Dynamics of excited state proton transfer in nitro substituted 10-hydroxybenzo[h]quinolines.

The ground state tautomerism and excited state intramolecular proton transfer (ESIPT) of 10-hydroxybenzo[h]quinoline (HBQ) and its nitro derivatives, 7-nitrobenzo[h]quinolin-10-ol (2) and 7,9-dinitrobenzo[h]quinolin-10-ol (3), have been studied in acetonitrile using steady state as well as time dependent spectroscopy and quantum-chemical calculations. In addition to the enol form absorbance in the range 360-390 nm, the absorption spectra of 2 and 3 exhibit a red shifted band at ∼450 nm. Chemometric data processing, based on individual band decomposition, allowed us to estimate the position of the ground state enol-keto tautomeric equilibrium (ΔG values of 1.03 and 0.62 kcal mol-1 respectively for 2 and 3). The fluorescence stems from the keto form even if the enol form is optically excited as proven by the shape of the excitation spectra indicating that ESIPT takes place. The Stokes shift of the substituted compounds is substantially lower compared to HBQ, which follows from the fact that the substitution occurs in the formal cyclohexa-2,4-dienone moiety and leads to a decrease of the HOMO level of the keto tautomer. The pump-probe experiments show that in the nitro substituted HBQs 2 and 3 ESIPT occurs with a time constant of 0.89 ps and 0.68 ps, respectively. In both cases a mixture of the enol and proton transfer forms is optically excited. The enol form exhibits then the ESIPT and subsequently both fractions take the same relaxation path. We propose that in 2 and 3 the ESIPT path exhibits a potential energy barrier resulting in an incoherent rate governed process while in HBQ the ESIPT proceeds as a ballistic wavepacket motion along a path without significant barriers. The theoretical calculations (M06-2X/TZVP) confirm the existence of a barrier in the ground and excited states as result of the substitution.

4-Hydroxy-1-naphthaldehydes: proton transfer or deprotonation.

A series of naphthaldehydes, including a Mannich base, have been investigated by UV-Vis spectroscopy, NMR and theoretical methods to explore their potential tautomerism. In the case of 4-hydroxy-1-naphthaldehyde concentration dependent deprotonation has been detected in methanol and acetonitrile. For 4-hydroxy-3-(piperidin-1-ylmethyl)-1-naphthaldehyde (a Mannich base) an intramolecular proton transfer involving the OH group and the piperidine nitrogen occurs. In acetonitrile the equilibrium is predominantly at the OH-form, whereas in methanol the proton transferred tautomer is the preferred form. In chloroform and toluene, the OH form is completely dominant. Both 4-hydroxy-1-naphthaldehyde and 4-methoxy-1-naphthaldehyde (fixed enol form) show dimerization in the investigated solvents and the crystallographic data, obtained for the latter, confirm the existence of a cyclic dimer.

Enhanced recovery after colorectal surgery. Results from a prospective observational two-centre study.

BACKGROUND AND AIMS: Enhanced recovery after surgery (ERAS) has reduced the median hospital stay from 8-10 days with traditional peri-operative routines to four days. The aim of the present study was to introduce the principles of ERAS in our hospital and measure the effect on hospital stay, complications and quality of life after discharge from hospital. MATERIAL AND METHODS: 94 consecutive patients, 40 males, 54 females, median age 66 years, were included in a prospective non-randomised observational study at Haukeland University Hospital and Haugesund Hospital from October 2000 until February 2003. After a three-month preparation period, the principles of ERAS were implemented. The results were evaluated with questionnaires and by follow-ups 8-10 and 30 days after surgery. The results were compared to the results of colorectal surgery before introduction of accelerated recovery. RESULTS: 45 (48%) and 73 (78%) patients were discharged within three and five days after surgery with ERAS, compared to zero and seven (5%) patients with traditional recovery. The complication rate with ERAS was 31%, and the readmission rate was 15%. After one week, 57% had resumed their daily activities at home. After 30 days, 65% of the patients had resumed their normal and leisure activities. CONCLUSION: After a proper preparation period, ERAS principles may be implemented in surgical department, and is followed by a reduced median hospital stay and rapid return to normal daily activities for most patients after colorectal surgery.

Binding of topotecan to a nicked DNA oligomer in solution.

Topotecan (TPT) is in clinical use as an antitumor agent. It acts by binding to the covalent complex formed between nicked DNA and topoisomerase I, and inserts itself into the single-strand nick, thereby inhibiting the religation of the nick and acting as a poison. A crystal structure analysis of the ternary complex has shown how the drug binds (B. L. Staker, K. Hjerrild, M. D. Feese, C. A. Behnke, A. B. Burgin, L. Stewart, Proc. Natl. Acad. Sci. U.S.A., 2002, 99, 15 387-15 392), but has left a number of unanswered questions. Herein, we use NMR spectroscopy and molecular modeling to show that the solution structure of a complex of TPT with nicked natural DNA is similar, but not identical to the crystal conformation, and that other geometries are of very low population. We also show that the lactone form of TPT binds approximately 40 times more strongly than the ring-opened carboxylate.

Purification and structural analysis of a type III antifreeze protein from the european eelpout Zoarces viviparus.

It has recently been reported that the eelpout Zoarces viviparus synthesizes a family of antifreeze proteins (AFP) similar in sequence to type III AFPs. A method has been set up to separate these antifreeze proteins from blood serum of this teleost species. A total of nine proteins with antifreeze activity have been isolated, several to a purity suited for NMR experiments. One of the proteins, Zvafp13, has been subject to partial structure determination by NMR. 1D- and 2D-H NMR analyses were carried out. In the 1D-experiments it was observed that the protein contained 28 slow-exchanging amides, suggesting a compact structure. The 2D-experiments were utilized to assign observed signals to specific amino acids. From TOCSY- and NOESY-experiments 35 out of a total of 66 amino acids were assigned. The amide exchange pattern, protein primary sequence, chemical shifts and NOE-cross-peaks between amides and -protons in the -sheets suggest that Zvafp13 structurally resembles the recombinant type III AFP rQAE m1.1.

Personality traits and cancer survival: a Danish cohort study.

We conducted a population-based prospective cohort study in Denmark to investigate associations between the personality traits and cancer survival. Between 1976 and 1977, 1020 residents of the Copenhagen County completed a questionnaire eliciting information on personality traits and various health habits. The personality traits extraversion and neuroticism were measured using the short form of the Eysenck Personality Inventory. Follow-up in the Danish Cancer Registry for 1976-2002 revealed 189 incidents of primary cancer and follow-up for death from the date of the cancer diagnosis until 2005 revealed 82 deaths from all-cause in this group. A Cox proportional-hazards model was used to estimate the hazard ratios (HRs) of death from all-cause according to extraversion and neuroticism adjusting for potential confounding factors. A significant association was found between neuroticism and risk of death (HR, 2.3 (95% CI=1.1-4.7); Linear trend P=0.04) but not between extraversion and risk of death (HR, 0.9 (0.4-1.7); Linear trend P=0.34). Similar results were found when using cancer-related death. Stratification by gender revealed a strong positive association between neuroticism and the risk of death among women (Linear trend P=0.03). This study showed that neuroticism is negatively [corrected] associated with cancer survival. Further research on neuroticism and cancer survival is needed.

Profiles of a high-aspect-ratio grating determined by spectroscopic scatterometry and atomic-force microscopy.

The new and fast scatterometry method called optical diffraction microscopy is compared with atomic-force microscopy by use of cross-section scanning-electron microscope images as references. The sample is a high-aspect-ratio grating with a period of approximately 1000 nm. To allow the atomic-force microscope to track all parts of the grating profile, the grating is investigated at different tilt angles. The measured quantities of the profile include sidewall angle gamma (approximately 90 degrees), groove height h (approximately 2000 nm), and degree of filling f (approximately 40%). The two methods, which respond to quite different material properties, give consistent results within standard uncertainties of u(gamma)

Tautomerism of sterically hindered schiff bases. Deuterium isotope effects on 13C chemical shifts.

A series of sterically hindered o-hydroxy Schiff bases derived from o-hydroxyaceto- and benzophenones with very short intramolecular hydrogen bonds were described qualitative and quantitatively by deuterium isotope effects on (13)C chemical shift, (n)DeltaC(XD), (n)DeltaF(XD), (1)J(N,H) coupling constants, deltaNCH(3) chemical shifts and UV spectra. All the investigated compounds are found to be tautomeric. The tautomeric character is described by the signs of the deuterium isotope effects on the (13)C chemical shifts. For the 3-nitro-5-chloro derivatives at low temperature, the equilibrium is shifted almost fully toward the proton transferred form in CD(2)Cl(2). Intrinsic deuterium isotope effects on chemical shifts of these compounds as well as (1)J(N,H) coupling constants suggest that a zwitterionic resonance form is dominant for the proton transferred form. Structures, (1)H, (19)F, and (13)C chemical shifts, and deuterium isotope effects on (13)C chemical shifts are calculated by ab initio methods. The potential energy functions and the total deuterium isotope effects are calculated, and they are shown to correspond well with the experimental findings.

Comorbid personality disorder predicts suicide after major depression: a 10-year follow-up.

OBJECTIVE: To identify psychopathological predictors for suicide in a population of major depressed Diagnostic Statistical Manual-III (DSM-III) in-patients. METHOD: A total of 210 previous participants in multicentre antidepressant drug trials, carried out in a randomized double-blind design, were followed prospectively through a maximum of 10 years. Patients with a drug or alcohol abuse were excluded. The association between suicide and the pretreatment psychopathological profile was analysed using survival statistics. RESULTS: The suicide rate for non-melancholic depressed patients was significantly higher than for melancholic depressed patients. Comorbid personality disorder was independently associated with an increased suicide rate [relative hazard 3.41(CI: 1.15-10.10)]. CONCLUSION: The study indicates that the non-melancholic aspect of depression, and especially comorbid personality disorder, is associated with an increased suicidal vulnerability.

A lithium clinic for bipolar patients: 2-year outcome of the first 148 patients.

OBJECTIVE: This paper describes the outcome for the first 148 patients referred to a lithium clinic. METHOD: Two-year follow-up data from treatment charts are reported for all patients entering a lithium clinic in the study period. RESULTS: Lithium was given as the only mood stabilizer in 132 (89.2%) of the cases. Thirty-two (21.6%) patients were readmitted with a new affective disorder episode. Twenty-nine (19.6%) patients discontinued treatment prematurely. Variables predicting the recurrence of new affective disorder episodes as well as premature discontinuation of treatment were identified. CONCLUSION: The majority of bipolar patients received lithium for prophylaxis against recurrent affective disorder episodes. The outcome was moderate but comparable to the 30-40% improvement usually reported in follow-up studies of bipolar patients given long-term prophylactic treatment with lithium. Better long-term treatment results for bipolar patients depend on both the development of more effective mood stabilizing drugs or drug combinations and the improvement of patients' adherence to treatment.

1H NMR of compounds with low water solubility in the presence of erythrocytes: effects of emulsion phase separation.

When lipophilic compounds like diethyl phthalate (DEP) were added to water, two sets of resonances appeared in the 1H NMR spectrum, whereas when added in concentrations above approximately 3.5 mM to erythrocytes in a high haematocrit suspension, only one set of resonances was observed at the low-frequency position. The appearance of one set of resonances at lower frequency was found to be common to a series of lipophilic compounds in erythrocytes. The appearance of the NMR spectra is ascribed to the existence of an emulsion, meaning two different phases of a compound: a "droplet" (resonances to lower frequency) and aqueous dissolved phase (resonances to higher frequency). The absence of the resonances from the dissolved phase in erythrocyte solution is ascribed to exchange broadening. The absolute chemical shift of the compound in its "droplet" phase was also measured using a cylindrical/spherical microcell. This arrangement mimicked the geometry of the dissolved versus the phase-separated species and thus obviated the effect of a difference in magnetic susceptibility between the "droplet" solute and its aqueous solution. Factors influencing the formation of emulsion phases such as erythrocytes, haemoglobin and smaller proteins were investigated; they are found to be effective in the order given.

Sorption of polycyclic aromatic compounds to humic and fulvic acid HPLC column materials.

Two different humic acids (HA) and a fulvic acid (FA) were chemically immobilized to a high performance liquid chromatography (HPLC) silica column material. The immobilization was performed by binding amino groups in HA/FA to the free aldehyde group in glutardialdehyde attached to the silica gel. The HPLC column materials were compared with a blank column material made by applying the same procedure but without immobilizing HA or FA. Also, a column was made by binding carbonyl groups in HA to amino groups attached to the silica gel. The humic substances were selected to secure appropriate variation of their structural features. The retention factors of 45 polycyclic aromatic compounds (PAC) to the four columns were determined by HPLC. The advantage of the technique is a large number of compounds can easily be studied. The binding procedure does not appear to cause a drastic selection between the HA molecules. The k' values obtained for the two Aldrich HA columns agree in general reasonably. The retention or sorption of the compounds increased with the size of the PAC and the number of lipophilic substituents, but decreased when polar substituents were present. The PAC retention was much stronger to the two HA columns than to the FA and blank column, both for hydrophobic polycyclic aromatic hydrocarbons (PAH) and the polar PAC. Other factors impacting the PAC binding may be specific interactions with HA and the ionic strength of the aqueous phase. The technique has been applied to do direct determinations of Koc.

A nicked duplex decamer DNA with a PEG(6) tether.

A dumbbell double-stranded DNA decamer tethered with a hexaethylene glycol linker moiety (DDSDPEG), with a nick in the centre of one strand, has been synthesised. The standard NMR methods, E.COSY, TOCSY, NOESY and HMQC, were used to measure (1)H, (31)P and T:(1) spectral parameters. Molecular modelling using rMD-simulated annealing was used to compute the structure. Scalar couplings and dipolar contacts show that the molecule adopts a right-handed B-DNA helix in 38 mM phosphate buffer at pH 7. Its high melting temperature confirms the good base stacking and stability of the duplex. This is partly attributed to the presence of the PEG(6) linker at both ends of the duplex that restricts the dynamics of the stem pentamers and thus stabilises the oligonucleotide. The inspection of the global parameters shows that the linker does not distort the B-DNA geometry. The computed structure suggests that the presence of the nick is not disturbing the overall tertiary structure, base pair geometry or duplex base pairing to a substantial extent. The nick has, however, a noticeable impact on the local geometry at the nick site, indicated clearly by NMR analysis and reflected in the conformational parameters of the computed structure. The (1)H spectra also show much sharper resonances in the presence of K(+) indicating that conformational heterogeneity of DDSDPEG is reduced in the presence of potassium as compared to sodium or caesium ions. At the same time the (1)H resonances have longer T:(1) times. This parameter is suggested as a sensitive gauge of stabilisation.

Inositol phosphates from barley low-phytate grain mutants analysed by metal-dye detection HPLC and NMR.

Inositol phosphates from barley low-phytate grain mutants and their parent variety were analysed by metal-dye detection HPLC and NMR. Compound assignment was carried out by comparison of retention times using a chemical hydrolysate of phytate [Ins(1,2,3,4,5,6)P(6)] as a reference. Co-inciding retention times indicated the presence of phytate, D/L-Ins(1,2,3,4,5)P(5), Ins(1,2,3,4,6)P(5), D/L-(1,2,4,5,6)P(5), D/L-(1,2,3,4)P(4), D/L-Ins(1,2,5,6)P(4) and D/L-Ins(1,4,5,6)P(4) in PLP1B mutants as well as the parent variety. In grain extracts from mutant lines PLP1A, PLP2A and PLP3A unusual accumulations of D/L-Ins(1,3,4,5)P(4) were observed whereas phytate and the above-mentioned inositol phosphates were present in relatively small amounts. Assignment of D/L-Ins(1,3,4,5)P(4) was corroborated by precise co-chromatography with a commercial Ins(1,3,4,5)P(4) standard and by NMR spectroscopy. Analysis of inositol phosphates during grain development revealed accumulation of phytate and D/L-Ins(1,3,4,5)P(4), which suggested the tetrakisphosphate compound to be an intermediate of phytate synthesis. This assumption was strengthened further by phytate degradation assays showing that D/L-Ins(1,3,4,5)P(4) did not belong to the spectrum of degradation products generated by endogenous phytase activity. Metabolic scenarios leading to accumulation of D/L-Ins(1,3,4,5)P(4) in barley low-phytate mutants are discussed.

Stable ion study of regioisomeric carboxonium-substituted pyrenium ions: directive effects, charge delocalization mode, and conformational aspects.

Regioisomeric monoacyl- and monobenzoyl-substituted pyrenes are diprotonated in FSO(3)H.SbF(5) (4:1)/SO(2)ClF to give persistent carboxonium-pyrenium dications, whereas diacetyl- and dibenzoylpyrenes are diprotonated to give dicarboxonium dications. The resulting dications were studied by low-temperature NMR at 500 MHz. Conformational aspects of the carboxonium group in various regioisomers are addressed by a combination of NOED spectra and 2D-NMR and AM1 calculations. Charge delocalization pathways are gauged and compared on the basis of the magnitude of Deltadelta (13)C values.

[Repetitive transcranial magnetic stimulation. A method in the treatment of depressions]. / Repetitiv transkranial magnetisk stimulation. En metode til behandling af depressioner.

Transcranial magnetic stimulation (TMS) has been used as a diagnostic tool in neurology for more than a decade. Recent research indicates that it when applied repeatedly as repetitive transcranial magnetic stimulation (rTMS) has an antidepressant effect. RTMS is based on the principle of electro-magnetism. An electromagnetic coil placed on the scalp produces a time-varying magnetic field, which gives rise to a current in the proximity of the cerebral cortex. Unlike electroconvulsive therapy (ECT) rTMS does normally not give rise to epileptic seizures and does not require anaesthesia. This review covers a critical summary of the literature on the subject. The results of recent placebo-controlled, randomized trials are promising. However, further investigations are required, before rTMS can be fully integrated in the antidepressant therapeutic armamentarium.

[A survey of forensic psychiatric resources. Trends in the flow of patients to a new unit of forensic psychiatry, Sygehus Fyn, December 31, 1985 to December 31, 1995]. / En retspsykiatrisk ressourceopgørelse. Udviklingen i patientbelastningen i en nyetableret retspsykiatrisk afdeling, Sygehus Fyn, Middelfart, 31.12.1985-31.12.1995.

The study covered 163 patients sentenced to special measures. All of them were from the county of Funen, which is a representative part of Denmark regarding forensic psychiatry. On the cross-sectional date 31st December each year the total number of patients treated in the unit was the recorded. The number of patients sectioned to psychiatric treatment in hospital increased by 150% during the observation period. The recorded rise covered both offenders sentenced according to the section 16 and section 69 of the Danish penal code and reflected an increasing number of schizophrenic patients and to lesser-extent patients with personality disorder. The increasing number of beds occupied by forensic patients was in accordance with the development in the total number of patients treated in the unit.

[Psychiatric observations 1986-1993. Sygehus Fyn, Middelfart, the unit of forensic psychiatry]. / Mentalobservationer 1986-1993. Sygehus Fyn, Middelfart, retspsykiatrisk afdeling.

Two hundred and sixty psychiatric reports for law courts conducted between 1986-1993 at the Unit of Forensic Psychiatry, Middelfart were reviewed. The aim was to record a number of essential characteristics with special focus on the number of reports, demographic data, diagnosis and type of criminal act. All the offenders were inhabitants of the county of Funen, where about 50-60 reports for law courts were carried out each year during the period of investigation. Serious crimes (homicide, attempted suicide, violence, arson and rape), were mainly (74%) committed by offenders with personality disorder, of whom few were sentenced to special measures. However, a higher percentage than expected of individuals charged with arson were psychotic (30%) and mentally retarded (10%). Schizophrenics and individuals with other types of non-affective psychosis covered a higher percentage of persons charged with violence compared to manic-depressive individuals. Fifty percent of the offenders were chronic drug abusers.

13C NMR, X-ray, and differential scanning calorimetry investigations of truncated BPTI (aprotinin) analogues.

Truncated BPTI missing residues 1 and 2 is investigated together with variants thereof (Lys-15, Arg-17, and Arg-42 are replaced by other residues in various combinations). A comparison of the X-ray structure of BPTI with that of 3-58BPTI(K15R,R17A,R42S) shows only minor variations for the backbone, but the lack of salt bridge between the terminals and the lack of two N-terminal residues provide a structure open at one end. Comparisons of amide exchange rates show a dramatic increase for the most slowly exchanging NH protons of 3-58BPTI and the analogues thereof, as compared to those of the wild-type despite only small differences in the structures. The amide exchange rates for truncated analogues increase with decreasing TTEP (temperature top endothermic peak) values. On the basis of the known structural changes comparisons to 13C chemical shifts are made. 13C chemical shifts are assigned using the D-isotope and HMBC techniques. Excellent resolution is obtained in these 1D natural abundance spectra. 13C NMR chemical shifts are shown to be able to gauge structural changes. A comparison of 13C chemical shifts of WT BPTI (aprotinin) and 3-58BPTI reveals effects caused by (i) the removal of the salt bridge of the terminii, (ii) the charge of the N-terminus, and (iii) the increased mobility of the side chain of Tyr-23. Small effects are also seen due to a conformational change of the aromatic ring of Phe-4. Ring current shifts at 13C chemical shifts are calculated. The difference in the calculated ring current effects are small comparing the wild-type with 3-58BPTI(K15R,R17A,R42S) provided the structures are relaxed. Protein unfolding as a function of pH and temperature is studied by DSC. Unfolding occurs at lower temperature with N-terminally truncated analogues, and the maximum is shifted toward higher pH.