[Bilateral breast reduction and obesity: What is the ideal resection enabling significant improvement in back pain according to the body mass index?] / Mastoplastie bilatérale de réduction et obésité : quel est le poids de résection idéal pour obtenir une amélioration significative des douleurs rachidiennes en fonction de l'indice de masse corporelle ?

INTRODUCTION: Dorsal pain is the first symptoms about which patients with macromasty complain. Health insurance reimbursement takes place if the resection weight is at least 300grams per breast. However, this weight is not correlated with the body mass index (BMI). In this context, we sought to determine the ideal resection weight leading to significant BMI-based improvement. MATERIALS AND METHODS: This is a multicentre prospective study of patients operated between November 2016 and July 2017. In the year following the surgical procedure, we studied overall improvement using the INDIC questionnaire. Any INDIC improvement of at least 50% was considered positive. These data were then compared to tissue resection weights and BMI. In order to refine our results, age, bra size, comorbidities and complications were also identified. RESULTS: Forty-one patients were included in our study. Average age was 41.5±11.4years. Average BMI was 27.9±4.1kg/m2. The bra cap chosen after the procedure were C. Average resection weight was 663±352g per breast. The preoperative and postoperative INDIC scores were 734.9±226.6 points and 225.3±319.1 points, respectively (P=0.001). Significant improvement was achieved at 12months in 71.8% of patients. A correlation of 38.7g/kg/m2 was found between breast resection weight and BMI. CONCLUSION: This study clarifies the correlation between the breast resection weight required to relieve optimal back pain and BMI. It defines three categories of patients: patients with standard weights (1830). Overweight and obese patients require greater tissue excretion to be relieved optimally. These findings underline a need to adjust the health insurance threshold for these types of patients.

[Light sources usable by the plastic surgeon in the absence of photographic studio]. / Sources lumineuses utilisables par le chirurgien plasticien en l'absence de studio photographique.

Medical photography is an important part of the medical file and is widely used in medical communication, especially in our discipline. His practice has to be the most standardized and reproducible as possible, which distinguishes it from artistic photography. Photography fix the light reflecting from a subject, so surgeon have to control of the light source in any environment. In the absence of dedicated studio, using external cobra or ring flashes with special diffusers allow the surgeon to have light sources adapted to the different conditions encountered in daily practice.

Five-year outcomes in kidney transplant patients converted from cyclosporine to everolimus: the randomized ZEUS study.

ZEUS study was an open-label, 12-month, multicenter study in which 300 de novo kidney transplant recipients were randomized to continue receiving cyclosporine (CsA) or convert to everolimus at 4.5 months posttransplant. Five-year follow-up data were available for 245/269 patients (91.1%) who completed the core 12-month study (123 everolimus, 109 CsA). At 5 years, adjusted estimated GFR was 66.2 mL/min/1.73 m(2) with everolimus versus 60.9 mL/min/1.73 m(2) with CsA; the mean difference was 5.3 mL/min/1.73 m(2) in favor of everolimus (95% CI 2.4, 8.3; p < 0.001 [intent-to-treat population]). In a post hoc analysis of patients remaining on study drug at 5 years (everolimus 77, CsA 86), mean difference was 8.2 mL/min/1.73 m(2) (95% CI 4.3, 12.1; p < 0.001) in favor of everolimus. The cumulative incidence of biopsy-proven acute rejection postrandomization was 13.6% with everolimus versus 7.5% with CsA (p = 0.095), largely accounted for by grade I rejection (16/21 patients and 7/11 patients, respectively). Postrandomization, graft loss, mortality, serious adverse events and neoplasms were similar in both arms. In conclusion, conversion of kidney transplant patients to everolimus at 4.5 months posttransplant is associated with a significant improvement in renal function that is maintained to at least 5 years. The increase in early mild acute rejection did not affect long-term graft function.

Biomechanical evaluation of fixation properties of fibrin glue for ventral incisional hernia repair.

INTRODUCTION: Use of adhesives for mesh fixation in hernia is increasing. There has been minimal study of mesh incorporation and interface strength with adhesive fixation for ventral hernia repair. The purpose of this study was to evaluate the fixation properties of fibrin glue as it compared to suture fixation of mesh in an onlay position. METHODS: Twenty-four mongrel pigs were divided into three study arms based on time points for biomechanical evaluation: 24 h (n = 8), 7 days (n = 8), and 14 days (n = 8). Initial procedures included placement of two 4 × 6 cm pieces of wide-pore polypropylene mesh in an onlay position. One was fixated with 4 ml of fibrin glue and the other with four interrupted 2-0 polypropylene sutures. The shear strength of fixation was evaluated using a uniaxial testing device along with histological evaluation. Maximum force was normalized by the width of the mesh. RESULTS: Mesh-tissue interface of glued and sutured specimens at 7 and 14 days did not fail in our testing configuration. Only at the 24-h time point the mesh detached from the tissue, and the sutured interface (10.4 N/cm) was significantly stronger than glued interface (4.9 N/cm, p = 0.004). Histopathologic and gross evaluations of the specimens revealed similar histologic features at all time points for both glued and sutured specimens. CONCLUSIONS: With mesh in the onlay position, fixation to the abdominal wall occurs quickly. Though sutures were stronger at 24 h, as early as 1 week, the strength of the fixation exceeded the tissue or the mesh strength in our testing configuration for both glue and suture groups. Fixation strength is independent of technique at the latter time points. There are potential clinical advantages to the exclusive use of fibrin glue for fixation including acute post-operative pain, chronic post-operative pain, and recurrence for ventral incisional hernia repair.

Everolimus and early calcineurin inhibitor withdrawal: 3-year results from a randomized trial in liver transplantation.

The feasibility of de novo everolimus without calcineurin inhibitor (CNI) therapy following liver transplantation was assessed in a multicenter, prospective, open-label trial. Liver transplant patients were randomized at 4 weeks to start everolimus and discontinue CNI, or continue their current CNI-based regimen. The primary endpoint was adjusted estimated GFR (eGFR; Cockcroft-Gault) at month 11 post randomization. A 24-month extension phase followed 81/114 (71.1%) of eligible patients to month 35 post randomization. The adjusted mean eGFR benefit from randomization to month 35 was 10.1 mL/min (95% confidence interval [CI] -1.3, 21.5 mL/min, p = 0.082) in favor of CNI-free versus CNI using Cockcroft-Gault, 9.4 mL/min/1.73 m(2) (95% CI -0.4, 18.9, p = 0.053) with Modification of Diet in Renal Disease (four-variable) and 9.5 mL/min/1.73 m(2) (95% CI -1.1, 17.9, p = 0.028) using Nankivell. The difference in favor of the CNI-free regimen increased gradually over time due to a small progressive decline in eGFR in the CNI cohort despite a reduction in CNI exposure. Biopsy-proven acute rejection, graft loss and death were similar between groups. Adverse events led to study drug discontinuation in five CNI-free patients and five CNI patients (12.2% vs. 12.5%, p = 1.000) during the extension phase. Everolimus-based CNI-free immunosuppression is feasible following liver transplantation and patients benefit from sustained preservation of renal function versus patients on CNI for at least 3 years.

Improvement in gastrointestinal and health-related quality of life outcomes after conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in liver transplant recipients.

OBJECTIVE: To evaluate improvement in gastrointestinal (GI) symptoms and health-related quality of life (HRQoL) in liver transplant recipients switched from mycophenolate mofetil (MMF) to enteric-coated mycophenolate sodium (EC-MPS). METHODS: A multicenter, open-label, single-arm study was undertaken in maintenance liver transplant recipients who reported GI complications with MMF therapy. The patients were switched to equimolar doses of EC-MPS at baseline. The primary end point was the change in the Gastrointestinal Symptom Rating Scale (GSRS) total score after 6 to 8 weeks of treatment with EC-MPS. Other key assessments for GI symptoms and HRQoL included the GSRS subscores, the Gastrointestinal Quality of Life Index (GIQLI), the Psychological General Well-Being Index, and the Overall Treatment Effect (OTE). Paired t-test was used to assess the difference in the mean score changes over time. RESULTS: A total of 34 patients were enrolled and switched to equimolar doses of EC-MPS. After 6 to 8 weeks of EC-MPS treatment, mean GSRS total score improved significantly from 2.88 ± 0.66 to 2.10 ± 0.78. Mean improvement in GSRS total score (-0.77 score points; P = .001) exceeded the minimal clinically important difference. Significant improvements were observed in all GSRS subscales (P < .05), GIQLI total scores (P = .001), and GIQLI subscales "GI symptoms" (P < .001) and "physical function" (0.013). Patients who continued EC-MPS reported sustained benefits compared with patients who switched back to MMF after 6 to 8 weeks of treatment with EC-MPS. On the OTE scale, improvement in symptoms was reported in 76.5% and 61.8% of the patients as perceived by the physicians and the patients. Improvement in HRQoL was reported by 41.2% of the patients. No deaths, biopsy proven acute rejections, or graft losses were reported during the study. CONCLUSION: Conversion from MMF to EC-MPS was associated with a significant improvement in GI symptoms and HRQoL in liver transplant recipients.

Propagação vegetativa de Aloysia triphylla (L'Hér. ) Britton em função da concentração de AIB e do comprimento das estacas / Vegetative propagation of Aloysia triphylla (L'Hér. ) Britton according to IBA and length of cuttings

A Aloysia triphylla (L'Hér.) Britton é uma planta medicinal de porte arbustivo com folhas aromáticas que possuem óleo essencial rico em citral. A crescente demanda da indústria farmacêutica e cosmética pelo óleo essencial de A. triphylla promoveram grande interesse sobre o cultivo dessa espécie. A estaquia é um dos principais métodos de propagação devido à dificuldade em obter sementes, e também pela vantagem dos descendentes serem iguais à planta-matriz. O objetivo do trabalho foi avaliar o efeito de diferentes concentrações de AIB e do comprimento das estacas no enraizamento de estacas de A. triphylla. O experimento foi conduzido em ambiente protegido no período de Novembro de 2010 a Janeiro de 2011. O delineamento experimental foi inteiramente casualizado em esquema fatorial onde os fatores foram cinco concentrações de ácido indol butírico (AIB) (mg L-1): 0, 250, 500, 1000 e 1500, e quatro comprimentos de estaca: 4, 6, 8 e 10 cm. As estacas tiveram a base imersa em solução de AIB e foram colocadas para enraizar em substrato comercial Mecplant®. As variáveis analisadas foram: comprimento do sistema radicular, percentagem de estacas enraizadas (%), número de brotações, massa fresca e seca da parte aérea, e massa seca das raízes. Nas condições em que o estudo foi realizado os resultados mostraram que o comprimento das estacas e concentração de AIB afetam o desenvolvimento das estacas, apresentando ajuste quadrático e linear para as variáveis analisadas. As mudas obtidas a partir de estacas com 10 cm e concentração de 1500 mg L-1 de AIB apresentaram a maior percentagem de enraizamento e as maiores médias para o comprimento do sistema radicular, número de brotações, massa fresca e seca da parte aérea.

Aloysia triphylla (L'Hér.) Britton is a medicinal plant shrub with aromatic leaves, which have essential oil rich in citral. The increasing demand of the pharmaceutical and cosmetic industries for the A. triphyllaessential oil provided a greater interest in the cultivation of this species. Cutting is one of the main methods of propagation, due to the difficulty in obtaining seeds and also for the benefit of descendants being equal to the parent plant. The objective of this study was to evaluate the effect of different concentrations of IBA and length of cuttings in the rooting of A. triphylla. The experiment was carried out in a protected environment in the period from November 2010 to January 2011. The experimental design was completely randomized using the factorial design where the factors were five concentrations of indole butyric acid (IBA) (mg L-1): 0, 250, 500, 1000 and 1500, and four lengthsforthe cuttings: 4, 6, 8 and 10 cm. The cutting base was immersed in a solution of IBA and placed into the rooting Mecplant ® commercial substrate. The variables analyzed were: root length, percentage of rooted cuttings (%), number of shoots, fresh and dry weight of the shoots, and dry weight of the roots. Under the conditions in which the study was conducted, the results showed that the length of the cuttings and IBA concentration affect the development of the cuttings, with linear and quadratic adjustment for the variables analyzed. The seedlings of cuttings with 10cm and the concentration of 1500 mg L-1 IBA showed the highest percentage of rooting and the highest averages for length of the root system, number of shoots, fresh and dry weight of the shoots.

Conversion from cyclosporine to everolimus at 4.5 months posttransplant: 3-year results from the randomized ZEUS study.

The long-term effect of conversion from calcineurin inhibitor (CNI) therapy to an mTOR inhibitor requires clarification. Following completion of the 12-month, open-label, multicenter ZEUS study, in which 300 kidney transplant recipients were randomized to continue cyclosporine (CsA) or convert to everolimus at 4.5 months posttransplant, outcomes were assessed at month 36 (n = 284; 94.7%). CNI therapy was reintroduced in 28.4% of everolimus patients by month 36. The primary efficacy endpoint, estimated glomerular filtration rate (Nankivell, ANCOVA) was significantly higher with everolimus versus the CsA group at month 24 (7.6 mL/min/1.73 m(2) , 95%CI 4.3, 11.0 mL/min/1.73 m(2) ; p < 0.001) and month 36 (7.5 mL/min/1.73 m(2) , 95%CI 3.6, 11.4 mL/min/1.73 m(2) ; p < 0.001). The incidence of biopsy-proven acute rejection from randomization to month 36 was 13.0% in the everolimus arm and 4.8% in the CsA arm (p = 0.015). Patient and graft survival, as well as incidences of malignancy, severe infections and hospitalization, were similar between groups. Kidney transplant patients who are converted from CsA to everolimus at month 4.5 and who remain on everolimus thereafter may achieve a significant improvement in renal function that is maintained to 3 years. There was a significantly higher rate of rejection in the everolimus arm but this did not exert a deleterious effect by 3 years posttransplant.

Omeprazole impairs the absorption of mycophenolate mofetil but not of enteric-coated mycophenolate sodium in healthy volunteers.

In 2 crossover studies, 12 healthy volunteers (6 male/6 female) received a single oral dose of mycophenolate mofetil (MMF) 1000 mg or an equimolar dose of enteric-coated mycophenolate sodium (EC-MPS) 720 mg fasting with and without coadministered omeprazole 20 mg bid. The plasma concentrations of mycophenolic acid (MPA) and of the inactive metabolite mycophenolic acid glucuronide (MPA-G) were measured by high-performance liquid chromatography (HPLC). In addition, dissolution of MMF 500 mg or EC-MPS 360 mg tablets was determined using an USP paddle apparatus in aqueous buffer of pH 1 to 7. The bioavailability of MPA following administration of MMF or EC-MPS was similar except for the time to peak concentration, which was longer in the EC-MPS group. Concomitant treatment with omeprazole lowered significantly C(max) and AUC(12h) of MPA following administration of MMF. The pharmacokinetics of EC-MPS was not affected. Dissolution of MMF in aqueous buffer decreased dramatically at pH above 4.5. The EC-MPS tablet was stable up to pH 5. Above, EC-MPS was quantitatively disintegrated and MPS quantitatively dissolved. There is strong evidence that impaired absorption of MMF with concomitant proton pump inhibitors is due to incomplete dissolution of MMF in the stomach at elevated pH.

Avaliação de substratos orgânicos na produção de mudas de hortelã (Mentha gracilis R. Br. e Mentha x villosa Huds.) / Evaluation of organic substrates on mint (Mentha gracilis R. Br. and Mentha x villosa Huds.) seedling production

A determinação de substratos alternativos viáveis para a produção de mudas de plantas medicinais é de grande relevância, pois o aproveitamento de resíduos de atividades agrícolas representa alternativa para problemas ambientais e sociais. Os experimentos foram realizados em ambiente protegido e a campo, na Universidade Tecnológica Federal do Paraná, Campus Dois Vizinhos, com o objetivo de avaliar substratos orgânicos para produção de mudas de hortelã para cultivo a campo. O delineamento experimental foi blocos casualizados, com três repetições, em esquema fatorial, sendo avaliados quatro substratos [esterco bovino + vermiculita + areia (1:1:1), esterco bovino + areia + solo (1:1:1), solo + vermiculita + cama-de-aviário (1:1:1) e substrato organo-mineral Plantmax® HA] e duas espécies de menta (Mentha gracilis e Mentha x villosa). Foram analisadas a altura da plantas e o número de folhas aos 07, 14 e 21 dias após o transplantio, índice de mortalidade, massa fresca e seca da parte aérea e das raízes. Não houve interação entre as espécies de menta e substratos para as variáveis analisadas. O substrato organo-mineral Plantmax® apresentou os melhores resultados para o número de folhas (8,44), altura (8,46 cm), produção de massa fresca (1,56 g planta-1), seca (0,23 g planta-1) e 100 por cento de pegamento de mudas a campo o que para o produtor de menta é de grande interesse. Com base nos resultados obtidos, pode-se concluir que para a produção de mudas de Mentha gracilis e Mentha villosa o substrato Plantmax® HA é o mais recomendado.

The determination of viable alternative substrates is of great importance for the production of medicinal seedlings since the use of residues from agricultural activities represents an alternative to solve environmental and social problems. The experiments were carried out in protected environment and in the field, located in the Federal Technological University of Paraná, Dois Vizinhos Campus, Paraná State, Brazil. The aim of this work was to evaluate organic substrates for the production of mint seedlings in the field. Experimental design was in randomized blocks, with three replicates, in a factorial arrangement evaluating four substrates [bovine manure + vermiculite + sand (1:1:1); bovine manure + sand + soil (1:1:1); soil + vermiculite + poultry manure (1:1:1); and the organomineral substrate Plantmax® HA] and two mint species (Mentha gracilis and Mentha x villosa). Plant height and leaf number were evaluated at 07, 14 and 21 days after transplanting, besides death rate and fresh and dry matter of shoots and roots. There was no interaction between mint species and substrates for the evaluated variables. The organomineral substrate Plantmax® HA presented the best results for leaf number (8.44), height (8.46 cm), fresh matter (1.56 g plant-1), dry matter (0.23 g plant-1) and set (100 percent seedlings in the field), which is of great interest for the mint producer. Based on these results, we concluded that the substrate Plantmaxâ HA is the most recommended for the production of Mentha x villosa and Mentha gracilis seedlings.

[Sound localization cues of binaural hearing]. / Die richtunggebenden Merkmale des räumlichen Hörens.

The ability to localize sound sources in space is of considerable importance to the human safety- and survival-system. Consequently the current scientific interest in improving the safety-standard i. e. in air-traffic control has provided a new momentum for investigating spatial hearing. This review deals with the nature and the relative salience of the localization cues. Localization refers to judgements of the direction and distance of a sound source but here we will deal with direction only. We begin with a short introduction into the so-called Duplex theory which dates back to John William Strutt (later Lord Rayleigh). The idea is that sound localization is based on interaural time differences (ITD) at low frequencies and interaural level differences (ILD) at high frequencies. If the head remains stationary neither a given ITD nor an ILD can sufficiently define the position of a sound source in space. On such a theoretical basis cones of confusion which open outward from each ear can be predicted ambiguously projecting any source on the surface of such a cone onto an interaural axis. Our restricted ability at localizing sound sources in the vertical median plane is another example of possible ambiguity. At the end of the 19th century scientists already realized that occlusion of the pinnae cavities decreases localization competence. As a result of later achievements in physics and signal-theory it became more obvious that the pinnae may provide an additional cue for spatial hearing and that the outer ear together with the head and the upper torso form a sophisticated direction-dependent filter. The action of such a filter is mathematically described by the so-called Anatomical Transfer Function (ATF). The spectral patterning of the sound produced by the pinnae and the head is most effective when the source has spectral energy over a wide range and contains frequencies above 6 kHz, that is it contains wavelengths short enough to interact with the anatomical characteristics of the outer ears. Scientific findings further suggest that spectral patterns like peaks and notches may also be exploited monaurally, albeit an a priori-knowledge at the central-auditive level concerning the corresponding transfer functions and relevant real-world sounds is required. Binaural spectral cues are more likely to play a major role in localization. They are derived from another transfer function, the so-called Interaural Transfer Function (ITF), being the ratio of the ATFs at the two ears. The contributions of all these cues may sometimes not be enough to prevent the listener from opting for the wrong direction. But things can be eased by allowing head-movements: More than 60 years ago science reasoned that small head movements could provide the information necessary to resolve most of the ambiguities. Recent studies have proved that these findings have been accurate all along.

Synthesis and activity of novel and selective I(Ks)-channel blockers.

Since the discovery of the I(Ks)-potassium channel as the slowly activating component of the delayed rectifier current (I(k)) in cardiac tissue, the search for blockers of this current has been intense. During the screening of K(ATP)-channel openers of the chromanol type we found that chromanol 293B was able to block I(Ks). Chromanol 293B is a sulfonamide analogue of the K(ATP)-channel openers but had no activity on this target. Experiments were initiated to improve the activity and properties based on this lead compound. As a screening model we used Xenopus oocytes injected with human minK (KCNE1). Variations of the aromatic substituent and the sulfonamide group were prepared, and their activity was evaluated. We found that the greatest influence on activity was found in the aromatic substituents. The most active compounds were alkoxy substituted. We chose HMR1556 ((3R, 4S)-(+)-N-[-3-hydroxy-2,2-dimethyl-6-(4,4,4-trifluorobutoxy)chroman-4-yl]-N-methyl-ethanesulfonamide) 10a for development as an antiarrhythmic drug. The absolute configuration, resulting from an X-ray single-crystal structure analysis, was determined.

Resorcarenes in the boat conformation as building blocks for hydrogen-bonded assemblies including two ammonium cations.

Crystal structures are reported for various co-crystals of rccc-resorcarenes with triethylammonium chloride. Usually, two molecules of a C2v-symmetric tetraester 2 in the boat conformation are linked through four hydrogen-bonded chloride anions to give dimeric assemblies. Two of the chloride anions may be replaced by four hydrogen-bonded ethanol molecules in an otherwise similar structure. These assemblies, which consist of six or eight components, posses voluminous, negatively charged chambers in which two triethylammionium cations, 3+, are included as guests by strong electrostatic and hydrogen-bonding interactions. The host-guest N-H...Cl hydrogen bonds were clearly detected at 173 K. These are the first examples of hydrogen-bonded, solid-state capsules trapping two ions of the same charge in close proximity. In the 1:2 complex with 3+ Cl-, the molecule of the parent resorcarene 1 also adopts a boat conformation whose cavity is considerably extended by four hydrogen-bonded chloride anions. The pocket formed in this way again includes two 3+ ions as a result of electrostatic and hydrogen bonding host-guest interactions. All these structures show that the boat conformers of resorcarenes can be used as a novel motif for the construction of hydrogen-bonded assemblies capable of molecular inclusion and encapsulation.

The chemical structure of mumbaistatin, a novel glucose-6-phosphate translocase inhibitor produced by Streptomyces sp. DSM 11641.

The characterization of the structure of mumbaistatin (1), an effective inhibitor of the glucose-6-phosphatase system (EC 3.1.3.9), is reported. Isolation of mumbaistatin from cultures of Streptomyces sp. DSM 11641 was achieved by anion-exchange and reversed-phase chromatography. The acid-labile inhibitor was methylated for the structure determination. Single-crystal X-ray structure analysis of a triply methylated dehydration product, C31H24O11, revealed the structure of an aromatic dispirodiketal (2), a compound containing a previously undescribed ring system. Extensive 2D-NMR experiments with mumbaistatin and with the methylation products showed that mumbaistatin itself possesses the hydroxydiketodicarboxylic acid structure 1, C28H20O12, which, in the presence of acid or upon activation through methyl ester formation, undergoes self-condensation with loss of water to the dispirodiketal form (2). Mumbaistatin is an anthraquinone derivative, whose open-chain diketo form acts as a specific and powerful inhibitor of glucose-6-phosphate translocase: IC50=5 nM. The activity towards the same enzyme of the cyclized dispirodiketal derivatives is roughly one thousand times lower.

Kodaistatins, novel inhibitors of glucose-6-phosphate translocase T1 from Aspergillus terreus thom DSM 11247. Isolation and structural elucidation.

Two novel compounds, kodaistatin A, C35H34O11, molecular weight 630, and kodaistatin C, C35H34O12, molecular weight 646, have been isolated from cultures of Aspergillus terreus Thom DSM 11247 by solid-phase extraction, size-exclusion chromatography, and various preparative HPLC steps. The use of a range of 2D NMR measurements, in particular 13C-13C correlation measurements, has led to the clarification of the structure of kodaistatin A. Kodaistatin C is a hydroxylated derivative of kodaistatin A. Both natural products contain hydroxylated aspulvinones and identical highly substituted polyketide units. An X-ray single crystal structure analysis of aspulvinon E demonstrated the z-configuration at the central double bond. The kodaistatins are effective inhibitors of the glucose-6-phosphate translocase component of the glucose-6-phosphatase system (EC 3.1.3.9), an enzyme system which is important for the control of blood glucose levels. The IC50 is 80 nM for kodaistatin A and 130 nM for kodaistatin C.

Chlorogenic acid and synthetic chlorogenic acid derivatives: novel inhibitors of hepatic glucose-6-phosphate translocase.

The enzyme system glucose-6-phosphatase (EC 3.1.3.9) plays a major role in the homeostatic regulation of blood glucose. It is responsible for the formation of endogenous glucose originating from gluconeogenesis and glycogenolysis. Recently, chlorogenic acid was identified as a specific inhibitor of the glucose-6-phosphate translocase component (Gl-6-P translocase) of this enzyme system in microsomes of rat liver. Glucose 6-phosphate hydrolysis was determined in the presence of chlorogenic acid or of new synthesized derivatives in intact rat liver microsomes in order to assess the inhibitory potency of the compounds on the translocase component. Variation in the 3-position of chlorogenic acid had only poor effects on inhibitory potency. Introduction of lipophilic side chain in the 1-position led to 100-fold more potent inhibitors. Functional assays on isolated perfused rat liver with compound 29i, a representative of the more potent derivatives, showed a dose-dependent inhibition of gluconeogenesis and glycogenolyosis, suggesting glucose-6-phosphatase as the locus of interference of the compound for inhibition of hepatic glucose production also in the isolated organ model. Gl-6-P translocase inhibitors may be useful for the reduction of inappropriately high rates of hepatic glucose output often found in non-insulin-dependent diabetes.

Structures of quinoxaline antibiotics.

The crystal structures of three quinoxaline antibiotics-echinomycin 2QN, triostin C and the C222(1) form of triostin A--have been determined, and the structure of the P2(1)2(1)2(1) form of triostin A has been re-refined against our previously reported data. The molecular conformations are compared with those deduced from NMR data and those reported for two complexes of triostin A with oligonucleotides. Although the depsipeptide ring conformations are basically similar, the effective twofold molecular symmetry is violated by the folding of one of the quinoxaline chromophores in echinomycin 2QN and by a rotation of one of the ester planes with the formation of an intramolecular hydrogen bond in triostin C. In the oligonucleotide complexes of triostin A the chirality of the disulfide bridge is inverted. The alanine NH groups are involved in intermolecular hydrogen bonds in all four structures, and (except in echinomycin 2QN) the stacking of the chromophores in the crystal emulates the intercalation involved in DNA complex formation. In echinomycin 2QN, the antibiotic molecules are hydrogen bonded to form a helix along the crystallographic 6(5) screw axes, with a channel of disordered solvent running through the middle of the helix. Crystal data: (1), echinomycin 2QN, C53H66N10O12S2.2.5(C3H6O).2.5(H2O), M(r) = 1289.5, hexagonal, P6(5), a = b = 22.196(15), c = 24.64 (2) A, V = 10,513 (13) A3, Z = 6, Dx = 1.222 Mg m-3, lambda (Cu K alpha) = 1.5418 A, mu = 1.275 mm-1, T = 193 K, R = 9.0% for 4828 I > 2 sigma (I) and 11.8% for all 7102 unique reflections; (2), triostin C, C54H70N12O12S2.0.67(CHCl3).0.67(H2O), M(r) = 1234.2, orthorhombic, P2(1)2(1)2(1), a = 16.054 (8), b = 17.128 (9), c = 22.706 (12) A, V = 6244 (6) A3, Z = 4, Dx = 1.313 Mg m-3, lambda (Mo K alpha) = 0.71073 A, mu = 0.239 mm-1, T = 188 K, R = 7.7% for 4678 I > 2 sigma (I) and 14.0% for all 7260 unique reflections; (3), triostin A, C50H62N12O12S2.2(C7H14O2), M(r) = 1347.6, orthorhombic, P2(1)2(1)2(1), a = 20.94 (2), b = 18.53 (2), c = 18.80 (2) A, V = 7292 (13) A3, Z = 4, Dx = 1.228 Mg m-3, lambda (Cu K alpha) = 1.5418 A, mu = 1.245 mm-1, T = 293 K, R = 6.8% for 2116 I > 2 sigma (I) and 9.3% for all 2928 unique reflections; (4), triostin A, C50H62N12O12S2.HCl.2(C3H7NO), M(r) = 1269.9, monoclinic, C222(1), a = 10.622 (10), b = 17.035 (17), c = 35.21 (3) A, V = 6371 (10) A3, Z = 4, Dx = 1.324 Mg m-3, lambda (Mo K alpha) = 0.71073 A, mu = 0.199 mm-1, T = 153 K, R = 7.5% for 2164 I > 2 sigma (I) and 13.2% for all 3402 unique reflections. Extensive use was made of restraints on the geometrical and displacement parameters in the successful anisotropic refinement of these structures against weak data.

Aurantimycins, new depsipeptide antibiotics from Streptomyces aurantiacus IMET 43917. Production, isolation, structure elucidation, and biological activity.

Aurantimycins A (1), B (2) and C (3) were isolated from the mycelium of Streptomyces aurantiacus JA 4570 as new representatives of the azinothricin group of hexadepsipeptide antibiotics. Their structures were settled by X-ray diffraction analysis of crystalline aurantimycin A (1), high field homo- and heteronuclear 2D NMR experiments, high-resolution mass spectrometry and amino acid analysis. Aurantimycins are characterized by a new side chain containing fourteen carbon atoms. They display strong activity against Gram-positive bacteria and cytotoxic effects against L-929 mouse fibroblast cells.

Nicergoline in senile dementia of Alzheimer type and multi-infarct dementia: a double-blind, placebo-controlled, clinical and EEG/ERP mapping study.

In a double-blind, placebo-controlled study on the therapeutic efficacy and central effects of nicergoline, an ergot alkaloid with metabolic, antithrombotic and vasoactive action, 112 patients with mild to moderate dementia, diagnosed according to DSM III-R criteria (MMS 13-25), living in pensioners' homes, were included. Fifty-six were subdiagnosed as senile dementia of the Alzheimer type (SDAT), 56 as multiinfarct dementia (MID), based on computed tomography and Hachinski scores (< or = 49 SDAT, > or = 7 MID). They received, after 2 weeks' run-in period (placebo), randomized for 8 weeks either 2 x 30 mg nicergoline (NIC) or 2 x 1 placebo (PLAC) orally. The four subgroups (SDAT/NIC. SDAT/PLAC, MID/NIC, MID/PLAC; 4 x 28 patients) were comparable in regard to age and sex. Only four, four, four and two patients of the respective groups did not finish the study for minor reasons. Confirmatory statistical analysis demonstrated in the target variable-the Clinical Global Impression (CGI)-a significant superiority of Global Impression (CGI)-a significant superiority of NIC over PLAC in both the SDAT and MID groups. Global improvement (CGI item 2) was seen in both nicergoline subgroups (3 and 3), while no changes occurred under placebo (4 and 4, respectively). The responder versus non-responder ratio was in the SDAT/NIC group 16/8, versus 8/16 in the SDAT/PLAC group (chi 2 = 4.1, P = 0.04); in the MID/NIC group 17/7, versus 7/19 in the MID/PLAC group (chi 2 = 7.96, P < 0.005). Furthermore, there was a significant improvement of the Mini-Mental State and the SCAG score in both the MID and SDAT group after 8 weeks of nicergoline, which was significantly superior to the minimal improvement or no change in placebo-treated SDAT and MID patients. EEG mapping demonstrated in NIC-treated SDAT and MID patients a significant decrease in delta and theta, increase in alpha 2 and beta activity and an acceleration of the centroid of the total power spectrum as compared with pretreatment, while opposite changes occurred in PLAC-treated SDAT and MID patients. The differences between PLAC and NIC reached the level of statistical significance. Event-related potential (ERP) recordings demonstrated a significantly shortened P300 latency under NIC treatment in both SDAT and MID patients, while there was a trend towards lengthening under PLAC. Thus, nicergoline improved vigilance and information processing at the neurophysiological level, which leads at the behavioural level to clinical improvement both in degenerative and vascular dementia.