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.     

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.     

Analysis of surgical management of calvarial tumours and first results of a newly designed robotic trepanation system.

This study was performed to evaluate the surgical strategy in patients with calvarial tumours, in order to design and modify a robot-assisted trepanation system. A total of 75 patients underwent craniectomy for the treatment of calvarial tumours during the 10-year period from 1993 to 2002. The patients' complaints, the size, location and histology of the tumour, and the various cranioplasty techniques used were analysed retrospectively. In a second procedure several craniectomies at typical locations according to the study's results were performed in a laboratory setting using a hexapod robotic tool, constructed at the Helmholtz-Institute, RWTH Aachen University, and plastic model heads. The workflow was documented and the reproducibility and the accuracy of the procedure were registered. A total of 83 surgical procedures were performed on 75 patients. The majority (87 %) of lesions treated surgically were located in the frontal, temporal and anterior parts of the parietal region. Histological examination revealed benign lesions in 66 % of the patients and dural involvement in 46 %. According to these results craniectomies were performed using the robotic system. Mean positioning accuracy of the robotic system while milling was 0.24 mm, with a standard deviation of 0.04 mm, and maximum error under 1 mm. Craniectomies leaving a 1-mm layer of the tabula interna intact to ensure a healthy dura were performed in several regions successfully. The majority of calvarial tumours, requiring surgical treatment in our patients, were located in cosmetically relevant areas in which drilling can be carried out with the robotic trepanation system. Consequently, the surgical approach had to be planned carefully in order to achieve a good cosmetic outcome.     

Etanercept decreases tumor necrosis factor-α activity in chronic wound fluid

High levels of tumor necrosis factor-alpha (TNF-alpha), a pro-inflammatory cytokine, are present in the wound fluid of chronic nonhealing wounds. This leads to increased inflammation, cytokine expression, and ultimately results in impaired wound healing and tissue destruction. Etanercept is a recombinant fusion protein that consists of the soluble TNF receptor (p75) linked to the Fc portion of human IgG1. It is an effective inhibitor of TNF-alpha and has been shown to provide rapid and sustained improvement in rheumatoid arthritis by acting as a soluble receptor binding TNF-alpha and preventing its proinflammatory activities. Therefore, the aim of this study was to determine whether Etanercept could inhibit TNF-alpha activity in chronic wound fluid. Wound fluid was collected from the venous leg ulcers of 16 different patients. The effect of Etanercept on TNF-alpha activity was evaluated using both a TNF-alpha bioassay and an enzyme-linked immunoassay. Etanercept was found to reduce the cytotoxic effect of chronic wound fluid on L929 fibroblasts by approximately 30% and neutralized TNF-alpha binding in the enzyme-linked immunoassay by up to 80%. Direct application of Etanercept to chronic wounds may therefore reduce the inflammatory activity of TNF-alpha, which could reduce the chronicity of venous leg ulcers and thus aid in the healing of these wounds.     

Influences of obese (ob/ob) and diabetes (db/db) genotype mutations on lumber vertebral radiological and morphometric indices: Skeletal deformation associated with dysregulated systemic glucometabolism

Background  

Both diabetes and obesity syndromes are recognized to promote lumbar vertebral instability, premature osteodegeneration, exacerbate progressive osteoporosis and increase the propensity towards vertebral degeneration, instability and deformation in humans.     

Outcomes of low-vision services using optometric and multidisciplinary approaches: a non-randomized comparison

Consecutive patients (n = 215) who were referred to optometric (55%) or multidisciplinary (45%) low-vision services and above 50 years of age were recruited from four hospitals in the Netherlands. They completed two vision-related quality of life questionnaires, the Vision Quality of Life Core Measure (VCM1) and the Low Vision Quality of Life Questionnaire (LVQOL), before their first visit with low-vision services and 1 year later. At follow-up, patients referred to multidisciplinary low-vision services had lower scores on the mobility subscale of the LVQOL than patients referred to optometric low-vision services [5.3 points; 95% confidence interval (CI): 0.2-10.5]. Paired sample t-tests for the two groups of patients taken together show improvement for the VCM1 (3.1 points; 95% CI: 0.6-5.6) and deterioration for the basic aspects of vision (3.5 points; 95% CI: 1.1-5.9) and the mobility (6.6 points; 95% CI: 3.7-9.5) subscales of the LVQOL. In conclusion, people referred to optometric services showed less deterioration in mobility than those referred to multidisciplinary services. No differences were observed for any of the other subscales of the LVQOL and the VCM1. Future research in this field should include randomized controlled designs comparing low-vision services with no treatment or placebo.     

Third, fourth, and sixth cranial nerve palsies following closed head injury.

BACKGROUND: The relationship between the circumstances and severity of closed head injury (CHI) and the clinical and imaging features of cranial nerve 3, 4, and 6 palsies has not been rigorously addressed in a large study. METHODS: Retrospective chart review of 210 consecutive patients with CHI examined at a single tertiary care center from 1987 to 2002. Patients were located by searching the ophthalmology inpatient consultation and neuro-ophthalmology outpatient databases and hospital emergency room billing codes for a diagnosis of traumatic 3, 4, or 6 cranial nerve palsy (Cranial Nerve Injury Group) and a diagnosis of CHI without traumatic 3, 4, or 6 nerve palsy (Control Group). The Cranial Nerve Injury Group was then subdivided into two groups: those with injuries to an individual cranial nerve and those with multiple (including bilateral) cranial nerve injuries. Comparisons between groups were based on age, gender, type of accident, Glasgow Coma Scale (GCS), documented loss of consciousness (LOC), type of ocular injury, presence of systemic injury, need for rehabilitation, physical therapy and cognitive scores, and imaging features. RESULTS: The Cranial Nerve Injury Group had a significantly higher severity of head injury, more CT abnormalities, and worse short-term neurologic outcomes as compared with the Control Group. These trends were also found when each cranial nerve injury subgroup was compared with the Control Group. Those with cranial nerve 3 palsy had the most severe head injury; those with cranial nerve 4 palsy had an intermediate level of head injury; and those with cranial nerve 6 palsy had the lowest level of head injury. There were no consistent associations between the location of the imaging abnormalities and which cranial nerve was damaged. CONCLUSIONS: CHI with palsy of an ocular motor nerve was more severe than CHI without ocular motor nerve palsy, as measured by the GCS, intracranial and skull imaging abnormalities, and a greater frequency of inpatient rehabilitation. Palsy of cranial nerve 3 was associated with relatively more severe CHI than was palsy of cranial nerves 4 or 6. The location of the imaging abnormalities did not correlate with a particular cranial nerve injury.