Survival of rats with experimental chronic heart failure depending on pharmacodynamic and pharmacokinetic parameters of angiotensin-converting enzyme inhibitors and β-adrenoceptor blockers

Lipophilic inhibitors of angiotensin-converting enzyme increased 6-month survival and/or lifetime of rats with experimental chronic heart failure. These drugs had no effect on the mortality rate of animals with acute decompensation of the disease. β-Adrenoceptor blockers without intrinsic sympathomimetic activity not only prolonged 6-month survival and lifetime, but also decreased the mortality rate of rats with decompensation of chronic heart failure. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 141, No. 1, pp. 45–48, January, 2006     

Mechanical properties,electronic structure and bonding of α- and β-tricalcium phosphates with surface characterization

The mechanical properties and electronic structure of α- and β-tricalcium phosphate (TCP) crystals are studied by using two ab initio density functional methods, the Vienna Ab initio Simulation Package (VASP) and the orthogonalized linear combination of atomic orbitals method. Based on the VASP optimized crystal structures, the elastic constants of α- and β-TCP are obtained using an effective stress–strain computational scheme. From the calculated elastic constants, the bulk modulus, shear modulus, Young’s modulus and Poisson’s ratios are obtained. The results show that the mechanical properties of the two crystals are comparable and that α-TCP is somewhat softer than β-TCP. Comparison with experimental extrapolations of the elastic constants shows significant differences, which attest to the difficulty of obtaining single crystal samples. The calculated electronic structure results show that both crystals are large gap insulators with a direct band gap of 4.89 eV for α-TCP and 5.25 eV for β-TCP. Effective charge calculations show that, on average, β-TCP has slightly less charge transfer per Ca than α-TCP. The (0 1 0) ((0 0 1)) surface model for α-TCP (β-TCP) is studied using a supercell slab geometry and fully relaxed to obtain the optimized structures. The estimated surface formation energies are 0.777 and 0.842 J m^?2 for α-TCP and β-TCP, respectively. The electronic structures of the two surface models are compared with the bulk models. Charge density analysis shows that the surfaces of both TCP crystals are positively charged overall owing to the presence of Ca ions near the surfaces.     

Development of botanical principles for clinical use in cancer: where are we lacking?

Development of drugs from plant sources (botanicals) for the treatment of cancer has not been successful in India, despite a plethora of medicinal plants and an equal number of experiments demonstrating anti-cancer activity of plant principles in vitro. There are several pitfalls in our approach to botanical drug development. Foremost is the lack of industry-academia collaborations in this field. Research goals in Indian academic institutions are generally short-term and mostly aimed at fulfilling the minimum requirements of a doctoral/MD or MPharm thesis. Secondly, quality assurance of herbal formulations is difficult to achieve and good manufacturing practices are expensive to implement. This could introduce bias during the biological evaluation of botanicals. A systematic approach covering a wide range of investigations including but not limited to mechanistic studies, potential herb-drug interactions, pharmacokinetics and bioavailability could help in the optimization of herbal formulations in the preclinical stage of development before they can be considered for clinical trials. Government initiatives such as Ayurveda, Unani, Siddha and Homeopathic have encouraged research in these areas, but are insufficient to promote focused and aggressive evaluation of potential herbs. Particular emphasis should be given to clinical pharmacokinetics, drug interactions and clinical trials in specific cancers for the evaluation of dosage, safety, efficacy and concomitant use with chemotherapy. Only such policies can result in meaningful evaluation of botanicals for cancer therapy.     

Risk factors for, and clinical relevance of, faecal extended-spectrum β-lactamase producing Escherichia coli (ESBL-EC) carriage in neutropenic patients with haematological malignancies

The purpose of this study was to assess the risk factors for, and the clinical relevance of, faecal carriage by extended-spectrum β-lactamase producing Escherichia coli (ESBL-EC) in neutropenic cancer patients (NCP). An observational prospective multicentre cohort study was conducted over 2 years at two teaching hospitals. Patients with acute leukaemia or undergoing stem cell transplantation were included during neutropenia episodes. Rectal swabs were obtained at hospital admission and weekly thereafter until discharge or death. ESBL-EC colonized episodes were compared with non-colonized episodes. ESBL-EC strains were studied by PCR and isoelectric focusing, and molecular typing was performed by pulsed field gel electrophoresis (PFGE). Among 217 episodes of neutropenia, the prevalence of ESBL-EC faecal carriage was 29% (14% at hospital admission). Multivariate analysis identified previous antibiotics as the only independent risk factor for ESBL-EC faecal colonization (OR 5.38; 95% CI 2.79–10.39). Analysis of ESBL-EC isolates revealed a polyclonal distribution with CTX-M predominance (81.3%). E. coli bacteraemia was mainly caused by non-ESBL producing strains and its rate was similar in both groups (13% vs. 11%). We found no association between ESBL-EC carriage and an increased risk of ESBL-EC bacteremia or a negative influence on other clinical outcomes, including length of hospitalisation, early and overall mortality rates. ESBL-EC faecal colonization is frequent in NCP but difficult to identify by epidemiological or clinical features on presentation. Prior antibiotic therapy is the major associated risk factor. In this setting colonization does not appear to have a significant clinical relevance. Thus, routine testing for ESBL-EC faecal carriage does not seem to be beneficial.     

Antiarthritic profile of BF-389 — A novel anti-inflammatory agent with low ulcerogenic liability

BF-389, dihydro-4-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2methyl-2H-1,2-oxazin-3(4H)-one, is a potent, orally active, antiarthritic and analesis agent with low ulcerogenic potential. A comparison of the activity profiles of BF-389 and naproxen showed similarities in: (1) suppression of developing and chronic adjuvant arthritis (AA); (2) maximal inhibitory response, as shown by theE(max0 values in the developing and established AA models; (3) inhibition of bone degenerative changes associated with chronic adjuvant arthritis; and (4) analgesic activity in the acetic acid and phenylquinone writhing assays. Though BF-389 has been shown to be a potent inhibitor of cyclooxygenase, IC₅₀=0.84±0.25 M against the production of PGE₂ in vitro, there is a great difference from most cyclooxygenase inhibitors; it also inhibits the 5-lipoxygenase enzyme. For BF-389, the IC₅₀ for invitro LTB₄ formation was found to be 3.65±1.19 M. The ulcerogenic potential of BF-389 was compared to that of naproxen using a five-dayin vivo ulcerogenic rat assay. The UD₅₀ for naproxen was found to be approximately 30 mg/kg/day, p.o. Based upon efficacy in the DEV AA and EST AA models, UD₅₀/ED₅₀ values for naproxen were estimated to be 0.7 and 1.9, respectively. For BF-389 the UD₅₀ was shown to be 520 (389–695) mg/kg/day, p.o., and the corresponding UD₅₀/ED₅₀ values were calculated to be 84 and 28, respectively, thus demonstrating the wide margin of safety between efficacy and ulcerogenicity in rats.     

Age-related differences in the response of blood stroke volume to stimulation of the sympathetic ganglion in rats with β-adrenoceptor blockade

Blood stroke volume in rats aging 21 and 56 days decreased during -adrenoceptor blockade with propranolol, but increased again by the 15th minute after treatment. Suprathreshold stimulation of the stellate ganglion decreased the stroke volume and increased the heart rate in control animals. Electrical stimulation after -adrenoceptor blockade was followed by a further decrease in stroke volume in young rats. In 100-day-old animals this parameter remained unchanged, while the cardiac output improved.Translated from Byulleten Eksperimentalnoi Biologii i Meditsiny, Vol. 138, No. 10, pp. 393–396, October, 2004     

Age-related differences in the response of blood stroke volume to stimulation of the sympathetic ganglion in rats with β-adrenoceptor blockade

Blood stroke volume in rats aging 21 and 56 days decreased during -adrenoceptor blockade with propranolol, but increased again by the 15th minute after treatment. Suprathreshold stimulation of the stellate ganglion decreased the stroke volume and increased the heart rate in control animals. Electrical stimulation after -adrenoceptor blockade was followed by a further decrease in stroke volume in young rats. In 100-day-old animals this parameter remained unchanged, while the cardiac output improved.Translated from Byulleten Eksperimentalnoi Biologii i Meditsiny, Vol. 138, No. 10, pp. 393–396, October, 2004     

Cefotaxime for the detection of extended-spectrum β-lactamase or plasmid-mediated AmpC β-lactamase and clinical characteristics of cefotaxime-non-susceptible Escherichia coli and Klebsiella pneumoniae bacteraemia

We investigated the performance of cefotaxime for the detection of extended-spectrum β-lactamase (ESBL) or plasmid-mediated AmpC β-lactamase (pAmpC) and the clinical characteristics of cefotaxime-non-susceptible Escherichia coli or Klebsiella pneumoniae (CTXNS-EK) bacteraemia. All of the consecutive bloodstream isolates between 2005 and 2010 in a Japanese university hospital were characterised using polymerase chain reaction (PCR). Risk factors and outcomes of CTXNS-EK were analysed by multivariate logistic regression analysis. We identified 58 CTXNS-EK (15.6%) from 249 E. coli and 122 K. pneumoniae. Cefotaxime with a minimum inhibitory concentration (MIC) of >1 μg/mL had a sensitivity of 98.3% and a specificity of 99.7% for the detection of ESBL or pAmpC. CTXNS-EK had increased from 4.5% in 2005 to 23% in 2009. Risk factors for CTXNS-EK were previous isolation of multidrug-resistant bacteria, use of oxyimino-cephalosporins or fluoroquinolones, and high Sequential Organ Failure Assessment (SOFA) score. Patients with CTXNS-EK bacteraemia less frequently received appropriate empirical therapy than patients with cefotaxime-susceptible EK bacteraemia (81% vs. 97%, p<0.001) and died within 30 days (21% vs. 5%, p=0.001). Using the current breakpoints of the Clinical and Laboratory Standards Institute (CLSI) or the European Committee on Antimicrobial Susceptibility Testing (EUCAST), cefotaxime alone can identify ESBL or pAmpC producers. CTXNS-EK is an important and increasingly prevalent bacteraemia pathogen.     

Mediastinal adipose tissue expresses a pathogenic profile of 11 β-hydroxysteroid dehydrogenase Type 1, glucocorticoid receptor,and CD68 in patients with coronary artery disease

ObjectiveCardiac visceral fat is accepted to be a new marker for cardiometabolic risk due to its association with increased cardiovascular risk factors. This study aimed to compare the expression of 11 beta hydroxysteroid dehydrogenases (11β-HSD)-1, glucocorticoid receptor (GCR), and CD68 in mediastinal and subcutaneous adipose tissues (MAT, and SAT, respectively) and to assess their possible relationships with the development of coronary artery disease (CAD).Methods and resultsExpression of 11β-HSD-1, GCR, and CD68 mRNA levels were measured by quantitative real-time polymerase chain reaction in MAT and SAT tissues of 37 patients undergoing coronary artery bypass grafting due to CAD (CAD group) and 19 non-CAD patients (controls) undergoing heart valve surgery. 11β-HSD-1 in MAT and SAT and GCR expression in MAT and SAT were found to be significantly increased in CAD group when compared with controls (P<.05, respectively). In CAD group, 11β-HSD-1 mRNA levels were found to be significantly higher in MAT compared to SAT (P<.05). CD68 mRNA levels were significantly higher in MAT of CAD group compared to controls (P<.05). Immunohistochemical analyses demonstrated the presence of CD68+ cells and increased 11β-HSD-1 expression in MAT of CAD group compared to SAT.ConclusionThe present study demonstrate that the mediastinal fat exhibits a pathogenic mRNA profile of 11β-HSD-1, GCR, and CD68. The identification of 11β-HSD-1 expression within the mediastinal fat, along with increased GCR expressions and the presence of CD68+ cells highlight that MAT potentially contributes to the pathogenesis of CAD.     

Old but Vigorous, Keeping Pace with Time——Written for the Expert of Preventive Medicine, Professor Yu Enshu

ProfessorYuEnshuisoneofthezoonosisfoundersinChina.Bytheyearof2 0 0 3athisvenerableageof85,however,hestillgoestoworkinlaboratoryeveryday,be ingthechiefeditoroftheJournalofChineseZoonoses.Andhisserialmonographsandpublicationsreflectallhiscreatingandendlessprobingspirits.HewasborninGaicountyofLiaoningprovinceonApril3 ,1 91 8.GraduatingfromManchuriaMedicalUni versitywithexcellentachievementin 1 944,hewasaskedtoremainattheMicrobiologicalDepartmentoftheuniver sityforfurtherstudy.In 1 946,hewas…     

Medium-term clinical results of unicompartmental knee arthroplasty for the treatment for spontaneous osteonecrosis of the knee with four to 15 years of follow-up

BackgroundUnicompartmental knee arthroplasty (UKA) is an option for the treatment of spontaneous osteonecrosis of the knee (SONK). However, there are limited studies focusing on this area. This study presents medium-term clinical outcome data of UKA for SONK.MethodsWe reviewed 50 SONK knees in 48 patients that were treated by UKA. The mean age, height, and body weight were 73 years, 153 cm, and 57 kg, respectively. The mean follow-up was 8.4 years (range, four to 15 years). Preoperatively, we measured the size and the volume (estimated by width × length × depth) of the necrotic bone mass on T1-weighted magnetic resonance imaging. The clinical results were evaluated serially at follow-up visits radiographically and with the Knee Society Scoring (KSS) and Oxford Knee Scoring (OKS) systems.ResultsThere were no revisions, re-operations, or major complications. The mean sizes of the necrotic lesions were 17.2 mm (14.7–22.3 mm) in width, 28.2 mm (6.2–34.7 mm) in length, and 11.3 mm (3.2–14.5 mm) in depth. The mean volume was approximately 5.4 cm³ (0.7–10.3 cm³). The mean flexion of the knee, KSS Knee Score, Function Score, and OKS increased from a preoperative 128.7–137.5°, 52.3–91.3, 39.7–90.2, and 21.6–40.2, respectively, at the latest follow-up. At the last follow-up, all patients had good or excellent OKS.ConclusionsThis study demonstrates that UKA is a good option and is reliable for the treatment of SONK irrespective of necrotic bone mass size.     

Changes of tension and [Ca2+]i during β-adrenoceptor activation of single,intact fibres from mouse skeletal muscle

-Adrenergic agonists increase tension production in fast-twitch skeletal muscle, but the underlying mechanism is unknown. In the present study we have exposed intact, single fibres from a mouse muscle to the ₂-adrenergic agonist terbutaline. Fibres were stimulated to produce 350-ms tetani at 20–100 Hz while measuring the myoplasmic Ca²⁺ concentration ([Ca²⁺]_i) and tension. The fluorescent indicator Indo-1 was used to measure [Ca²⁺]_i. Application of terbutaline resulted in marked increases of both tetanic [Ca²⁺]_i and tension. Terbutaline had no significant effect on myofibrillar function as judged from normal Ca²⁺ sensitivity and tension production at saturating [Ca²⁺]_i. The rate of [Ca²⁺]_i and tension decline during relaxation was not affected by terbutaline, thus indicating a normal function of the sarcoplasmic reticulum (SR) Ca²⁺ pumps. The effect of terbutaline developed gradually over 5–10 min when fibres were stimulated each minute; the full effect of terbutaline was also obtained after a 10-min rest period in terbutaline. The [Ca²⁺]_i at rest was not affected by terbutaline. In conclusion, -adrenergic stimulation increases tetanic tension by enhancing SR Ca²⁺ release.