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.

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.

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.

3,4-Diphenyl-1H-pyrazole-1-propanamine antidepressants.

A small series of compounds is described in which a narrow SAR has identified N,N-dimethyl-3,4-diphenyl-1H-pyrazole-1-propanamine, 3, as a potential antidepressant with reduced side effects. The isomeric N,N-dimethyl-4,5-diphenyl-1H-pyrazole-1-propanamine was completely inactive in the primary antidepressant screens. Compounds were synthesized by Michael addition of acrylonitrile to diphenylpyrazole followed by reductive alkylation of the resultant diphenylpyrazolepropionitriles. Compound 3 was equipotent with imipramine in standard antidepressant assays in animals but showed no significant anticholinergic action and did not antagonize the antihypertensive effects of clonidine and guanethidine.

Gene technology-based antimetabolite design: the use of an in vitro protein expression system to facilitate antimetabolite design for virally-induced human diseases and malignant conditions.

A precondition for the chemotherapeutic treatment of a variety of virally-induced human diseases and malignant conditions is a highly selective interaction of the drug molecule to be used with it's biological target. To ensure the development of novel, effective drugs, it is essential that the biological target is well characterised with regard to it's structure and activity. Such characterisation relies upon adequate amounts of pure target being available. One of the most important enzymatic importers for antimetabolites is the enzyme thymidine kinase. In this article an in vitro protein expression system is described which facilitates the production of milligram amounts of pure and biologically active thymidine kinase, from a number of important biological sources. Results have shown that the in vitro produced enzyme has the exact biochemical propeties of the in vivo enzyme. Thus the in vitro protein expression system is an ideal vechicle to facilitate an in depth investigation of the enzyme's biological properties.

Correction of post-traumatic flexion contracture of the elbow by anterior capsulotomy.

Despite prolonged conservative therapy, including splinting, bracing, and supervised exercise programs, significant flexion contracture of the elbow after local trauma may remain both a functional and a cosmetic impairment. We studied the cases of fifteen patients who underwent a relatively limited surgical procedure consisting of anterior capsulotomy of the elbow without tenotomy of the biceps tendon or myotomy of the brachialis muscle. The mean preoperative flexion deformity of 48 degrees was reduced to a mean postoperative deformity of 19 degrees (a 61 per cent improvement). Two groups of patients were identified. Eleven patients who did not have significant preoperative evidence of intra-articular degenerative (post-traumatic) changes in the joint achieved a 65 per cent improvement in extension, with one patient having continued pain with vigorous activity. Four patients who had significant preoperative post-traumatic arthrosis achieved a 50 per cent improvement in extension; however, three of these four patients continued to have significant pain. Limited anterior capsulotomy is a safe and effective means of decreasing post-traumatic flexion contracture of the elbow in properly selected patients. Better overall results are obtained in elbows without significant post-traumatic arthrosis.

Hydrogen bonding monitored by deuterium isotope effects on carbonyl 13C chemical shift in BPTI: intra-residue hydrogen bonds in antiparallel beta-sheet.

Deuterium isotope effects on carbonyl 13C magnetic shielding were measured for the backbone carbonyl groups in BPTI (basic pancreatic trypsin inhibitor), and interpreted as a measure of hydrogen bond energies. The effects originate from peptide amide proton deuterium substitution and were observed on carbonyl carbons separated by two or three covalent bonds from the amide H/D. Two-bond isotope effects depend on the energy of the hydrogen bond donated by NH/D. Calibration of the effect with model compound data leads to hydrogen bond enthalpies less than 4.7 kcal/mol. Isotope effects over three bonds from the amide H/D to the carbonyl carbon of the same amino acid residue are observed for seven carbonyl resonances in BPTI. The three-bond isotope effects are highly related to the various backbone conformations. The largest effects are observed for residues with an approximate syn- periplanar conformation of the H-N-C alpha-C = O atoms, as realized for many residues in the BPTI antiparallel beta-sheet. The residues that show measurable three-bond effects have unusually short distances between H and O. The size of this effect decreases rapidly with increased O..H distance in the open five-membered ring. This observation suggests appreciable interactions in these rings.

Effects of N-terminal extension peptides on the structure and stability of bovine pancreatic trypsin inhibitor studied by 1H n.m.r.

Four N-terminal extended species of the wild-type bovine pancreatic trypsin inhibitor (WT-BPTI), Arg-BPTI (1-BPTI), Met-Glu-Ala-Glu-BPTI (4-BPTI), Ser-Ile-Glu-Gly-Arg-BPTI (5-BPTI) and Gly-Ser-Ile-Glu-Gly-Arg-BPTI (6-BPTI) have been studied by 1H n.m.r. The overall structure of the protein is largely unaffected by the addition of extension peptides. pH titration effects on the C-terminal Ala 58 H beta chemical shift indicate that the structure of 1-BPTI at neutral pH is very similar to that of the WT protein, with a salt bridge between the main chain terminal charges. A salt bridge interaction is prevented by addition of the longer extension peptides. Temperature stabilities are measured by high temperature hydrogen isotope exchange and by microcalorimetry. The stability of 1-BPTI is equal to that of WT-BPTI. A slight decrease in stability is observed for longer extensions, following the order WT-BPTI = 1-BPTI < 5-BPTI = 6-BPTI < 4-BPTI. Small changes in chemical shift are observed for 30 invariant resonances in 4-, 5- and 6-BPTI and for a subset of this group in 1-BPTI. These protons are distributed over about half of the BPTI molecule. The size of the chemical shift changes for many resonances follow the same ranking as the temperature stability. The chemical shift effects are attributed to charge and dielectric effects from extension peptides that probably share a common orientation on the surface of BPTI.

Low cost auxiliary system for broadband NMR on strongly magnetic systems.

A low cost auxiliary system consisting of He cryostat, superconducting magnet, and sample holder assembly with field probe has been constructed. The system meets the requirements of NMR on strongly paramagnetic or ordered magnetic materials, which are accurate temperature settings over a wide range, high NMR frequencies, high and accurate magnetic fields of moderate homogeneity, and exact crystal orientations in the fields. The following values are achieved: The temperature setting in the range 1.7-400 K varies less than 0.5% for 10 min, which is the typical recording time of a spectrum. The distance from the NMR oscillator to the sample is only 55 cm (wavelength of approximately 550 MHz radiation), giving a tolerable He evaporation rate of 0.35 l/h. The maximum field at 4.2 K is 43.2 kG, which can be measured with an accuracy better than +/-100 ppm. The homogeneity at maximum field over a central sphere 8 mm in diameter is 5 G. The uncertainty on the crystal orientation in the field is +/-1/2 degree.

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.

Leslie matrix models.

A review of the Leslie matrix model theory and its literature 1941-1987 is presented. The point of view is that of a mathematician who focuses on the parts of the theory which are relevant to demography. Works of a decidedly applied nature are not dealt with.

[Spontaneous seizures improve severe dementia conditions. Dementia contra depression-induced pseudodementia and electric stimulation therapy of depressed patients with epilepsy]. / Spontane kramper bedrer svaer demenstilstand. Demens kontra depressionsbetinget pseudodemens og elektrostimulationsbehandling af deprimerede patienter med epilepsi.

On the basis of two case reports, the differential diagnostic difficulties between pseudodementia conditioned by depression and genuine dementia are discussed and the particular conditions present in connection with electroconvulsive therapy (ECT) in patients with reduced seizure thresholds. Differentiation between genuine and dementia conditioned by depression must be made mainly on the basis of the clinical picture, particularly the temporal course of the condition. Every condition of dementia involves the possibility of an underlying depression and antidepressive treatment should be offered on wide indications. In this connection, ECT treatment may be the most effective and mildest form of therapy. Epilepsy does not counterindicate ECT treatment which, on the other hand, has an anticonvulsive effect. Occurrence of spontaneous seizures in connection with ECT treatment does not necessarily indicate withdrawal of treatment which may be continued provided certain prerequisites are observed.

[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.

[Mortality--suicide and natural death--among depressed patients. Relation to type of depression]. / Dødelighed--selvmord og naturlig død--blandt deprimerede patienter. Relationen til depressionstype.

A total of 219 inpatients with a DSM-III diagnosis of major depression, (150 women and 69 men), were followed prospectively for three to ten years and mortality was recorded. The patients were previous participants in psychopharmacological multicentre trials, which were carried out for the purpose of comparing the antidepressant effect of newer selective serotonin reuptake inhibitors (SSRI), citalopram and paroxetine, with that of the tricyclic antidepressant drug, clomipramine. Diagnostic classification according to the Newcastle-I Scale into endogenous and nonendogenous depression was performed. The observed mortality was significantly greater than that expected. The increased mortality was essentially due to suicides and mainly found among women. Patients scored as being nonendogenously depressed had a significantly higher suicide rate than endogenously depressed patients. The excess number of suicides in the nonendogenous group largely occurred within the first year of observation. No association was found between response to the antidepressant treatment in the trial and the suicide risk during the first three years of observation.

[Educational requirements of younger psychiatrists]. / Yngre psykiateres uddannelsesønsker.

In order to define the requirements junior medical staff in postgraduate psychiatric training would wish to make for future postgraduate training in adult psychiatry, a questionnaire with 66 questions was sent in June 1990 to postgraduate trainees at all departments of child psychiatry and adult psychiatry in the country. Response was anonymous. The article deals with the responses from 264 persons either intending to undergo specialist training in adult psychiatry or having already completed it. Sixty-four percent stated a need for better individual clinical guidance. The majority stated that eight hours every week should be earmarked for formal tuition and research (two hrs clinical tuition, two hrs theory, two hrs supervision in psychotherapy, and two hrs for research). On average, the trainees had used 4200 DKK of their own income and four free days on courses over the previous year. Twenty-four months was proposed as adequate for an introductory appointment. The majority held that appointments should be made on the basis of the traditional curriculum vitae (82%) and a personal interview (86%), while about 20% believed that written or oral references should also be a requirement. Sixty-nine percent believed that selection of applicants for teaching appointments should be made locally with central supervision. Twenty-six percent felt they had been passed over in appointment situations, and 68% claimed it was due to nepotism. Recommendations for modifications of the future postgraduate training according to the responses are proposed, and it is concluded that earmarked resources are necessary, if the intention in the educational reform now in progress is to be realized.