Combination therapy in Alzheimer's disease: a review of current evidence

Treating dementia has become a major challenge in clinical practice. Presently, acetylcholinesterase inhibitors are the first-line drugs in the treatment of Alzheimer's disease (AD). These options are now complemented by memantine, which is approved for the treatment of moderate-to-severe AD. Altogether, a minimum of six agent classes already exist, all of which are approved for clinical use and are either already being tested or ready for phase III clinical trials for the treatment of AD. These include cholinesterase inhibitors, blockers of the NMDA receptor, antioxidants or blockers of oxidative deamination (including Gingko biloba), anti-inflammatory agents, neurotrophic factors (including hormone replacement therapy and drugs acting on insulin signal transduction) and antiamyloid agents (including cholesterol-lowering therapy). These approaches hold promise for disease modification and have a potential to be used as combination therapy for cognitive enhancement. Presently, only nine clinical studies have been published that have investigated the effects of a combination regimen on cognitive performance or AD. Among those, one study was conducted in elderly cognitively intact persons; the others involved patients with AD. Only five of the treatment studies followed a randomised, controlled design. Not all studies favoured the superior efficacy of combination therapy over monotherapy. Some studies, however, showed some evidence for synergistic combination effects of symptomatic therapy, including delay or prevention of disease progression in AD patients. In addition, six studies investigated the effects of AChE inhibitor in combination with antipsychotic or antidepressant therapy on behavioural aspects of AD symptomatology. In four of those studies there were indications that combination therapy had greater efficacy over monotherapy. The treatment of AD patients requires optimised options for all stages of illness based on the available drugs. There is a great need for further well designed studies on combination therapy in AD.     

Lumbar spine radiography: digital flat-panel detector versus screen-film and storage-phosphor systems in monkeys as a pediatric model

PURPOSE: To assess image quality and exposure dose requirements of a flat-panel detector system versus screen-film and storage-phosphor systems for radiographic depiction of the lumbar spine in Cynomolgus monkeys as a pediatric model. MATERIALS AND METHODS: Twenty Cynomolgus monkeys underwent anteroposterior radiography of the lumbar spine. The size and weight of these monkeys are comparable to those of infants 3-4 months of age. Images were acquired with speed class 400 screen-film, flat-panel, and storage-phosphor systems with identical exposure dose. All other conditions were matched exactly. Additional images were acquired with the flat-panel and storage-phosphor systems at exposure doses equivalent to speed classes 800 and 1600. All images were obtained at 66 kVp without antiscatter grid. Images were assessed independently by three radiologists for visibility of 60 anatomic structures by using a five-point confidence scale. Scores were calculated for the seven combinations of imaging mode and exposure dose and were compared by using the Friedman test. RESULTS: Scores were 1.70 (speed class 400), 1.97 (speed class 800), and 2.27 (speed class 1600) for the flat-panel system; 2.50 (speed class 400) for the screen-film system; and 2.58 (speed class 400), 2.77 (speed class 800), and 3.13 (speed class 1600) for the storage-phosphor system. Scores for the flat-panel system at speed classes 400 and 800 were significantly lower (indicating better visibility) than those of the screen-film and storage-phosphor systems (P <.05). CONCLUSION: The flat-panel system is superior to screen-film and storage-phosphor systems in lumbar spine radiography in monkeys. With the flat-panel system, exposure dose can be reduced by 75% without loss in image quality.     

Implementation and evaluation of a Web-based continuing education course in injury prevention and control

Training in injury prevention and control represents a major deficit in the fields of health promotion and public health. Internet-based distance learning is an innovative method of offering continuing education to professionals, but this approach has not yet been widely researched or implemented with public health audiences. VINCENTweb involved the development and evaluation of a no-cost continuing education course on injury prevention and control presented exclusively on the World Wide Web. The course was evaluated using online surveys at baseline and follow-up. Participants, especially those with lower education levels, provided positive feedback about the course and reported high levels of learning and satisfaction. This article describes the development and evaluation of VINCENTweb and discusses the implications for developing future Internet-based courses in public health.     

Diagnostic potential of virtual cystoscopy of the bladder: MRI vs CT. Preliminary report

The aim of the study was to evaluate the diagnostic potential of the half-Fourier acquired single-shot turbo spin echo (HASTE) sequence for MRI cystoscopy compared with CT cystoscopy and the gold standard conventional cystoscopy. The MRI- and CT cystoscopy was performed in 29 patients with bladder tumors documented at cystoscopy and a control group using a 1.5-T unit (6-mm slice thickness) and a helical CT (3-mm collimation, pitch 1) after filling the bladder with air. Axial MRI and CT images were transferred to a workstation for application of virtual cystoscopy and compared with routine cystoscopy. Axial images and virtual cystoscopies were read by three readers for size and location of tumors. Forty-seven tumors were diagnosed at cystoscopy (12<1 cm, 35≥1 cm). The sensitivity for detection of tumors smaller than 1 cm was 88.9% at MRI cystoscopy and 100% for tumors of 1 cm or larger. These results were not statistically different from the other modalities. Three tumors smaller than 1 cm were not detected at CT cystoscopy, four not all identical at MRI cystoscopy. One tumor with a wall thickening was detected on axial CT and MR images and CT cystoscopy by all observers, but only by two at MRI cystoscopy. The MRI cystoscopy is a diagnostic modality with results comparable to conventional and CT cystoscopy. Electronic Publication     

Changes in Candida albicans colonization and morphology under influence of voriconazole

The aim was the investigation of fungal colonization and morphological alterations under the influence of voriconazole in an in vitro system. Voriconazole stopped growth and colonization of Candida albicans (wild type SC5314) on cover slips in microtiter plates dependent on drug concentration, the time of Candida growth before the input of voriconazole and oxygen concentration. The direct microscopy by fluorescence staining with the optical brightener Blancophor showed short bizarrely deformed mycelia looking swollen. The colonization on cover glass was diminished. Microcolonies or starting of biofilm formation as in the control was not observed. The metabolic activity was demonstrated by vital staining with FUN 1 resulting in red fluorescent structures in the yeast forms and mycelia in the controls. Under voriconazole influence the remaining cells only showed a green or pale yellow fluorescence. Most of the cells lost their metabolic activity.     

Uptake of meta-iodobenzylguanidine in neuroendocrine tumours is mediated by vesicular monoamine transporters

The radio-iodinated noradrenaline analogue meta-iodobenzylguanidine (MIBG) can be used for scintigraphy and radiation therapy of neuroendocrine (NE). The aim of the present study was to study the importance of vesicular monoamine transporters (VMATs) for the uptake of (123)I-MIBG in NE tumours. In nude mice, bearing the human transplantable midgut carcinoid GOT1, all organs and xenografted tumours accumulated (123)I after i.v. injection of (123)I-MIBG. A high concentration of (123)I was maintained in GOT1 tumours and adrenals, which expressed VMATs, but rapidly decreased in all other tissues. In the VMAT-expressing NE tumour cell lines GOT1 and BON and in VMAT-expressing primary NE tumour cell cultures (carcinoids, n=4 and pheochromocytomas, n=4), reserpine significantly reduced the uptake of (123)I-MIBG. The membrane pump inhibitor clomipramine had no effect on the uptake of (123)I-MIBG in GOT1 and BON cells, but inhibited the uptake in one out of four primary carcinoid cell cultures and three out of four primary pheochromocytoma cell cultures. In conclusion, VMATs and secretory granules are of importance for the uptake and retention of (123)I-MIBG in NE tumours. Information about the type and degree of expression of VMATs in NE tumours may be helpful in future to select patients suitable for radiation therapy with radio-iodinated MIBG.     

Pathophysiological Measurement and Results After Laparoscopic Fundoplication for Gastroesophageal Reflux Disease

Purpose: Both surgical and conservative treatments for gastroesophageal reflux disorder (GERD) are controversial. The aim of this prosepective study was to examine outcomes after laparoscopic antireflux surgery. Methods: The subjects were 143 patients who underwent laparoscopic antireflux surgery. Following diagnostic procedures 126 patients were allocated to a total fundoplication group (360°C, Nissen-DeMeester) and 17, to a posterior semifundoplication group (250–270°, Toupet). All complications were registered, and pathophysiological and outcome data were examined 3, 6, and 9 months after surgery. Results: By 6 months after surgery the mean lower esophageal sphincter (LES) pressure had improved significantly, to 14.8 mmHg in the Nissen-DeMeester group, and to 12.1 mmHg in the Toupet group, corresponding to successful prevention of esophageal reflux in both groups. Dysphagia was more common in the early postoperative period after total fundic wrap (17% vs 12%), but this difference disappeared in time. All patients reported complete relief of reflux symptoms, although two of those who underwent the Nissen-DeMeester fundoplication experienced relapse of GERD and required open reconstruction (1.4%). The laparoscopic procedure was converted to open surgery in three patients (2%). There were no associated deaths and the perioperative complication rate was 4.2%. Conclusion: Laparoscopic antireflux surgery is an effective treatment for GERD. More than 93% of the patients in this series rated their outcome as good to excellent following the operation. Received: December 10, 2001 / Accepted: May 7, 2002 Reprint requests to: K. Ludwig     

Strength training by children and adolescents

Pediatricians are often asked to give advice on the safety and efficacy of strength training programs for children and adolescents. This review, a revision of a previous American Academy of Pediatrics policy statement, defines relevant terminology and provides current information on risks and benefits of strength training for children and adolescents.