A walking model to assess the onset of analgesia in osteoarthritis knee pain.

OBJECTIVE: To assess a walking model utilizing a set of standardized treadmill walks to measure acute analgesic response in osteoarthritis (OA) of the knee. DESIGN: Randomized, double-blind, placebo-controlled, multiple dose, three-period crossover study. Patients > or =45 years of age (N=22) with symptomatic knee OA were randomized to naproxen 500 mg bid, tramadol/acetaminophen 37.5 mg/325 mg in forced titration, or placebo in each of three periods. Patients performed multiple 20-minute treadmill walks on Day 1 and Day 3 at a consistent self-selected pace predetermined at screening. Pain intensity (PI) during the walks was assessed on an 11-point numerical rating scale at 0, 3, 6, 9, 12, 15, 18, and 20 min. The primary endpoint was the time-weighted average (TWA) change from baseline PI on Day 3 for the two self-paced walks for the active treatments vs placebo. Time to moderate pain (TTMP) was a key secondary endpoint. RESULTS: Compared with placebo, the TWA change from baseline PI on Day 3 was significantly better with tramadol/acetaminophen (P=0.043) but not with naproxen (P=0.089). TWA change from baseline on Day 1 was also significantly better with both tramadol/acetaminophen (P=0.001) and naproxen (P=0.048) compared with placebo. TTMP was significantly better for tramadol/acetaminophen and naproxen than placebo (P<0.001 to P=0.015) for walks on Day 1 after a single dose and on Day 3. CONCLUSIONS: This novel OA pain model was able to discriminate both tramadol/acetaminophen and naproxen from placebo after single and multiple doses. ClinicalTrials.gov identifier: NCT00772967.

Mortality associated with Acinetobacter baumannii infections experienced by lung transplant recipients.

Lung transplantation (LTX) requires continual systemic immunosuppression, which can result in infections that may compromise recipient survival. A recent outbreak of Acinetobacter baumannii at our institution resulted in infections experienced in both LTX recipients and nontransplant patients. A retrospective review was conducted of patients who had A. baumannii recovered from blood, other normally sterile body fluids, and/or respiratory secretions and who had clinical follow-up extending to 1 year postinfection. A. baumannii was considered "multidrug-resistant" when its growth was not inhibited by minimum inhibitory concentrations of multiple antibiotics. Despite the resistance profile, patients were treated with a combination of antibiotics, which included tigecycline, colistimethate, and when susceptible, imipenem. Once infection was diagnosed, immunosuppression was reduced in all LTX recipients. Six LTX recipients became infected with A. baumannii and were contrasted to infections identified in 14 non-LTX, nonimmunosuppressed patients. A. baumannii was persistently recovered in 4 of 6 LTX recipients (66.7%) compared with only 1 of 14 (7.1%) non-LTX patients (χ(2) = 9.9, p = 0.005). LTX recipients received antibiotic therapy for an average of 76 ± 18.4 days compared with 16.0 ± 6.8 days for the non-LTX patients (p = 0.025, Mann-Whitney U test). All 4 of the 6 (66.7%) LTX recipients died as a consequence of their infection compared with 1 of 14 (7.1%) of the non-LTX patients (χ(2) = 9.9, p = 0.005). Despite receiving more antibiotic therapy, LTX recipients who were infected with multidrug-resistant A. baumannii were less likely to clear their infection and experienced greater mortality compared with non-LTX patients.

Correction of displaced peritoneal dialysis catheters with an angular stiff rod.

BACKGROUND: Fluoroscopically guided guidewire manipulations are readily available and inexpensive methods of correcting malfunctioning peritoneal dialysis catheters, with reported success rates ranging from 25% to 67%. PURPOSE: To improve the success rates of guidewire manipulations with a modified technique. MATERIAL AND METHODS: Using a stiff rod and a stiff wire under fluoroscopy guidance, catheters that had migrated were drawn back into the rectovesical pouch. An angular rod was used to lever the catheter downward, and the guidewire was used to push the catheter down. RESULTS: No complications developed, and immediate success was achieved in 13 of 14 interventions. With this technique, catheter patency in chronic ambulatory peritoneal dialysis (CAPD) patients (11/12) was higher than that of previously reported methods. Durable success was maintained in nine of 12 patients after a single intervention. All re-manipulations (2/2) were successful. CONCLUSION: Although used in only 14 interventions in 12 patients, the outcome was promising. This method is a safe and favorable alternative to other guidewire manipulations, based on absence of complications and high success.

Endovascular stent placement in patients with hepatic artery stenoses or thromboses after liver transplant.

Hepatic artery stenosis or thrombosis following liver transplant is a potentially life-threatening complication. Successful liver transplant depends on uncompromised hepatic arterial inflow. Early diagnosis and treatment of complications prolong graft survival. Interventional radiologic techniques are frequently used to treat hepatic artery complications. Twenty patients with hepatic artery stenoses (n = 11) or thromboses (n = 9) were included in this study. Eighteen of the 20 patients were successfully treated by stent placement. In 9 patients, early endovascular interventions were performed 1 to 7 days after surgery. Two patients were operated owing to the effects of dissection and bleeding from the hepatic artery. Repeat endovascular interventions were performed 10 times in 6 patients. Follow-up ranged from 5 months to 4.5 years. Nine patients with patent hepatic arteries died during follow-up owing to reasons unrelated to the hepatic artery interventions. In 3 patients, the stents became occluded at 3, 5, and 9 months after surgery but no clinical symptoms were present.

Multidetector computed tomographic angiography findings of splenic artery steal syndrome in liver transplantation.

AIMS: Splenic artery steal syndrome, a common complication in liver transplantation, is diagnosed by conventional angiography showing an enlarged splenic artery and by dynamic findings. The aim of this study was to determine multidetector computed tomographic angiography (MDCTA) findings of splenic artery steal syndrome to develop diagnostic criteria. MATERIALS AND METHODS: Ten patients were diagnosed as displaying splenic artery steal syndrome among 198 liver transplant patients. The diagnosis was confirmed by celiac angiography. In eight of them, MDCTA was performed. Axial and coronal maximum-intensity projection images were obtained in arterial and portal phases. We measured the diameter of the celiac trunk and of the splenic, left gastric, common hepatic, superior mesenteric artery, and transplant hepatic arteries. We also measured the diameter of the proximal and the distal segments of the abdominal aorta, along with the size of the spleen, the ratio of the splenic artery to the common hepatic artery, the ratio of splenic artery to transplant hepatic artery, the diameter of portal vein and superior mesenteric vein. The control group consisted of liver transplant patients with normal liver enzyme levels. We performed Student t test for statistical examination. RESULTS: The diameter of the splenic artery (P<.05), the size of the spleen (P<.01), and the ratio of the splenic to the transplant hepatic arteries (P<.05) was significant between the two groups. The diameter of the splenic artery was larger than 4 mm in all patients in the study group. CONCLUSIONS: Conventional angiography was mandatory for the diagnosis of splenic artery steal syndrome. MDCTA is a noninvasive method. Some computed tomography criteria are important for early diagnosis and treatment.

Nonvascular complications in pediatric liver recipients: multidetector computed tomography evaluation.

In pediatric liver transplantation postoperative diagnosis of complications is crucial for graft salvage. Multidetector computed tomography (MDCT) is a technique to evaluate complications. In this study we present nonvascular abdominal complications encountered in pediatric recipients after liver transplantation. We retrospectively examined 113 MDCT examinations in 43 pediatric patients who underwent liver transplantation between 1997 and 2005. Computed tomography (CT) examinations were made by a 16-detector multislice CT scanner. The pathological findings on CT images were: intraperitoneal free fluid, intrahepatic bile duct dilatation, graft liver infarction, perihepatic and intraperitoneal fluid collections (six biloma), colonic and/or intestinal dilatation, splenic infarction, perihepatic hematoma, right adrenal hemorrhage, perihepatic abscess, incisional hernia, intrahepatic biloma and periportal collar. In one patient intestinal hemorrhage was suspected. Intestinal perforation was suspected in three patients. Among these three patients, one patient died before any surgical intervention. In two patients the diagnosis was confirmed at surgery. In pediatric patients, the short examination time, brief sedation duration, and high-resolution images make MDCT an effective radiological method to evaluate nonvascular transplant complications.

An accessible pharmacodynamic transcriptional biomarker for notch target engagement.

γ-Secretase mediates amyloid production in Alzheimer's disease (AD) and oncogenic activity of Notch. γ-Secretase inhibitors (GSIs) are thus of interest for AD and oncology. A peripheral biomarker of Notch activity would aid determination of the therapeutic window and dosing regimen for GSIs, given toxicities associated with chronic Notch inhibition. This study examined the effects of GSI MK-0752 on blood and hair follicle transcriptomes in healthy volunteers. The effects of a structurally diverse GSI on rhesus blood and hair follicles were also compared. Significant dose-related effects of MK-0752 on transcription were observed in hair follicles, but not blood. The GSI biomarker identified in follicles exhibited 100% accuracy in a clinical test cohort, and was regulated in rhesus by a structurally diverse GSI. This study identified a translatable, accessible pharmacodynamic biomarker of GSI target engagement and provides proof of concept of hair follicle RNA as a translatable biomarker source.

Sacroiliac pain and CT-guided steroid injection treatment: high-grade arthritis has an adverse effect on outcomes in long-term follow-up.

OBJECTIVE: The sacroiliac joint (SIJ) is one of the major sources of low back pain that can lead to severe morbidity. Possible SIJ pain requires a thorough evaluation and treatment option. The purpose of this study was to analyze the possible relationships between computed tomography (CT) grading of SIJ arthritis and the effectiveness of intraarticular steroid injection treatment under CT guidance. PATIENTS AND METHODS: A total of 61 patients with SIJ pain who were treated with CT guided intraarticular steroid injection were retrospectively reviewed. Visual analog scale (VAS) scores for pain control were recorded for short-term (day after injection, first week, third week) and long-term (sixth months and final control) follow-up times. SIJ arthritis was graded using CT images according to the New York criteria. Patients were assigned into low-grade (0, 1 and 2) and high-grade (3 and 4) groups. The relationship between arthritis grades and VAS scores in short and long-term follow-ups were statistically analyzed. RESULTS: Mean age and follow-up was 54.8 years (range: 41-68 years) and 27.8 months (range: 24-36 months), respectively. In 40 patients there was low-grade arthritis, while 21 patients were characterized on having high-grade sacroiliac arthritis detected during the radiological evaluation. There was no statistically significant difference between low and high-grade arthritis in regard to short-term VAS scores. On contrary, for long-term VAS scores, there was significant difference between low- and high-grade arthritis. CONCLUSIONS: Steroid injection treatment for SIJ pain is not effective on a long-term basis for patients with high-grade arthritis, and although they have had decreased VAS scores in the short-term, after 2 years of follow-up, their VAS scores significantly increased leading to symptomatic sacroiliac joint pain.

Acute eosinophilic pneumonia. A summary of 15 cases and review of the literature.

Idiopathic acute eosinophilic pneumonia (AEP) is an acute febrile illness that may be mistaken for an infectious pneumonia. Patients are often young and otherwise healthy. Clues to considering this disorder in a differential diagnosis include the acuity and severity of the clinical presentation and an initial chest X-ray with diffuse infiltrates, often interstitial, and the presence of Kerley B lines and/or evidence of pleural fluid. The diagnosis can be made through examination of bronchoalveolar lavage fluid in most cases, with careful exclusion of other similar eosinophilic lung disease. Although it can lead to life-threatening respiratory failure, AEP is easily treatable with corticosteroids. This disease has not been reported to recur in any patients to this point.

Generation and death of cells in the dorsal lateral geniculate nucleus and superior colliculus of the wallaby, Setonix brachyurus (quokka).

To study postnatal cell generation in primary visual centres of the quokka, tritiated thymidine was injected into pouch-young aged postnatal day (P)1-P85. Brains were examined at P100, just before eye-opening, when primary visual projections are essentially mature. Neurons in the dorsal lateral geniculate nucleus (dLGN) and superior colliculus (SC) were generated at P1-P10 and P1-P18 respectively. Peak numbers of labelled cells were seen at P3 and P5 in the dLGN and SC. Cell death was assessed in the dLGN and SC of young aged P10-P150. Low numbers of dying cells were seen in the dLGN throughout this period, with a small peak at P85. A more substantial peak of cell death was seen in the SC, also at P85. In the quokka, the time interval between the peaks of cell generation and of cell death in the dLGN and SC is 70-80 days, considerably longer than the interval of 40 days between birth and death of retinal cells.

Distinctive pattern of organisation in the retinofugal pathway of a marsupial: I. Retina and optic nerve.

The nasotemporal division in the retina and the pattern of crossed and uncrossed axons in the optic nerve were determined in an Australian marsupial, a wallaby, Setonix brachyurus (the quokka), following unilateral horseradish peroxidase injections into primary visual centres. The gross morphology of the nerve was also examined. Ipsilaterally projecting ganglion cells were restricted to the temporal retina, whereas those that project contralaterally were located in all retinal regions. The morphological study of the nerve showed that fasciculation patterns, evident along much of the length of the nerve, became indistinct centrally and were replaced in the prechiasmatic region by dorsoventrally oriented fissures. In this prechiasmatic region, axons were oriented in two directions. Whereas the majority were aligned centroperipherally with the long axis of the nerve, a proportion were aligned dorsoventrally in the fissures. Labelling with HRP revealed that uncrossed axons were restricted to the lateral region of the optic nerve and possibly to discrete fascicles, whereas those destined to cross at the chiasm occupied all regions of the nerve but were less dense on the lateral side. This spatial distribution of crossed and uncrossed projections did not change along the length of the nerve. These results demonstrate that fibre organisation in the marsupial optic nerve is different than that found in eutherian mammals.

Distinctive pattern of organisation in the retinofugal pathway of a marsupial: II. Optic chiasm.

In the mammalian optic chiasm retinal axons from each eye divide into two populations, those that decussate and those that remain uncrossed. In eutherian (placental) mammals, the separation of these pathways is not reflected in the structure of the chiasm. The two populations from each eye are mixed through each hemichiasm, segregating only at the midline, where the uncrossed projection turns back. In this study the optic chiasm of a marsupial, the wallaby, Setonix brachyurus (quokka) has been investigated with staining and neuronal tracing techniques. The chiasm of this mammal is quite different from that of eutherian mammals. In coronal section it can be morphologically subdivided into three regions, a central body in which fasciculated groups of axons from each eye interdigitate across the midline, and two distinct lateral regions, one on each side, which contain the uncrossed retinal projections. In the rostral chiasm the lateral regions are separated from the main body of the chiasm by vertically oriented fibre-free regions. Caudally, the lateral regions increase in size and become less distinct as increasing numbers of contralaterally projecting axons that have crossed the midline project into them. However, the two populations remain predominantly segregated in this region. As the lateral regions develop, the central body of the chiasm becomes thinner and finally detaches at the midline to form the two optic tracts. The routes taken by retinal axons through the eutherian and marsupial chiasm appear to be fundamentally different. Therefore, the developmental factors that determine the laterality of retinal projections are likely to show significant differences in the two mammalian groups.

Development of the chiasm of a marsupial, the quokka wallaby.

We have previously shown that the mature optic chiasm of a marsupial is divided morphologically into three regions, two lateral regions in which ipsilaterally projecting axons are confined and a central region containing only contralaterally projecting axons. By contrast, in the chiasms of eutherian (placental) mammals studied to date, there is no tripartite configuration. Ipsilaterally and contralaterally projecting axons from each eye are mixed in the caudal nerve and in each hemichiasm and encounter axons from the opposite eye near the midline of the chiasm. Here, we show that, unlike eutherians, marsupials have astrocytic processes in high concentrations in lateral regions of the nerve and rostral chiasm. Early in development, during the period when optic axons are growing through the chiasm, many intrachiasmatic cells are seen with densities five to eight times higher in lateral than in central chiasmatic regions. Such cells continue to be added to all chiasmatic regions; later in development, considerably more are added centrally, as the chiasm increases in volume. In the mature chiasm, cell densities are similar in all regions. By contrast to the marsupial, cell addition in the chiasm of a placental mammal, the ferret, is almost entirely restricted to later developmental stages, after axons have grown through the chiasm, and there are no obvious spatial variations in the distribution of cells during the period examined. During development, similar to the adult marsupial, ipsilaterally projecting axons do not approach the chiasmatic midline but remain confined laterally. We propose that the cells generated early and seen in high densities in the lateral chiasmatic regions of the marsupial may play a role in guiding retinal axons through this region of pathway selection. These data suggest that there is not a common pattern of developmental mechanisms that control the path of axons through the chiasm of different mammals.

First evidence of diversity in eutherian chiasmatic architecture: tree shrews, like marsupials, have spatially segregated crossed and uncrossed chiasmatic pathways.

In the optic chiasm of mammals, axons either cross the midline to the opposite side of the brain or remain uncrossed. In the eutherian species studied to date, uncrossed axons in the caudal nerve are found in all regions. In the chiasm, they are dispersed through the hemichiasm, with many axons approaching the midline and then turning back to enter the same side of the brain as the originating eye. In marsupials, by contrast, uncrossed axons never approach the midline; instead, they remain grouped in the lateral nerve and chiasm. The impression gained from these data is that there is a major difference in chiasmatic architecture between eutherian and marsupial mammals. Therefore, the mechanisms by which axons choose their route through the chiasm was also thought to differ between the two major groups of mammals. However, the present study shows that the chiasm of a highly visual eutherian mammal, the tree shrew, is similar to that found in marsupials, with uncrossed axons confined to lateral regions and not approaching the midline. However, unlike marsupials, in the tree shrew, optic fascicles in the chiasm are often separated by thick collagen bundles. It is probable that the chiasmatic structure described to date for eutherian mammals is not ubiquitous, as was previously thought, and theories explaining the mechanisms by which axons chose their route through the chiasm during development will have to be expanded.

Morphology and birth dates of horizontal cells in the retina of a marsupial.

Most eutherian (placental) mammals have two horizontal cell types; however, one type only has been seen in rodents. In order to assess whether one type of horizontal cell or two is a basic mammalian feature, we have examined the morphology of horizontal cells in a marsupial, the quokka wallaby, by Golgi staining or horseradish peroxidase labelling. The birth dates of horizontal cells have also been determined by 3H-thymidine/autoradiography. There are two types of horizontal cell in the wallaby retina. One type has no axon and corresponds to the axonless cell in eutherian species; the other has shorter dendrites, an axon, and an axonal arbor, corresponding to the eutherian short-axon cell. As in eutherian mammals, the dendrites of each horizontal cell type lie in the outer plexiform layer (OPL) and contact cones and the axonal arbor of the short-axon cell contacts rods. The dendrites of the axonless cells are long, with an average length of 250 microns, and each cell has one, sometimes two, short, stubby processes, which branch off a dendrite, traverse the inner nuclear layer, and reach the inner plexiform layer. The dendritic field of these cells is elongated, and dendrites show a preferential orientation at right angles to the trajectory of overlying ganglion cell axons. Short-axon cells have a morphology similar to that seen in other species, although the axonal arbor is relatively small. Both types of horizontal cell are generated in the first phase of retinal cell generation.

Biphasic retinal neurogenesis in the brush-tailed possum, Trichosurus vulpecula: further evidence for the mechanisms involved in formation of ganglion cell density gradients.

We investigated cell generation in the retina of the brush-tailed possum (Trichosurus vulpecula) by using tritiated (3H)-thymidine labelling of newly generated cells. Animals aged between postnatal day (P) 5 and 85 each received a single injection of 3H-thymidine. Following autoradiographic processing, maps of labelled cells were constructed from retinal sections. Retinal cell generation takes place in two phases, the first is concluding in the retinal periphery at P53 as the second is seen to commence in midtemporal retina. In the first phase, cells in central retina are generated earlier than those in peripheral regions. In the second phase, cells complete their final division in midtemporal retina first and in the periphery last. Cells generated in the first phase comprise virtually all cells in the ganglion cell layer, amacrine cells, horizontal cells, and cones. Ganglion cells are produced at a slightly earlier stage than displaced amacrine cells, horizontal cells, or cones. Amacrine cells in the inner nuclear layer are the final cells produced in the first phase. When ganglion cells and amacrine cells are pooled, their combined rate of production matches that of the other cell types. These data indicate that the ratio of displaced amacrine cells: horizontal cells: cones: combined ganglion cells and amacrine cells does not change throughout development. However, the ratio of ganglion cells:macrines changes steadily as development proceeds to favour amacrine cells. In the second phase, sparse numbers of nonganglion cells in the ganglion cell layer and large numbers of bipolar and Müller cells are produced along with all rods. The two phases in the possum are similar to those seen in the wallaby, the quokka. However, fewer cells are added in central retina in the possum than in the quokka and cell addition continues for a more extended period in the periphery in the possum. We suggest that this difference in cell addition could account for the development of a more pronounced visual streak of retinal ganglion cells in the possum than in the quokka. A comparison of possum retinal cell generation with that of other marsupials adds support for the "homochrony theory."

Cell death in the inner and outer nuclear layers of the developing retina in the wallaby Setonix brachyurus (quokka).

We have examined the number and distribution of dying cells in the developing inner (INL) and outer (ONL) nuclear layers of sectioned quokka retinae (N = 31) from embryonic day (E)24 to postnatal day (P)192. Before birth, dying cells were seen in the optic fissure. Thereafter two major phases of cell death took place in the INL. The first phase was more pronounced within the vitread part with peak numbers of dying cells at P50. By contrast, during the second phase, cell death was more extensive in the sclerad portion; peak numbers of dying cells were recorded at P85 and P100 for the vitread and sclerad parts respectively. At these stages, photoreceptors were seen in the INL suggesting that these ectopic cells contribute to the pool of dying cells. The pattern of cell death broadly followed a central to peripheral sequence in the first phase but, in the second, was seen initially in mid-temporal retina and then became panretinal. Dying cells were seen in the ONL but in smaller numbers than in the INL. There was a peak of cell death at P26 which may represent death of mitotic cells at the ventricular surface. In the quokka, retinal cell genesis takes place in two phases (Harman and Beazley: Neuroscience 28:219-232, '89). The two major phases of cell death described here peak approximately 40 days after episodes of maximal cell genesis. These findings, together with data for the mouse, suggest that a biphasic pattern of cell genesis and cell death may be a feature of eutherian as well as marsupial retinal development.

Retinal pigment epithelium and photoreceptor maturation in a wallaby, the quokka.

Cell generation and the early stages of maturation of the retinal pigment epithelium (RPE) and photoreceptors were examined in a marsupial, the quokka, Setonix brachyurus. Results are presented for animals aged up to postnatal day (P)250. RPE cell generation was studied by analysis of cell number from wholemounted retinae and by tritiated thymidine (3HThy) autoradiography in sectioned material. For 3HThy autoradiography, quokkas aged P1-P200 were injected with 3HThy and killed either 6-20 hours later (pulse-kill) or at P100 or P250 (pulse-leave). The extent of pigmentation of the RPE sheet was examined from sections of embryonic and early postnatal stages. Retinae from animals aged P5 to P160 were also examined at the electron microscope. By P100, RPE cell number is within the range found in adults. New RPE cells are generated in a peripheral band which moves outwards as cells leave the cell cycle in more central locations. RPE cells thus complete their last cell division in a centre-to-periphery wave centred about the optic nerve head. At any given retinal location, RPE cells complete their last cell division earlier than the overlying layers of the neural retina. Cells of the RPE rapidly develop a mature morphology. For example, melanin granules are observed at P5 and Verhoeff's membrane (the terminal bar complex) is evident by P25. By contrast, photoreceptor development in this species is protracted; cone inner segments are observed by P40, whilst the first rod inner segments are observed at P60. Despite being generated earlier, morphological maturation of the cones appears retarded and prolonged compared with that of the rods. The last stages of RPE cell maturation occur late in development, in synchrony with the generation of rods.