a clinically acceptable and convenient dosage from for patients on H2-antagonist therapy.

Effects of treatment with lovastatin and pravastatin on daytime cognitive performance.

The HMG-CoA reductase inhibitors lovastatin and pravastatin have both proven to be effective and well tolerated in the treatment of hypercholesterolemia. To evaluate whether lovastatin or pravastatin might affect daytime cognitive function, a double-blind, placebo-controlled, two-period, incomplete block, crossover study was performed in 36 patients (24 per treatment) with primary hypercholesterolemia. Patients received placebo, lovastatin (40 mg), or pravastatin (40 mg) for 4 weeks. Following a 1-week washout period, patients were crossed over to either lovastatin, pravastatin, or placebo for an additional 4 weeks. Mental performance tests (digit symbol substitution, choice reaction time, auditory vigilance, selective reminding word recall, finger tapping), visual analogue rating scales, and the Profile of Mood States were administered before test drug administration and after 2 and 4 weeks of each treatment. After 4 weeks, no statistically significant differences between treatments in changes from baseline were observed on any parameter with the exception of digit symbol substitution, for which lovastatin and pravastatin were both significantly better than placebo but did not differ from each other. Low-density lipoprotein cholesterol was reduced 38% by lovastatin and 30% by pravastatin. In summary, neither of these chemically distinct HMG-CoA reductase inhibitors impaired daytime cognitive performance after 4 weeks of treatment in patients with primary hypercholesterolemia.

Effects of treatment with simvastatin and pravastatin on cognitive function in patients with hypercholesterolaemia.

The effects of equi-efficacious doses of the cholesterol-lowering drugs simvastatin (20 mg day-1) and pravastatin (40 mg day-1) on tests of cognitive function were investigated in a double-blind, placebo-controlled, 2-period (4 weeks per period), incomplete block, crossover study of 36 patients (24 per treatment) with hypercholesterolaemia. After 4 weeks neither of the active treatments differed significantly from placebo on any cognitive measure.

Characterization of the gcv control region from Escherichia coli.

We constructed a set of deletions upstream of the gcv promoter and analyzed the effects of the deletions on expression of a gcvT-lacZ gene fusion. A deletion that ends at position -313 upstream of the transcription initiation site (+1) results in reduced levels of gcvT-lacZ expression, but the fusion is still inducible by glycine and repressible by purines. A deletion that ends at position -169 results in loss of both GcvA- and Lrp-mediated activation of the gcvT-lacZ fusion. The endpoints of delta -313 and delta -169 also define a site that down-regulates gcvT-lacZ expression two- to threefold. A deletion that ends at position -89 upstream from the transcription initiation site still shows PurR-mediated repression, suggesting that PurR-mediated repression is not by direct interference with the GcvA- and Lrp-mediated regulatory mechanism(s). Gel mobility shift assays and DNase I footprinting showed that Lrp protein binds to multiple sites upstream of the gcv promoter, from about bp -92 to bp -229. The results suggest that the gcv regulatory region is complex, with numerous cis-acting sites that are required for normal gcv expression.