Particulate endocytosis mediates biological responses of human mesenchymal stem cells to titanium wear debris.

Continual loading and articulation cycles undergone by metallic (e.g., titanium) alloy arthroplasty prostheses lead to liberation of a large number of metallic debris particulates, which have long been implicated as a primary cause of periprosthetic osteolysis and postarthroplasty aseptic implant loosening. Long-term stability of total joint replacement prostheses relies on proper integration between implant biomaterial and osseous tissue, and factors that interfere with this integration are likely to cause osteolysis. Because multipotent mesenchymal stem cells (MSCs) located adjacent to the implant have an osteoprogenitor function and are critical contributors to osseous tissue integrity, when their functions or activities are compromised, osteolysis will most likely occur. To date, it is not certain or sufficiently confirmed whether MSCs endocytose titanium particles, and if so, whether particulate endocytosis has any effect on cellular responses to wear debris. This study seeks to clarify the phenomenon of titanium endocytosis by human MSCs (hMSCs), and investigates the influence of endocytosis on their activities. hMSCs incubated with commercially pure titanium particles exhibited internalized particles, as observed by scanning electron microscopy and confocal laser scanning microscopy, with time-dependent reduction in the number of extracellular particles. Particulate endocytosis was associated with reduced rates of cellular proliferation and cell-substrate adhesion, suppressed osteogenic differentiation, and increased rate of apoptosis. These cellular effects of exposure to titanium particles were reduced when endocytosis was inhibited by treatment with cytochalasin D, and no significant effect was seen when hMSCs were treated only with conditioned medium obtained from particulate-treated cells. These findings strongly suggest that the biological responses of hMSCs to wear debris are triggered primarily by the direct endocytosis of titanium particulates, and not mediated by secreted soluble factors. In this manner, therapeutical approaches that suppress particle endocytosis could reduce the bioreactivity of hMSCs to particulates, and enhance long-term orthopedic implant prognosis by minimizing wear-debris periprosthethic osteolysis.     

The value of a pantaloon cast test in surgical decision making for chronic low back pain patients: a systematic review of the literature supplemented with a prospective cohort study

The results of lumbar fusion in chronic low back pain (LBP) patients vary considerably, and there is a need for proper patient selection. Lumbosacral orthoses have been widely used to predict outcome, however, with little scientific support. The aim of the present study was to determine the value of a pantaloon cast test in selecting chronic LBP patients for lumbar fusion or conservative management. First, a systematic review of the literature was carried out in which two independent reviewers identified studies in Medline, Cochrane and Current Contents databases. Three papers met the selection criteria. In the only study with a control group, a significantly better outcome after fusion compared to conservative treatment was found in patients who reported significant pain relief while in a cast (i.e. a positive cast test). The results of lumbar fusion, however, were not significantly different for patients with a positive and those with a negative cast test. In addition to the review, a clinical cohort study of 257 LBP patients, who had been allocated to either lumbar fusion or conservative management by a temporary external transpedicular fixation trial, was performed. Prior to allocation, all had undergone a pantaloon cast test. Patients with no history of prior spine surgery and with a positive pantaloon cast test had a better outcome after lumbar fusion than those treated conservatively (P = 0.002, χ ² test). In patients with previous spine operations the outcomes were poor and the test was of no value. From the literature and the present patient cohort, it was concluded that only in chronic LBP patients without prior spine surgery, a pantaloon cast test with substantial pain relief suggests a favorable outcome of lumbar fusion compared to conservative management. The test has no value in patients who have had previous spine surgery.     

Introducing dental students to clinical patient care: The complete denture prosthodontics transition clinic

Using complete denture treatment as an introduction to clinical patient care for dental students, the purposes of the Complete Denture Prosthodontics Transition Clinic at the University of Colorado School of Dentistry are to reduce the time lapse between the preclinical complete denture prosthodontics course and the first denture patient experience, and to encourage development of student self-confidence and skills. In the 2002 spring semester, faculty at the University of Colorado School of Dentistry initiated the Complete Denture Prosthodontics Transition Clinic for DS-II (second-year) dental students, as an introduction to clinical patient care. Each patient was assigned to a team of two dental students. Three Division of Prosthodontics faculty members staffed each clinic session, providing a student-to-faculty ratio of approximately 6.6:1 and a patient-to-faculty ratio of approximately 3.3:1. All DS-II students in the Class of 2004 delivered their first complete dentures no later than 8 months (average, 184 days) after the last day of the preclinical complete denture prosthodontics course. The time from the diagnostic appointment through the denture placement appointment averaged 39 days for patients treated in this program, compared with an average of 98 days or more for previous classes. The program was successful in achieving the goal of reducing the time lapse between the preclinical complete denture prosthodontics course and the first denture patient experience.     

A presenilin 1 mutation (L420R) in a family with early onset Alzheimer disease,seizures and cotton wool plaques,but not spastic paraparesis

Over 100 mutations in the presenilin‐1 gene (PSEN1) have been shown to result in familial early onset Alzheimer disease (EOAD), but only a relatively few give rise to plaques with an appearance like cotton wool (CWP) and/or spastic paraparesis (SP). A family with EOAD, seizures and CWP was investigated by neuropathological study and DNA sequencing of the PSEN1 gene. Aβ was identified in leptomeningeal vessels and in cerebral plaques. A single point mutation, p.L420R (g.1508T > G) that gives rise to a missense mutation in the eighth transmembrane (TM8) domain of PS1 was identified in two affected members of the family. p.L420R (g.1508T > G) is the mutation responsible for EOAD, seizures and CWP without SP in this family.     

The development of a laparoscopic donor nephrectomy program in a de novo renal transplant program: Evolution of technique and results in over 200 cases.

BACKGROUND AND OBJECTIVES: In 1999, our institution began a kidney transplant program with collaboration between the departments of General Surgery/Transplantation and Urology. From the onset, donor nephrectomies were performed laparoscopically and are currently the domain of Urology, which had no prior laparoscopic experience before this undertaking. We reviewed our experience. METHODS: A database of our experience was kept prospectively from June 1999 to November 2004. Records of both donors and recipients were reviewed. Special attention was directed toward our changes in technique and their relationship to outcomes, with emphasis on graft extraction and overall complication rates. RESULTS: We reviewed the records of 205 consecutive procedures. We report excellent donor outcomes, including mean operative time (112 minutes), estimated blood loss (120 mL), and length of stay (2.3 days). Complication (14.1%) and open conversion (1.5%) rates were low. For the recipients, early (98.0%) and 1-year (94.7%) graft survival, and ureteral ischemia (2.4%) rates were also appropriate with contemporary experience. CONCLUSIONS: We report our results on laparoscopic donor nephrectomy in a de novo renal transplant program. Because of this experience, we have ventured into other horizons of urologic laparoscopy and currently produce enough volume to support a laparoscopic fellowship. We feel that a productive donor nephrectomy program can enhance urologic laparoscopic programs and should be taken advantage of when available.     

PET imaging of the dopamine transporter with 18F-FECNT: a polar radiometabolite confounds brain radioligand measurements.

18F-2beta-Carbomethoxy-3beta-(4-chlorophenyl)-8-(2-fluoroethyl)nortropane (18F-FECNT), a PET radioligand for the dopamine transporter (DAT), generates a radiometabolite that enters the rat brain. The aims of this study were to characterize this radiometabolite and to determine whether a similar phenomenon occurs in human and nonhuman primate brains by examining the stability of the apparent distribution volume in DAT-rich (striatum) and DAT-poor (cerebellum) regions of the brain. METHODS: Two rats were infused with 18F-FECNT and sacrificed at 60 min. Extracts of brain and plasma were analyzed by high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometric (LC-MS) techniques. Two human participants and 3 rhesus monkeys were injected with 18F-FECNT and scanned kinetically, with serial arterial blood analysis. RESULTS: At 60 min after the injection of rats, 18F-FECNT accumulated to levels about 7 times higher in the striatum than in the cortex and cerebellum. The radiometabolite was distributed at equal concentrations in all brain regions. The LC-MS techniques identified N-dealkylated FECNT as a major metabolite in the rat brain, and reverse-phase HPLC detected an equivalent amount of radiometabolite eluting with the void volume. The radiometabolite likely was 18F-fluoroacetaldehyde, the product expected from the N-dealkylation of 18F-FECNT, or its oxidation product, 18F-fluoroacetic acid. The distribution volume in the cerebellum increased up to 1.7-fold in humans between 60 and 300 min after injection and 2.0 +/- 0.1-fold (mean +/- SD; n = 3) in nonhuman primates between 60 and 240 min after injection. CONCLUSION: An 18F-fluoroalkyl metabolite of 18F-FECNT originating in the periphery confounded the measurements of DAT in the rat brain with a reference tissue model. Its uniform distribution across brain regions suggests that it has negligible affinity for DAT (i.e., it is an inactive radiometabolite). Consistent with the rodent data, the apparent distribution volume in the cerebellum of both humans and nonhuman primates showed a continual increase at late times after injection, a result that may be attributed to entry of the radiometabolite into the brain. Thus, reference tissue modeling of 18F-FECNT will be prone to more errors than analysis with a measured arterial input function.     

Caudate nucleus volume and cognitive performance: Are they related in childhood psychopathology?

BACKGROUND: Impaired neuropsychological test performance, especially on tests of executive function and attention, is often seen in children diagnosed with autism spectrum disorders (ASD). Structures involved in fronto-striatal circuitry, such as the caudate nucleus, may support these cognitive abilities. However, few studies have examined caudate volumes specifically in children with ASD, or correlated caudate volumes to cognitive ability. METHODS: Neuropsychological test scores and caudate volumes of children with ASD were compared to those of children with bipolar disorder (BD) and of typically developing (TD) children. The relationship between test performance and caudate volumes was analyzed. RESULTS: The ASD group displayed larger right and left caudate volumes, and modest executive deficits, compared to TD controls. While caudate volume inversely predicted performance on the Wisconsin Card Sorting Test in all participants, it differentially predicted performance on measures of attention across the ASD, BD and TD groups. CONCLUSIONS: Larger caudate volumes were related to impaired problem solving. On a test of attention, larger left caudate volumes predicted increased impulsivity and more omission errors in the ASD group as compared to the TD group, however smaller volume predicted poorer discriminant responding as compared to the BD group.