Development and characterization of lysine based tripeptide analogues as inhibitors of Sir2 activity

Sirtuins are NAD(+) dependent deacetylases that modulate various essential cellular functions. Development of peptide based inhibitors of Sir2s would prove useful both as pharmaceutical agents and as effectors by which downstream cellular alterations can be monitored. Click chemistry that utilizes Huisgen's 1,3-dipolar cycloaddition permits attachment of novel modifications onto the side chain of lysine. Herein, we report the synthesis of peptide analogues prepared using click reactions on N epsilon-propargyloxycarbonyl protected lysine residues and their characterization as inhibitors of Plasmodium falciparum Sir2 activity. The peptide based inhibitors exhibited parabolic competitive inhibition with respect to acetylated-peptide substrate and parabolic non-competitive inhibition with NAD(+) supporting the formation of EI2 and E.NAD(+).I-2 complexes. Cross-competition inhibition analysis with the non-competitive inhibitor nicotinamide (NAM) ruled out the possibility of the NAM-binding site being the second inhibitor binding site, suggesting the presence of a unique alternate pocket commodating the inhibitor. One of these compounds was also found to be a potent inhibitor of the intraerythrocytic growth of P. falciparum with 50% inhibitory concentration in the micromolar range.

Timing of puberty : Genetic regulation

In the general population, the timing of puberty is normally distributed. This variation is determined by genetic and environmental factors, but the exact mechanisms underlying these influences remain elusive. The purpose of this study was to gain insight into genetic regulation of pubertal timing. Contributions of genetic versus environmental factors to the normal variation of pubertal timing were explored in twins. Familial occurrence and inheritance patterns of constitutional delay of growth and puberty, CDGP (a variant of normal pubertal timing), were studied in pedigrees of patients with this condition. To ultimately detect genes involved in the regulation of pubertal timing, genetic loci conferring susceptibility to CDGP were mapped by linkage analysis in the same family cohort. To subdivide the overall phenotypic variance of pubertal timing into genetic and environmental components, genetic modeling based on monozygous twins sharing 100% and dizygous twins sharing 50% of their genes was used in 2309 girls and 1828 boys from the FinnTwin 12-17 study. The timing of puberty was estimated from height growth, i.e. change in the relative height between the age when pubertal growth velocity peaks in the general population and adulthood. This reflects the percentage of adult height achieved at the average peak height velocity age, and thus, pubertal timing. Boys and girls diagnosed with CDGP were gathered through medical records from six pediatric clinics in Finland. First-degree relatives of the probands were invited to participate by letter; altogether, 286 families were recruited. When possible, families were extended to include also second-, third-, or fourth-degree relatives. The timing of puberty in all family members was primarily assessed from longitudinal growth data. Delayed puberty was defined by onset of pubertal growth spurt or peak height velocity taking place 1.5 (relaxed criterion) or 2 SD (strict criterion) beyond the mean. If growth data were unavailable, pubertal timing was based on interviews. In this case, CDGP criteria were set as having undergone pubertal development more than 2 (strict criterion) or 1.5 years (relaxed criterion) later than their peers, or menarche after 15 (strict criterion) or 14 years (relaxed criterion). Familial occurrence of strict CDGP was explored in families of 124 patients (95 males and 29 females) from two clinics in Southern Finland. In linkage analysis, we used relaxed CDGP criteria; 52 families with solely growth data-based CDGP diagnoses were selected from all clinics. Based on twin data, genetic factors explain 86% and 82% of the variance of pubertal timing in girls and boys, respectively. In families, 80% of male and 76% of female probands had affected first-degree relatives, in whom CDGP was 15 times more common than the expected (2.5%). In 74% (17 of 23) of the extended families with only one affected parent, familial patterns were consistent with autosomal dominant inheritance. By using 383 multiallelic markers and subsequently fine-mapping with 25 additional markers, significant linkage for CDGP was detected to the pericentromeric region of chromosome 2, to 2p13-2q13 (multipoint HLOD 4.44, α 0.41). The findings of the large twin study imply that the vast majority of the normal variation of pubertal timing is attributed to genetic effects. Moreover, the high frequency of dominant inheritance patterns and the large number of affected relatives of CDGP patients suggest that genetic factors also markedly contribute to constitutional delay of puberty. Detection of the locus 2p13-2q13 in the pericentromeric region of chromosome 2 associating with CDGP is one step towards unraveling the genes that determine pubertal timing.

Anterior cruciate ligament reconstruction with special reference to magnetic resonance imaging of the postoperative outcome

Anterior cruciate ligament (ACL) tear is a common sports injury of the knee. Arthroscopic reconstruction using autogenous graft material is widely used for patients with ACL instability. The grafts most commonly used are the patellar and the hamstring tendons, by various fixation techniques. Although clinical evaluation and conventional radiography are routinely used in follow-up after ACL surgery, magnetic resonance imaging (MRI) plays an important role in the diagnosis of complications after ACL surgery. The aim of this thesis was to study the clinical outcome of patellar and hamstring tendon ACL reconstruction techniques. In addition, the postoperative appearance of the ACL graft was evaluated using several MRI sequences. Of the 175 patients who underwent an arthroscopically assisted ACL reconstruction, 99 patients were randomized into patellar tendon (n=51) or hamstring tendon (n=48) groups. In addition, 62 patients with hamstring graft ACL reconstruction were randomized into either cross-pin (n=31) or interference screw (n=31) fixation groups. Follow-up evaluation determined knee laxity, isokinetic muscle performance and several knee scores. Lateral and anteroposterior view radiographs were obtained. Several MRI sequences were obtained with a 1.5-T imager. The appearance and enhancement pattern of the graft and periligamentous tissue, and the location of bone tunnels were evaluated. After MRI, arthroscopy was performed on 14 symptomatic knees. The results revealed no significant differences in the 2-year outcome between the groups. In the hamstring tendon group, the average femoral and tibial bone tunnel diameter increased during 2 years follow-up by 33% and 23%, respectively. In the asymptomatic knees, the graft showed homogeneous and low signal intensity with periligamentous streaks of intermediate signal intensity on T2-weighted MR images. In the symptomatic knees, arthroscopy revealed 12 abnormal grafts and two meniscal tears, each with an intact graft. Among 3 lax grafts visible on arthroscopy, MRI showed an intact graft and improper bone tunnel placement. For diagnosing graft failure, all MRI findings combined gave a specificity of 90% and a sensitivity of 81%. In conclusion, all techniques appeared to improve patients' performance, and were therefore considered as good choices for ACL reconstruction. In follow-up, MRI permits direct evaluation of the ACL graft, the bone tunnels, and additional disorders of the knee. Bone tunnel enlargement and periligamentous tissue showing contrast enhancement were non-specific MRI findings that did not signify ACL deficiency. With an intact graft and optimal femoral bone tunnel placement, graft deficiency is unlikely, and the MRI examination should be carefully scrutinized for possible other causes for the patients symptoms.

Kampylobakteerit Korkeasaaren eläintarhan eläimissä

Kampylobakteerit on tunnistettu vasta viimeisten 30 vuoden aikana merkittäviksi ihmisten tautien aiheuttajiksi. Termofiiliset kampylobakteerit Campylobacter jejuni ja C. coli ovat yleisin bakteeriperäisten suolistoinfektioden syy maailmanlaajuisesti. Pääasiallinen oire on ripuli. C. jejuni voi aiheuttaa myös jälkitauteja, kuten reaktiivista niveltulehdusta, nokkosihottumaa tai kyhmyruusua (erytema nodosum). Näitä kuitenkin ilmaantuu harvoin (<1 %). Tärkein jälkitauti on Guillain-Barrén syndrooma, joka on akuutti ääreishermoja demyelinisoiva sairaus. Kesällä 2008 Helsingin yliopistossa toteutettiin tutkimus, jonka tarkoituksena oli kartoittaa kampylobakteerien esiintymistä Korkeasaaren eläintarhassa ja tunnistaa löytyneet kampylobakteerit lajitasolle. Aineisto koostui 196 tarhaeläimen ulostenäytteestä, kahdeksasta Korkeasaaressa vapaana olleen valkoposkihanhen ulostenäytteestä sekä 12 ympäristönäytteestä (vesinäytteitä). Vesinäytteet olivat eläinten kahluualtaista tai häkeissä kulkevista puroista. Ulostenäytteet olivat peräisin kaikkiaan 71 eläinlajista. Tutkituista eläinlajeista 40 oli nisäkkäitä, 26 oli lintuja ja viisi oli matelijoita. Näytteistä eristettyjen isolaattien tulosten perusteella ulostenäytteistä 21 (10,7 %) oli positiivisia kampylobakteerien suhteen. Eläinlajeja tarkasteltaessa kampylobakteerien suhteen positiivisia oli 17 (23,9 %) eläinlajia. Näistä kymmenen oli lintuja, kuusi nisäkkäitä ja yksi matelija. Positiiviseksi C. jejunin suhteen osoittautui 18 ulostenäytettä. Yhdestä emun näytteestä löytyi C. jejunin lisäksi myös C. coli. Kahdessa näytteessä, rubiini-ibis ja kannuskilpikonna, kasvoi jokin muu kampylobakteeri kuin C. jejuni tai C. coli. Eläinlajeja tarkasteltaessa voidaan todeta, että 15 (21,1 %) todettiin positiivisiksi C. jejunin suhteen. Näistä kymmenen oli lintuja ja viisi nisäkkäitä. C. coli löytyi vain yhdestä (1,4 %) eläinlajista (linnusta) sekä jokin muu kampylobakteeri kuin C. jejuni tai C. coli löytyi kahdesta (2,8 %) eläinlajista (yksi lintu ja yksi matelija). Vain yksi ulostenäyte osoittautui positiiviseksi arkobakteerin suhteen. Kyseessä oli rubiini-ibiksen näyte. Samasta näytteestä löydettiin myös C. jejuni. Kahdesta valkoposkihanhien näytteestä löytyi sekä helikobakteeri että C. jejuni. Viisi ympäristönäytettä osoittautui positiiviseksi arkobakteerien suhteen. Kolme positiivista näytettä oli lintualtaista ja kaksi nisäkkäiden altaista. Rubiini-ibiksen altaasta löytyi arkobakteerin lisäksi myös C. jejuni. Lähes kaikissa vesinäytteissä (9/12) oli koliformisia bakteereja Colilert® testillä yli määritysrajan (>2419,6 bakteeria 100 ml:ssa näytettä). Suurimmasta osasta vesinäytteitä (8/12) saatiin tulokseksi myös yli menetelmän määritysrajan E. colia. Kaikenkaikkiaan tulosten perusteella voi päätellä, että vierailijoiden riski saada kampylobakterioosi Korkeasaaren eläintarhassa on suhteellisen pieni. Ainoana suurempana riskitekijänä voisi pitää valkoposkihanhien ulostetta. Sitä on maassa runsaasti ja sitä saattaa myös kulkeutua kenkien mukana jopa kotiin asti. Eläintarhan työntekijöiden tulee muistaa hyvä käsihygienia oltuaan kosketuksissa joko eläimien kanssa tai käytyään näiden tarhoissa. Työntekijät saattavat myös levittää eläintarhan eläinten ulostetta saappaissaan vierailijoidenkin kulkureiteille.

Pain measurement and management in elderly patients : Clinical studies in long term hospital care and after cardiac surgery

The proportion of patients over 75 years of age, receiving all different types of healthcare, is constantly increasing. The elderly undergo surgery and anaesthetic procedures more often than middle-aged patients. Poor pain management in the elderly is still an issue. Although the elderly consumes the greatest proportion of prescribed medicines in Western Europe, most clinical pharmacological studies have been performed in healthy volunteers or middle-aged patients. The aim of this study was to investigate pain measurement and management in cognitively impaired patients in long term hospital care and in cognitively normal elderly patients after cardiac surgery. This thesis incorporated 366 patients, including 86 home-dwelling or hospitalized elderly with chronic pain and 280 patients undergoing cardiac surgery with acute pain. The mean age of patients was 77 (SD ± 8) years and approximately 8400 pain measurements were performed with four pain scales: Verbal Rating Scale (VRS), the Visual Analogue Scale (VAS), the Red Wedge Scale (RWS), and the Facial Pain Scale (FPS). Cognitive function, depression, functional ability in daily life, postoperative sedation and postoperative confusion were assessed with MMSE, GDS, Barthel Index, RASS, and CAM-ICU, respectively. The effects and plasma concentrations of fentanyl and oxycodone were measured in elderly (≥ 75 years) and middle-aged patients (≤ 60 years) and the opioid-sparing effect of pregabalin was studied after cardiac surgery. The VRS pain scores after movement correlated with the Barthel Index. The VRS was most successful in the groups of demented patients (MMSE 17-23, 11-16 and ≤ 10) and in elderly patients on the first day after cardiac surgery. The elderly had a higher plasma concentration of fentanyl at the end of surgery than younger patients. The plasma concentrations of oxycodone were comparable between the groups. Pain intensity on the VRS was lower and the sedation scores were higher in the elderly. Total oxycodone consumption during five postoperative days was reduced by 48% and the CAM-ICU scores were higher on the first postoperative day in the pregabalin group. The incidence of postoperative pain during movement was lower in the pregabalin group three months after surgery. This investigation demonstrates that chronic pain did not seem to impair daily activities in home-dwelling Finnish elderly. The VRS appeared to be applicable for elderly patients with clear cognitive dysfunction (MMSE ≤17) and it was the most feasible pain scale for the early postoperative period after cardiac surgery. After cardiac surgery, plasma concentrations of fentanyl in elderly were elevated, although oxycodone concentrations were at similar level compared to middle-aged patients. The elderly had less pain and were more sedated after doses of oxycodone. Therefore, particular attention must be given to individual dosing of the opioids in elderly surgical patients, who often need a smaller amount for adequate analgesia than middle-aged patients. The administration of pregabalin reduced postoperative oxycodone consumption after cardiac surgery. Pregabalin-treated patients had less confusion, and additionally to less postoperative pain on the first postoperative day and during movement at three months post-surgery. Pregabalin might be a new alternative as analgesic for acute postoperative and chronic pain management in the elderly. Its clinical role and safety remains to be verified in large-scale randomized and controlled studies. In the future, many clinical trials in the older category of patients will be needed to facilitate improvements in health care methods.

4-Nitro 2-picoline-l-oxide complexes of lanthanide perchlorates

4-Nitro 2-picoline-l-oxide (NPicO) complexes of the formulae La (NPicO)5 (CIO4)3, Ln2 (NPicO)9 (C1O4)6 (Ln = Pr, Nd, and Gd) and Ln (NPicO)4 (CIO4)3 (Ln == Tb, Dy, Ho and Yb) have been synthesised and characterised by analysis, electrolytic conductance, infrared, proton NMR and electronic spectral data. A tentative coordination number of 6 for all the complexes have been assigned

Matched thermochemical diagram for vacuum decarburization of ferroalloys

The carbon content of high carbon ferroalloy melts can be reduced by a vacuum treatment. Carbon and oxygen dissolved in the melt react to form CO. Although this process has been suggested in the literature, no comprehensive analysis of the equilibrium partial pressure of CO over an alloy melt with a given carbon and oxygen content has been reported. In this paper, a new type of matched thermochemical diagram is introduced, from which the feasibility of decarburization at reduced CO pressure and the minimum achievable carbon level can be graphically evaluated for any alloy composition and temperature. Carbon and oxygen potentials of different alloys are plotted as functions of temperature on two terminal diagrams. By projecting information from these plots onto a central diagram, containing data on the Gibbs' energy of mixing for the C-O system, equilibrium partial pressures of CO and CO2 are obtained. Nomograms on the central diagram give a direct indication of the equilibrium partial pressures at any given temperature. The carbon and oxygen activities in ferrochromium alloys have been assessed and the results are presented to illustrate the construction and use of the matched thermochemical diagrams.

Oxygen-Exchange Reactions Accompanying Oxidation of Vanadyl Sulfate by Diperoxovanadate

The absorption spectrum in the visible range and the, ESR spectrum of vanadyl sulfate were lost on addition of diperoxovanadate. The V-51-NMR spectra revealed that diperoxovanadate was reduced to vanadate and its oligomers. With excess vanadyl, tetrameric vanadate was found to be the major product, During this reaction oxygen was released into the medium. The oxygen-release reaction was inhibited by a variety of organic ligands-imidazole, benzoate, formate, mannitol, ethanol, Tris, DMPO, malate, and asparagine. An oxygen-consuming reaction emerged at high concentrations of some of these compounds, e.g. benzoate and ethanol. Using DMPO as the spin-trap, an oxygen-radical species with a 1:2:2:1 type of ESR spectrum was detected in the reaction mixtures resulting from vanadyl oxidation by diperoxovanadate which was unaffected by addition of catalase or ethanol. The results showed that secondary oxygen-exchange reactions occur which depend on and utilize the intermediates in the primary reaction during diperoxovanadate-dependent oxidation of vanadyl sulfate.

Intramolecular hydrogen bonds involving organic fluorine in the derivatives of hydrazides: an NMR investigation substantiated by DFT based theoretical calculations

The rare examples of intramolecular hydrogen bonds (HB) of the type the N-H center dot center dot center dot F-C, detected in a low polarity solvent in the derivatives of hydrazides, by utilizing one and two-dimensional solution state multinuclear NMR techniques, are reported. The observation of through-space couplings, such as, (1h)J(FH), and (1h)J(FN), provides direct evidence for the existence of intra-molecular HB. Solvent induced perturbations and the variable temperature NMR experiments unambiguously establish the presence of intramolecular HB. The existence of multiple conformers in some of the investigated molecules is also revealed by two dimensional HOESY and N-15-H-1 HSQC experiments. The H-1 DOSY experimental results discard any possibility of self or cross dimerization of the molecules. The derived NMR experimental results are further substantiated by Density Function Theory (DFT) based Non Covalent Interaction (NCI), and Quantum Theory of Atom in Molecule (QTAIM) calculations. The NCI calculations served as a very sensitive tool for detection of non-covalent interactions and also confirm the presence of bifurcated HBs.

Effect of H-2/CO Composition on Extinction Strain Rates of Counterflow Syngas Flames

This work presents a detailed experimental and numerical investigation of the effect of H-2/CO composition on extinction characteristics of premixed and nonpremixed syngas flames. Experimental measurements of local and global extinction strain rates in counterflow diffusion flames have been reported at atmospheric pressure for six different compositions of syngas fuel. The concentration of H-2 was varied from 5 to 20% with a 3% increment, and correspondingly, CO was decreased from 35 to 20% in steps of 3%. Particle imaging velocimetry has been used to determine the local extinction strain rates. Local extinction strain rates increased with an increase in the H-2/CO ratio in both nonpremixed and premixed flames. The predicted extinction strain rates for both nonpremixed and premixed counterflow flames using five different mechanisms available in the literature were compared with measurements. The Davis H-2/CO and Ranzi H-2/CO mechanisms predicted extinction strain rates within 10% of experimental values irrespective of the H-2/CO ratio. In the nonpremixed case, the Cl mechanism by Li et al., GRI 3.0, and the Ranzi H-2/CO mechanism predicted extinction strain rates well for low H-2/CO ratios (from 5:35 to 14:26) but deviated from experiments for higher H-2/CO values (17:23 and 20:20). In addition to kinetics, preferential diffusion effects were found to affect the reaction zone significantly and create distinct localized reaction zone structures in nonpremixed flames, which could contribute to discrepancies in extinction predictions.

La disciplina dell' adozione a Gortina

Abstract: The article presents Italian translation and commentary of Gortyn ‘code’ columns X.33-XII.23 about adoption’s legal dispositions. The epigraphic text is compared with literary sources of Athenian law in classical age, pointing out analogies and variances. The more substantial difference is that in Gortyn’s law the adoptive son had less prerogatives, in accordance with an archaic and aristocratic society

压-剪复合应力波作用下材料动态断裂韧性研究

提出亚微秒单脉冲应力波载荷作用下Ⅱ型裂纹的平板冲击实验技术 .加载率为dK dt～ 10 8MPa·m1 2 ·s-1.实验中由锰铜应力片和弹性波理论分别测定和计算了压应力 ;通过微观分析确定了动态裂纹的平均扩展长度 ;引进等效应力强度因子 ,用动态断裂理论确定了 6 0 #钢的动态断裂韧性KⅠd和KⅡd ;建立了亚微秒冲击载荷作用下确定材料动态断裂韧性的方法

Zustand der Herings- und Sprottenbestände in Nord- und Ostsee, östlichem Kanal und westlichen britischen Gewässern. Beurteilung durch die Herings- und Ostsee-Arbeitsgruppe des ICES, März/April 1999

Information is given about the results of the latest meeting of the Herring Assessment Working Group for the Area South of 62° N and the Baltic Fisheries Assessment Working Group, which were conducted in March and April at ICES headquarters in Copenhagen. The actual stock development and the catch options estimated for different assessment units of herring and sprat are presented. The spawning stock size of North Sea herring reached in 1998 for the first time since 1991 a level above the Minimum Biological Acceptable Level (MBAL) of 800 000 t. Keeping the fishery at the present level the spawning stock size should reach in 1999 a level of about 1.2 mio. t. For the Western Baltic Spring spawning herring stock no actual stock estimate was presented. Due to uncertainties in splitting the catches in North Sea autumn and Baltic spring spawners no analytical assessment was accepted.