Bioavailability of reduced nicotinamide-adenine-dinucleotide (NADH) in the central nervous system of the anaesthetized rat measured by laser-induced fluorescence spectroscopy

Drugs intended to increase wellness or quality of life ("lifestyle drugs") have gained popularity and/or importance over recent years. Biogenic substances like nicotinamide adenine dinucleotide (NADH) are supposed to increase the physical and intellectual performance without side-effects. NADH is an energy-delivering co-substrate in the respiratory chain. Clinical studies showed positive effects of peripherally given NADH in Morbus Parkinson and major depression. NADH can be measured by its fluorescence. In this study a pulsed N2-laser combined with a fibre-optic probe and photomultipliers was used to induce and measure NADH fluorescence in the rat cortex. The aims of the study were to assess the suitability of the laser-induced spectroscopy for in vivo and on-line measurement of NADH in neuroscience and the assessment of the central availability of NADH after peripheral administration. NADH (50 mg/kg) but not the precursor nicotinamide caused a significant rise of the NADH fluorescence intensity indicating an increase of the NADH concentration in the rat cortex. In conclusion, the results suggest that NADH given orally or intraperitoneally increases the amounts of NADH in the brain. The results may thus help to explain the clinical effects reported.     

Ravuconazole Eisai/Bristol-Myers Squibb

Eisai and Bristol-Myers Squibb (BMS) are developing the triazole, ravuconazole, as a potential treatment for fungal infection [187888]. Eisai selected the compound for further development on the basis of its good safety profile and well-balanced antifungal activity [187888]. Ravuconazole has a broader antifungal spectrum than fluconazole and itraconazole, particularly against strains of Candida krusei and Cryptococcus neoformans [271854], [342757], [370312]. By June 1999, the compound was undergoing phase II trials [327113]. In November 2001, it was reported that BMS was seeking a co-development partner for the compound [430011]. In October 2001, analysts at ABN Amro predicted sales of US $50 million in 2003 [444020].     

Cephalosporins in veterinary medicine - ceftiofur use in food animals

Cephalosporins are an important class of antibacterial agents in use today for both humans and animals. Four generations of cephalosporins have evolved, all of which contain the beta-lactam sub-structure first found in penicillin. The range of cephalosporins available for use in food-producing animals, which is the subject of this review, is limited compared to humans. A few first- and second-generation cephalosporins are approved worldwide strictly for treatment of mastitis infections in dairy cattle. A third-generation cephalosporin, ceftiofur, and a fourth-generation cephalosporin, cefquinome, have been developed strictly for veterinary use. Cefquinome has been approved in several countries for the treatment of respiratory disease in cattle and swine, foot rot in cattle and for mastitis in dairy cattle. Ceftiofur has worldwide approvals for respiratory disease in swine, ruminants (cattle, sheep and goats) and horses and has also been approved for foot rot and metritis infections in cattle. Ceftiofur has also been approved in various countries for early mortality infections in day-old chicks and turkey poults. This review summarizes cephalosporin use in general terms, and provides an overview of ceftiofur, in terms of its spectrum of activity, indications, metabolism, and degradation in the environment. The safety of ceftiofur is also reviewed, with respect to food-animal residues, rapid metabolism and degradation, and non-persistence of ceftiofur in the environment. The environmental fragility of cephalosporins have not been explored generally, but may be an important characteristic of this antibiotic class with respect to safety of use in animals.     

Tissue diagnosis of suspected lung cancer: selecting between bronchoscopy,transthoracic needle aspiration,and resectional biopsy

In pursuing a tissue diagnosis of a suspected lung cancer, there is a range of procedures to choose from. The principal goals are ideally to diagnose and pathologically stage the patient's lung cancer at the same time, preferably by using the safest, least invasive, and least costly tests. If there is clinical or radiographic evidence of extrapulmonary spread of disease, including supraclavicular N3 nodal involvement or a malignant pleural effusion, then radiology-guided or open biopsy will confirm tumor cell type and stage the patient as unresectable. For patients with symptoms, such as increasing cough or hemoptysis, that are suggestive of airways involvement. with or without radiographic finding of central lesions, sputum cytology is the least invasive study with a high specificity. A positive finding of cancer is especially helpful if the patient is not a surgical candidate because of anatomic location of the lesion or severe physiologic limitations. The limited sensitivity of sputum cytology and poor NPV may improve with improved sputum induction and collection and processing techniques. Bronchoscopy with direct examination of the visible airways is most often the preferred invasive diagnostic procedure. Although the procedure should be geared toward sampling the highest staged lesion to provide an accurate tissue staging at the time of diagnosis, additional procedures can be performed in sequence to sample different nodal stations, is well as the primary lung mass. The incidental finding of an unexpected central airways lesions or a synchronous second endobronchial lung primary will also affect plans for treatment. Autofluorescence bronchoscopy can improve the sensitivity for detecting early intraepithelial neoplasia. Bronchoscopy for central and peripheral lung masses that are suspected to be lung cancer should be performed with ROSE whenever available. For visible endobronchial lesions, given the similar yield of EBBX and EBNA, EBNA may provide an immediate diagnosis, thus obviating additional, possibly morbid, procedures such as BB or EBBX. For submucosal lesions, EBNA is superior. For central cancers that are peribronchial, TBNA performed as for regional nodal sampling should have a yield that is comparable to TBNA for staging. TBBX and TBNA of peripheral nodules that are smaller than 3 cm have a lower diagnostic yield. Coming generations of thin bronchoscopes and improved radiographic guidance systems may improve our ability to biopsy these lesions with greater accuracy and safety. Under all circumstances, immediate cytology feedback with ROSE will confirm the adequacy of the retrieved specimen for a definitive tissue diagnosis, thus avoiding the need for extra biopsies, or worse yet, the need for a second invasive procedure because of insufficient diagnostic material. ROSE is educational to the clinician and fellow-in-training in getting immediate feedback on the procedural techniques and in learning pulmonary pathology, as well. The diagnostic sensitivity of TTNA is high, especially for the larger peripheral-based lung lesion, and TTNA is a relatively rapid procedure. TTNA's sensitivity falls for smaller or more central lesions, where the false negative rate can approach 25% to 30%; the risk of pneumothoraces and bleeding increases with central biopsies. Furthermore, TTNA usually does not provide information about nodal staging, unless the TTNA is initially directed toward central lymph nodes. The central airways are not examined in the same appointment to address issues of resection margins when there may be central spread of disease. TTNA should, therefore, be held in reserve for cases in which the sputum cytology and subsequent bronchoscopy are negative, and the patient is not a surgical candidate or refuses surgery, even if the cancer is potentially resectable. TTNA may then provide the tissue diagnosis to permit initiation of cytotoxic chemotherapy and radiotherapy. TTNA may also be helpful in cases where the likelihood of cancer is only intermediate, such that a specific benign diagnosis or an adequate sample without cancer will greatly reduce the likelihood ratio of missing a cancer, and justify to the patient and physician an approach of careful observation. To maximize the yield of these diagnostic procedures, there must be continued improvement in the hands-on teaching of clinical fellows and pulmonary practitioners in the use of the various techniques of TBNA and TBBX, as well as the applications of new endoscopic technology, such as EBUS. Definitive curative surgery remains the goal for patients with lung cancer, with accurate pathological staging performed intraoperatively. Complete lobectomy or pneumonectomy remains the standard resectional approach. Therefore, for patients with sufficient cardiopulmonary reserve who can be clinically staged as IA or IB, either by good quality CT with contrast or increasingly with 18-FDG PET, the initial tissue diagnosis may be at the time of surgery, when a frozen section preceding a complete lobectomy with lymph node sampling will combine diagnosis and therapy.     

Melatonin excretion with affect disorders over age 60

Numerous studies have reported low melatonin secretion in depression, but other studies have suggested no deficit or an increase. Alterations of circadian phase or duration of melatonin secretion have also been described. Since melatonin secretion decreases as we age, it seemed interesting to examine melatonin and depression in an aging sample. Volunteers who complained of mood or sleep problems were recruited for studies in which fractional urine specimens were collected for 24 h, both at home and in the laboratory. The major metabolite, 6-sulfatoxymelatonin (aMT6s), was determined by radioimmunoassay. Of 72 volunteers aged 60-78 years, seven had current major depression and 55% had a lifetime history of an affective disorder. A 55-fold range of home aMT6s excretion rates was observed. A lifetime history of any affective disorder was significantly associated with greater log(10)[mesor] aMT6s excretion in home collections and laboratory collections, but current affective disorders were neither significantly related to melatonin excretion nor to aMT6s acrophase timing, onset, offset or duration. These results are only weakly consistent with a photoperiodic hypothesis of depression.     

Hydroxyethyl starch in balanced electrolyte solution (Hextend)--pharmacokinetic and pharmacodynamic profiles in healthy volunteers

Hextend is a new plasma volume expander containing 6% hydroxyethyl starch (HES) in a physiologically balanced medium of electrolytes, glucose, and lactate (weight average, molecular weight 670 kDa, molar substitution 0.75). This open-label study was designed to investigate the pharmacokinetic and pharmacodynamic profiles of Hextend in 21 healthy volunteers. We infused Hextend 10 ml/kg IV over 20 min and determined serum concentrations of HES at selected intervals over a 7-day period. Serum concentration-time curves indicated mixed pharmacokinetic behavior reflecting a two-compartment model in most subjects. The median serum half-life over 7 days was 38.2 h. The balanced formulation of the suspension medium did not seem to affect distribution, metabolism, or excretion of Hextend when compared with similar HES. Pharmacodynamic analysis demonstrated decreases in some plasma components compatible with the infusion of that volume of fluid and the duration of plasma volume expansion. Other plasma components remained unchanged, reflecting the benefit of a balanced electrolyte solution. Hemodilution was observed for 24--48 h after short-term infusion of Hextend. Some hemostatic indices showed moderate changes, and serum amylase demonstrated a temporary increase. Our study suggested that Hextend has pharmacokinetic and pharmacodynamic profiles that are similar to those of other HES. IMPLICATIONS: Hextend is a new plasma volume expander containing 6% hydroxyethyl starch in a physiologically balanced medium. This open-label volunteer study demonstrated that it has pharmacokinetic and pharmacodynamic profiles similar to those of established HES.     

WIRM: An Open Source Toolkit for Building Biomedical Web Applications

This article describes an innovative software toolkit that allows the creation of web applications that facilitate the acquisition, integration, and dissemination of multimedia biomedical data over the web, thereby reducing the cost of knowledge sharing. There is a lack of high-level web application development tools suitable for use by researchers, clinicians, and educators who are not skilled programmers. Our Web Interfacing Repository Manager (WIRM) is a software toolkit that reduces the complexity of building custom biomedical web applications. WIRM’s visual modeling tools enable domain experts to describe the structure of their knowledge, from which WIRM automatically generates full-featured, customizable content management systems.Biomedical research efforts are becoming increasingly reliant on the interoperability of autonomous heterogeneous software applications, involving widespread collaboration by teams of scientists and clinicians across multiple disciplines and institutions. Consequently, there is a need for a new generation of biomedical information systems that facilitate remote collaboration, data sharing, workflow management, and integration of heterogeneous knowledge sources. The diverse nature of experimental data and protocols dictates that each information system be custom-tailored through a domain-specific set of object classes, templates, interfaces, and workflow facilities. This suggests a need for template-based, adaptable frameworks that enable scientists, clinicians, and educators to create their own custom information systems. Such frameworks should provide high-level interfaces that empower domain experts to model the structure of their content and workflow requirements, according to their own domain knowledge.This article identifies the informatics requirements for such a framework and describes the architecture and implementation of a prototype open source toolkit that begins to meet those requirements: the Web Interfacing Repository Manager (WIRM). WIRM consists of a visual development environment and a high-level programming interface that allows health professionals to rapidly design and implement their own custom web-based interfaces to biomedical content.¹ WIRM enables a nonprogrammer to model domain knowledge as object-oriented schemas, using a menu-driven interface. Once schemas are defined, WIRM automatically generates a drill-down web information system for acquiring, querying, navigating, annotating, and editing instances of those schemas.WIRM has been released as an open source toolkit and has been used to build a wide range of applications for clinicians, researchers, and educators. As estimated by the developers, WIRM reduced implementation time for the applications by 50–75% over more traditional approaches. Planned improvements should increase the usability to point that a growing number of medical professionals will be able to create custom applications that improve the efficiency of their research efforts and expand their capacity to share knowledge.     

Validation of a new method for estimating resting energy expenditure of non-ambulatory tube-fed patients with severe neurodevelopmental disabilities

OBJECTIVE: We assessed the bias and precision of the Arlington Developmental Center (ADC) equations derived from our previous study and the Harris-Benedict equations for estimating resting energy expenditure in non-ambulatory, tube-fed patients with severe neurodevelopmental disabilities. METHODS: Fifteen non-ambulatory patients with neurodevelopmental disabilities referred to the nutrition consult service for evaluation of enteral tube feeding via a permanent ostomy who had a steady-state resting energy expenditure measurement performed by indirect calorimetry were included in the study. The predicted energy expenditure values were compared with the measured resting energy expenditure values and evaluated for bias and precision. RESULTS: Both ADC equations were more precise (95% confidence interval [CI]: 9-22% and 10-18% error, respectively) for the total population than the Harris-Benedict equations (95% CI: 17-40% error). The ADC-2 equation was precise (95% CI: 7-15% error) and unbiased (95% CI: -5 to 139 kcal/d) in contrast to the Harris-Benedict equations (95% CI: 23-54% error; bias, +230 to 365 kcal/d) for patients with cerebral palsy and fixed upper extremity contractures. The Harris-Benedict equations were precise and unbiased (95% CI: 3-14% error; bias, -182 to 39 kcal/d) for patients with cerebral palsy with preservation of upper body movement, whereas the ADC equations were biased toward underprediction and associated with greater error (95% CI: -367 to -73 kcal/d and 7-26% error; 95% CI: -379 to -109 kcal/d and 9-27% error, respectively). CONCLUSIONS: The ADC-2 equation was unbiased and more precise in non-ambulatory adult patients with severe neurodevelopmental disabilities and fixed upper extremity contractures, whereas the Harris-Benedict equations were more precise and unbiased for those with preservation of limited functional and non-functional upper extremity movement.     

Positive parenting and child psychosocial adjustment in inner-city single-parent African American families. The role of maternal optimism

The primary purposes of this study were to examine whether maternal optimism is related to positive parenting and child adjustment and whether it contributes beyond maternal depressive symptoms to our understanding. The participants were 141 African American single mothers and one of their children. Findings revealed that maternal optimism was associated with positive parenting and this association was only partially mediated by maternal depressive symptoms. Maternal optimism was not associated with child psychosocial adjustment, but positive parenting was associated with lower levels of both internalizing and externalizing difficulties. The utility of understanding the link between maternal optimism and parenting for prevention and intervention efforts aimed at enhancing quality of life and subsequent child adjustment is discussed, as well as directions for future research on maternal optimism.