Innovative clinical trial designs to rationalize TB vaccine development.

A recent trial of a leading tuberculosis (TB) vaccine candidate in 3000 South African infants failed to show protection over that from BCG alone, and highlights the difficulties in clinical development of TB vaccines. Progression of vaccine candidates to efficacy trials against TB disease rests on demonstration of safety and immunogenicity in target populations and protection against challenge in preclinical models, but immunologic correlates of protection are unknown, and animal models may not be predictive of results in humans. Even in populations most heavily affected by TB the sample sizes required for Phase 2b efficacy trials using TB disease as an endpoint are in the thousands. Novel clinical trial models have been developed to evaluate candidate TB vaccines in selected populations using biologically relevant outcomes and innovative statistical approaches. Such proof of concept studies can be used to more rationally select vaccine candidates for advancement to large scale trials against TB disease.

Testing the competition-colonization trade-off with a 32-year study of a saxicolous lichen community.

Competition-colonization trade-offs are theorized to be a mechanism of coexistence in communities structured by environmental fluctuations. But many studies that have tested for the trade-off have failed to detect it, likely because a spatiotemporally structured environment and many species assemblages are needed to adequately test for a competition-colonization trade-off. Here, we present a unique 32-year study of rock-dwelling lichens in New Mexico, USA, in which photographs were used to quantify lichen life history traits and interactions through time. These data allowed us to determine whether there were any trade-offs between traits associated with colonization and competition, as well as the relationship between diversity and disturbance in the community. We did not find evidence for a trade-off between competitive ability and colonization rate or any related life history traits. Interestingly, we did find a peak in all measures of species diversity at intermediate levels of disturbance, consistent with the intermediate disturbance hypothesis pattern. We suggest that the coexistence of the dominant species in this system is regulated by differences in persistence and growth rate mediating overgrowth competition rather than a competition-colonization trade-off.

Hand position effects on precision and speed in telerobotic surgery.

BACKGROUND: Many surgical robotic interfaces allow users to interact with robots over a wide potential range of motion, yet variation in operator performance across a range of motion remains unexamined. This research identifies and explores a new construct, the surgeon's 'comfortable working envelope' within the available range of motion, as a factor in surgical robotic interface design. METHODS: Task accuracy and completion time for a simple aimed movement task were analysed as a function of participant hand positions obtained via infrared motion tracking. RESULTS: Hand positions outside the 'comfortable working envelope' led to a 20% increase in error magnitude. With respect to the overall input device range of motion, there were large variations in performance, up to 31% difference in error magnitude and 11% difference in movement time. CONCLUSIONS: These results suggest that advanced surgical robots should have intelligent re-indexing strategies. Alternatively, the robot's control gain should adaptively change with respect to hand position to normalize a surgeon's performance throughout his/her working volume.

Thalidomide in the treatment of cancer cachexia: a randomised placebo controlled trial.

BACKGROUND: Proinflammatory cytokines, especially tumour necrosis factor alpha (TNF-alpha), play a prominent role in the pathogenesis of cancer cachexia. Thalidomide, which is an inhibitor of TNF-alpha synthesis, may represent a novel and rational approach to the treatment of cancer cachexia. AIMS: To assess the safety and efficacy of thalidomide in attenuating weight loss in patients with cachexia secondary to advanced pancreatic cancer. METHODS: Fifty patients with advanced pancreatic cancer who had lost at least 10% of their body weight were randomised to receive thalidomide 200 mg daily or placebo for 24 weeks in a single centre, double blind, randomised controlled trial. The primary outcome was change in weight and nutritional status. RESULTS: Thirty three patients (16 control, 17 thalidomide) were evaluated at four weeks, and 20 patients (eight control, 12 thalidomide) at eight weeks. At four weeks, patients who received thalidomide had gained on average 0.37 kg in weight and 1.0 cm(3) in arm muscle mass (AMA) compared with a loss of 2.21 kg (absolute difference -2.59 kg (95% confidence interval (CI) -4.3 to -0.8); p = 0.005) and 4.46 cm(3) (absolute difference -5.6 cm(3) (95% CI -8.9 to -2.2); p = 0.002) in the placebo group. At eight weeks, patients in the thalidomide group had lost 0.06 kg in weight and 0.5 cm(3) in AMA compared with a loss of 3.62 kg (absolute difference -3.57 kg (95% CI -6.8 to -0.3); p = 0.034) and 8.4 cm(3) (absolute difference -7.9 cm(3) (95% CI -14.0 to -1.8); p = 0.014) in the placebo group. Improvement in physical functioning correlated positively with weight gain (r = 0.56, p = 0.001). CONCLUSION: Thalidomide was well tolerated and effective at attenuating loss of weight and lean body mass in patients with cachexia due to advanced pancreatic cancer.

Effect of lower limb Sofield procedure on ambulation in osteogenesis imperfecta.

Ambulation status was evaluated in 34 patients pre- and post-Sofield procedure in patients with osteogenesis imperfecta. Three percent had improved ambulation, 42.4% remained the same and 54.6% were worse. Only 41.2% were ambulating postoperatively compared to 73.5% preoperatively. The Sofield procedure did not improve ambulation status.

Functional outcome of Sofield procedure in the upper limb in osteogenesis imperfecta.

The functional outcome of Sofield procedures done in the upper limb of five patients with severe osteogenesis imperfecta was studied. Fourteen procedures were done. Mean follow-up was more than 10 years. Function of the upper limb improved in all patients. No patient lost function.

Paraparesis after posterior spinal fusion in neurofibromatosis secondary to rib displacement: case report and literature review.

In patients with neurofibromatosis, rib displacement into the spinal canal is a rare cause of paraplegia. We report a patient with paraplegia caused by rib displacement whose signs and symptoms began after posterior in situ fusion for dysplastic scoliosis. There was complete recovery after anterior decompression and resection of the rib.

Clearance of refractory bile duct stones with extracorporeal shockwave lithotripsy.

BACKGROUND: Extracorporeal shockwave lithotripsy (ESWL) has been used since the mid-1980s to fragment bile duct stones which cannot be removed endoscopically. Early machines required general anaesthesia and immersion in a waterbath. AIMS: To investigate the effectiveness of the third generation Storz Modulith SL20 lithotriptor in fragmenting bile duct stones that could not be cleared by mechanical lithotripsy. METHODS: Eighty three patients with retained bile duct stones were treated. All patients received intravenous benzodiazepine sedation and pethidine analgesia. Stones were targeted by fluoroscopy following injection of contrast via a nasobiliary drain or T tube. Residual fragments were cleared at endoscopic retrograde cholangiopancreatography. RESULTS: Complete stone clearance was achieved in 69 (83%) patients and in 18 of 24 patients (75%) who required more than one ESWL treatment. Stone clearance was achieved in all nine patients (100%) with intrahepatic stones and also in nine patients (100%) referred following surgical exploration of the bile duct. Complications included six cases of cholangitis and one perinephric haematoma which resolved spontaneously. CONCLUSION: Using the Storz Modulith, 83% of refractory bile duct calculi were cleared with a low rate of complications. These results confirm that ESWL is an excellent alternative to surgery in those patients in whom endoscopic techniques have failed.

Bilateral adrenal non-Hodgkin's lymphoma with adrenal insufficiency.

A 74 year old women presented with lethargy and weight loss and was found to have profound adrenal insufficiency and bilateral adrenal mass lesions. Histological examination revealed non-Hodgkin's lymphoma. There was no evidence of lymphoma outside the adrenal glands. Isolated bilateral adrenal masses may rarely be due to primary adrenal non-Hodgkin's lymphoma, which is often associated with adrenal insufficiency.

Site selection by intestinal helminths of the Virginia opossum (Didelphis virginiana).

Digestive tract helminths of the Virginia opossum (Didelphis virginiana) were examined for site specificity and interspecific interactions. Thirty opossums were live-trapped at 2 localities in Georgia, killed, and their digestive tracts removed and divided into the following sections; esophagus, stomach, small intestine (20 equal sections), cecum, and large intestine (5 equal sections). Helminths present in each section were identified and counted. Three trematode, 1 cestode, 2 acanthocephala, and 6 nematode species were found. Two parasites (the acanthocephalan Centrorhynchus spinosus and the nematode Viannaia hamata) are new state records for Georgia and this is the first report of C. spinosus from an opossum. There was considerable overlap between the spatial distributions of many of the helminth species found in the small intestine though most species had different modal locations. Helminth species locations were unaffected by host sex or trapping locality. There was no evidence that the presence, absence, or intensity of any helminth species affected the location or intensity of other helminth species in the digestive tract.

Participatory design of an Internet-based information system for aging services professionals.

The Michigan Aging Services System, a World Wide Web-based information system, was developed for practicing gerontologists in the state of Michigan. A participatory design framework adapted from the software development literature guided the development process. Users from Michigan's aging network participated in the development process. Design data were collected using multiple techniques. The system's content was developed with extensive input from actual users. The content emerged into four main categories: News and Current Events, General Information, Policy and Program Information, and Population Information. The system content is briefly compared to that of World Wide Web sites published by other state units on aging.

Activation of nuclear factor kappa B in Crohn's disease.

OBJECTIVES AND DESIGN: The location and degree of activation of nuclear factor kappa (NFkappaB), a primary transcription factor that plays a regulating role in immune and inflammatory responses, was determined in Crohn's disease using full thickness specimens of bowel collected at surgery. MATERIALS AND METHODS: Resected specimens of inflamed and non-inflamed bowel were collected from thirteen patients with Crohn's disease and non-inflamed bowel from eleven control subjects. Prepared frozen sections were immunostained using a monoclonal antibody to the activated form of the p65 subunit of NFkappaB and the number of positive staining cells counted using a Lennox graticule. RESULTS: The number of cells positive for activated NFkappaB was significantly increased (p = 0.001 ) in all layers of inflamed Crohn's disease bowel, compared to non-inflamed bowel from controls. There was also a significant increase ( p = 0.009) in the number of positive cells, when compared to non-inflamed bowel from control subjects, in the submucosa of non-inflamed areas of Crohn's disease bowel. Cells positive for activated NFkappaB were provisionally identified by morphological criteria as mostly macrophages with some lymphocytes. There was no activation in endothelia. CONCLUSION: NFkappaB is activated within large mononuclear cells in all layers of inflamed areas of the bowel in Crohn's disease and may represent key events in the inflammatory process. Increased activation in the submucosa of non-inflamed Crohn's disease bowel provides further evidence of early immunological activation in macroscopically and microscopically uninvolved areas and an underlying abnormal immune system in Crohn's disease.

Ferric trimaltol corrects iron deficiency anaemia in patients intolerant of iron.

BACKGROUND: Oral iron supplements, which are usually in the form of ferrous (Fe2+) salts, are toxic to the gastrointestinal mucosa, and so intolerance is common, resulting in poor compliance and failure of treatment. The sugar derivative maltol strongly chelates iron, rendering it available for absorption and stabilized in the less toxic ferric (Fe3+) form. AIM: To test whether ferric trimaltol could correct iron deficiency anaemia in patients intolerant of ferrous sulphate. METHODS: Twenty-three patients were recruited from gastroenterology clinics, of whom 1 5 had inflammatory bowel disease, a group often difficult to treat with oral iron. Patients with iron deficiency anaemia and documented intolerance to ferrous sulphate were given 3 months of treatment with ferric trimaltol. RESULTS: Nineteen of 23 patients completed the treatment and anaemia was fully corrected in 14 of these, mean haemoglobin increased from 106 +/- 15 to 126 +/- 16 g/L, and there was a particularly low incidence of side-effects. Of 11 patients with inflammatory bowel disease who completed the study, nine fully corrected their anaemia. CONCLUSION: The results demonstrate that in patients intolerant of ferrous compounds, ferric trimaltol corrects iron deficiency and has a low incidence of side-effects.

Mesenteric vasculitis associated with Sézary syndrome.

A 71 year old lady with Sézary syndrome presented with chronic diarrhoea and cramping abdominal pains. A small bowel meal x ray examination showed two mid-ileal strictures. At laparotomy the small intestine was found to be sub-acutely obstructed and resection of a 15 cm ileal stricture and stricturoplasty of a second, 10 cm stricture were performed. Histological examination of the stricture revealed a mesenteric vasculitis with secondary ischaemic changes in the small bowel wall. Mesenteric vasculitis causing small bowel stricture may be associated with Sézary syndrome.

Predicting age-related differences in visual information processing using a two-stage queuing model.

Recent work on age-related differences in some types of visual information processing has qualitatively stated that younger adults are able to develop parallel processing capability, while older adults remain serial processors. A mathematical model based on queuing theory was used to quantitatively predict and parameterize age-related differences in the perceptual encoding and central decision-making aspects of a multiple-frame search task. Statistical results indicated main effects for frame duration, display load, age group, and session of practice. Comparison of the full model and a restricted model indicated an efficient contribution of the encoding speed parameter. The best-fitting parameter set indicated that (1) younger participants processed task information with a two-channel parallel system, while older participants were serial processors; and (2) perceptual encoding had a large impact on age-related differences in task performance. Results are discussed with implications for human factors design principles.

Gero-informatics and the Internet: locating gerontology information on the World Wide Web (WWW).

The Internet, and in particular the World Wide Web (WWW), are growing at a tremendous rate. Information useful to researchers and practitioners in gerontology is scattered and hard to locate, even for experts in the use of the WWW. In order to locate and organize access to this material, a WWW server was developed for gerontologists, using state-of-the-art Internet search techniques. This report provides background on the WWW, reasons for its growth, its potential usefulness to gerontologists, and the results of an exhaustive search of over 300 potential sites. Relevant information was discovered in 5 general categories of gerontology-related information: academic institutions, government agencies, biomedical and health research institutions, general interest sites and data archives.

Acetabular changes in an experimental model of developmental dysplasia of the hip (DDH).

We wished to correlate the morphological acetabular changes in developmental dysplasia of the hip (DDH) with changes at the tissue level. A secondary aim was to develop a way of measuring the dysplastic acetabulum. We studied the changes in rabbit acetabula after maintaining knee extension, measuring the major diameter from the acetabular notch to the farthest opposite point on the acetabular margin. The minor diameter was at right angles to this. The dysplastic acetabula showed elongation along the major diameter compared to control hips. Microscopic sections were made along major and minor diameters. The posterosuperior lip of the dysplastic acetabulum showed an early eversion of the acetabular cartilage. Growth of the articular cartilage in this new direction accounted for the acetabular elongation. As well as providing insight into the manner of acetabular shape change, the findings suggest the nature of remodeling required before normal acetabular growth can resume during treatment.

False aneurysm complicating closed femoral fracture in a child.

False aneurysms are a recognized but rare complication of closed fractures. The authors report the case of a false aneurysm of the superficial femoral artery complicating a closed transverse fracture of the femoral shaft in a child treated with skeletal traction. The literature of this entity is reviewed.