Excellent diagnostic characteristics for ultrafast gene profiling of DEFA1-IL1B-LTF in detection of prosthetic joint infections

The timely and exact diagnosis of prosthetic joint infection (PJI) is crucial for surgical decision-making. Intraoperatively, delivery of the result within an hour is required. Alpha-defensin lateral immunoassay of joint fluid (JF) is precise for the intraoperative exclusion of PJI; however, for patients with a limited amount of JF and/or in cases where the JF is bloody, this test is unhelpful. Important information is hidden in periprosthetic tissues that may much better reflect the current status of implant pathology. We therefore investigated the utility of the gene expression patterns of 12 candidate genes (TLR1, -2, -4, -6, and 10, DEFA1, LTF, IL1B, BPI, CRP, IFNG, and DEFB4A) previously associated with infection for detection of PJI in periprosthetic tissues of patients with total joint arthroplasty (TJA) (n = 76) reoperated for PJI (n = 38) or aseptic failure (n = 38), using the ultrafast quantitative reverse transcription-PCR (RT-PCR) Xxpress system (BJS Biotechnologies Ltd.). Advanced data-mining algorithms were applied for data analysis. For PJI, we detected elevated mRNA expression levels of DEFA1 (P < 0.0001), IL1B (P < 0.0001), LTF (P < 0.0001), TLR1 (P = 0.02), and BPI (P = 0.01) in comparison to those in tissues from aseptic cases. A feature selection algorithm revealed that the DEFA1-IL1B-LTF pattern was the most appropriate for detection/exclusion of PJI, achieving 94.5% sensitivity and 95.7% specificity, with likelihood ratios (LRs) for positive and negative results of 16.3 and 0.06, respectively. Taken together, the results show that DEFA1-IL1B-LTF gene expression detection by use of ultrafast qRT-PCR linked to an electronic calculator allows detection of patients with a high probability of PJI within 45 min after sampling. Further testing on a larger cohort of patients is needed.Web of Science5592697268

Genetic association of CDC2 with cerebrospinal fluid tau in Alzheimer's disease

We have recently reported that a polymorphism in the cell division cycle (CDC2) gene, designated Ex6 + 7I/D, is associated with Alzheimer's disease (AD). The CDC2 gene is located on chromosome 10q21.1 close to the marker D10S1225 linked to AD. Active cdc2 accumulates in neurons containing neurofibrillary tangles (NFT), a process that can precede the formation of NFT. Therefore, CDC2 is a promising candidate susceptibility gene for AD. We investigated the possible effects of the CDC2 polymorphism on cerebrospinal fluid (CSF) biomarkers in AD patients. CDC2 genotypes were evaluated in relation to CSF protein levels of total tau, phospho-tau and beta-amyloid (1-42) in AD patients and control individuals, and in relation to the amount of senile plaques and NFT in the frontal cortex and in the hippocampus in patients with autopsy-proven AD and controls. The CDC2 Ex6 + 7I allele was associated with a gene dose-dependent increase of CSF total tau levels (F-2,F- 626 = 7.0, p = 0.001) and the homozygous CDC2Ex6 +7II genotype was significantly more frequent among AD patients compared to controls (p = 0.006, OR = 1.57, 95% CI 1.13-2.17). Our results provide further evidence for an involvement of cdc2 in the pathogenesis of AD. Copyright (C) 2005 S. Karger AG, Basel

Pseudoaneurysm overlying an osteochondroma: a noteworthy complication

Pseuodaneurysms are an extremely rare complication of osteochondromas. We describe a case of traumatic pseudoaneurysm of the brachial artery presenting as a soft tissue mass in a patient who was treated for an osteochondroma 3 years earlier. This case demonstrates that radiographic follow-up of large osteochondromas is mandatory and that, in patients with soft tissue masses and a history of osteochondroma, pseudoaneurysms should be included in the differential diagnosis

Elevated cerebrospinal fluid pressure in patients with Alzheimer's disease

BACKGROUND: Abnormalities in cerebrospinal fluid (CSF) production and turnover, seen in normal pressure hydrocephalus (NPH) and in Alzheimer's disease (AD), may be an important cause of amyloid retention in the brain and may relate the two diseases. There is a high incidence of AD pathology in patients being shunted for NPH, the AD-NPH syndrome. We now report elevated CSF pressure (CSFP), consistent with very early hydrocephalus, in a subset of AD patients enrolled in a clinical trial of chronic low-flow CSF drainage. Our objective was to determine the frequency of elevated CSFP in subjects meeting National Institutes of Neurological and Communicative Diseases and Stroke – Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria for AD, excluding those with signs of concomitant NPH. METHODS: AD subjects by NINCDS-ADRDA criteria (n = 222), were screened by history, neurological examination, and radiographic imaging to exclude those with clinical or radiographic signs of NPH. As part of this exclusion process, opening CSFP was measured supine under general anesthesia during device implantation surgery at a controlled pCO(2 )of 40 Torr (40 mmHg). RESULTS: Of the 222 AD subjects 181 had pressure measurements recorded. Seven subjects (3.9%) enrolled in the study had CSFP of 220 mmH(2)0 or greater, mean 249 ± 20 mmH(2)0 which was significantly higher than 103 ± 47 mmH(2)O for the AD-only group. AD-NPH patients were significantly younger and significantly less demented on the Mattis Dementia Rating Scale (MDRS). CONCLUSION: Of the AD subjects who were carefully screened to exclude those with clinical NPH, 4% had elevated CSFP. These subjects were presumed to have the AD-NPH syndrome and were withdrawn from the remainder of the study

Cerebral hypoperfusion accelerates cerebral amyloid angiopathy and promotes cortical microinfarcts

Cortical microinfarcts (CMIs) observed in brains of patients with Alzheimer’s disease tend to be located close to vessels afflicted with cerebral amyloid angiopathy (CAA). CMIs in Alzheimer’s disease are preferentially distributed in the arterial borderzone, an area most vulnerable to hypoperfusion. However, the causal association between CAA and CMIs remains to be elucidated. This study consists of two parts: (1) an observational study using postmortem human brains (n = 31) to determine the association between CAA and CMIs, and (2) an experimental study to determine whether hypoperfusion worsens CAA and induces CMIs in a CAA mouse model. In postmortem human brains, the density of CMIs was 0.113/cm2 in mild, 0.584/cm2 in moderate, and 4.370/cm2 in severe CAA groups with a positive linear correlation (r = 0.6736, p < 0.0001). Multivariate analysis revealed that, among seven variables (age, disease, senile plaques, neurofibrillary tangles, CAA, atherosclerosis and white matter damage), only the severity of CAA was a significant multivariate predictor of CMIs (p = 0.0022). Consistent with the data from human brains, CAA model mice following chronic cerebral hypoperfusion due to bilateral common carotid artery stenosis induced with 0.18-mm diameter microcoils showed accelerated deposition of leptomeningeal amyloid β (Aβ) with a subset of them developing microinfarcts. In contrast, the CAA mice without hypoperfusion exhibited very few leptomeningeal Aβ depositions and no microinfarcts by 32 weeks of age. Following 12 weeks of hypoperfusion, cerebral blood flow decreased by 26% in CAA mice and by 15% in wild-type mice, suggesting impaired microvascular function due to perivascular Aβ accumulation after hypoperfusion. Our results suggest that cerebral hypoperfusion accelerates CAA, and thus promotes CMIs

Chordoma: clinical characteristics, management and prognosis of a case series of 25 patients

<p>Abstract</p> <p>Background</p> <p>Adequate surgery still remains the only curative treatment of chordoma. Interesting clinical data on advanced disease with molecularly targeted therapies were reported.</p> <p>Methods</p> <p>We described the clinical outcome of a series of chordoma patients followed at Regina Elena National Cancer Centre of Rome from 2004 to 2008.</p> <p>Results</p> <p>Twenty-five consecutive patients with sacral (11 patients), spine (13 patients), and skull base (1 patient) chordoma went to our observation. Six patients (24%) had primary disease, 14(56%) a recurrent disease, and 5(20%) a metastatic spreading. Surgery was the primary option for treatment in 22 out of 25 patients. Surgical margins were wide in 5 (23%) and intralesional in 17(77%) patients; 3 out of 4 in-house treated patients obtained wide margins. After first surgery, radiotherapy (protons or high-energy photons) were delivered to 3 patients. One out of the 5 patients with wide margins is still without evidence of disease at 20 months from surgery; 2 patients died without evidence of disease after 3 and 36 months from surgery. Sixteen out of 17 (94%) patients with intralesional margins underwent local progression at a median time of 18 months with a 2-year local progression-free survival of 47%. The 5-year metastasis-free survival rate was 78.3%. Seventeen patients with locally advanced and/or metastatic disease expressing platelet-derived growth factor receptor (PDGFR) β were treated with imatinib mesylate. A RECIST stabilization of the disease was the best response observed in all treated cases. Pain relief with reduction in analgesics use was obtained in 6 out of 11 (54%) symptomatic patients. The 5- and 10-year survival rates of the entire series of patients were 76.7 and 59.7%, respectively.</p> <p>Conclusions</p> <p>Despite progress of surgical techniques and the results obtained with targeted therapy, more effort is needed for better disease control. Specific experience of the multidisciplinar therapeutic team is, however, essential to succeed in improving patients' outcome.</p

Frequent deletion of the CDKN2A locus in chordoma: analysis of chromosomal imbalances using array comparative genomic hybridisation

The initiating somatic genetic events in chordoma development have not yet been identified. Most cytogenetically investigated chordomas have displayed near-diploid or moderately hypodiploid karyotypes, with several numerical and structural rearrangements. However, no consistent structural chromosome aberration has been reported. This is the first array-based study characterising DNA copy number changes in chordoma. Array comparative genomic hybridisation (aCGH) identified copy number alterations in all samples and imbalances affecting 5 or more out of the 21 investigated tumours were seen on all chromosomes. In general, deletions were more common than gains and no high-level amplification was found, supporting previous findings of primarily losses of large chromosomal regions as an important mechanism in chordoma development. Although small imbalances were commonly found, the vast majority of these were detected in single cases; no small deletion affecting all tumours could be discerned. However, the CDKN2A and CDKN2B loci in 9p21 were homo- or heterozygously lost in 70% of the tumours, a finding corroborated by fluorescence in situ hybridisation, suggesting that inactivation of these genes constitute an important step in chordoma development