Radiological follow-up of endovascularly treated intracranial aneurysms: a survey of current practice in the UK and Ireland.

PURPOSE: Due to the risk of intracranial aneurysm (IA) recurrence and the potential requirement for re-treatment following endovascular treatment (EVT), radiological follow-up of these aneurysms is necessary. There is little evidence to guide the duration and frequency of this follow-up. The aim of this study was to establish the current practice in neurosurgical units in the UK and Ireland. METHODS: A survey was designed with input from interventional neuroradiologists and neurosurgeons. Neurovascular consultants in each of the 30 neurosurgical units providing a neurovascular service in the UK and Ireland were contacted and asked to respond to questions regarding the follow-up practice for IA treated with EVT in their department. RESULTS: Responses were obtained from 28/30 (94%) of departments. There was evidence of wide variations in the duration and frequency of follow-up, with a minimum follow-up duration for ruptured IA that varied from 18 months in 5/28 (18%) units to 5 years in 11/28 (39%) of units. Young patient age, previous subarachnoid haemorrhage and incomplete IA occlusion were cited as factors that would prompt more intensive surveillance, although larger and broad-necked IA were not followed-up more closely in the majority of departments. CONCLUSIONS: There is a wide variation in the radiological follow-up of IA treated with EVT in the UK and Ireland. Further standardisation of this aspect of patient care is likely to be beneficial, but further evidence on the behaviour of IA following EVT is required in order to inform this process.

CT scan exposure in children with ventriculo-peritoneal shunts: single centre experience and review of the literature.

PURPOSE: A computed tomography (CT) scan in childhood is associated with a greater incidence of brain cancer. CT scans are used in patients with ventriculo-peritoneal (VP) shunts in whom shunt dysfunction is suspected. We wanted to assess the CT scan exposure in a cohort of children with VP shunts and attempt to quantify their radiation exposure. METHODS: A single-centre retrospective analysis was performed recording CT head scans in children younger than 18 years with VP shunts. Hospital coding data was cross-referenced with electronic records and radiology databases both in our neurosurgery unit and in hospitals referring to it. RESULTS: One hundred and fifty-two children with VP shunts were identified. The mean time with shunt in situ was 5.4 years (± 4.61). A mean of 3.33 CT scans (range 0-20) were performed on each child, amounting to 0.65 (± 0.87) CTs per shunt year. Based on 2 msv of radiation per scan, this equates to an average exposure of 1.31 msv per child per shunt year. CONCLUSION: Children who have multiple CT head scans for investigation of possible shunt dysfunction are at a greater risk of developing cancer. We discuss the implications of this increased risk and discuss strategies to limit radiation exposure in children with VP shunts.

Observed rupture of unruptured intracranial aneurysms.

Aim: To study the aneurysms where pre and post-rupture imaging was available to determine the impact of rupture on morphology and size of the aneurysm.Methods: A retrospective case series where all cases of ruptured aneurysms over a 5-year period were evaluated and cases identified where pre and post rupture imaging was available. These were then studied in detail.Results: The actual change in the volume of the aneurysm pre and post rupture was quite small and the underlying shape/morphology did not change at all.Conclusion: Post-rupture morphology of aneurysms can be used as representative of pre-rupture morphology. Further larger studies in collaboration with other neurosurgical centres to corroborate this view would be helpful.

Neurofibromatosis type 1 and male breast cancer: emerging risk factor?

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder characterized by the appearance of cafe au lait spots, neurofibromas and Lisch nodules. There is an established link between NF1 and the development of breast cancer in women; however, due to the rarity of both NF1 and male breast cancer, the same link has yet to be elucidated in men. The concurrent presentation of NF1 and male breast cancer is a very rare phenomenon with only a handful of case descriptions in the literature. To the best of our knowledge, there have only been four other reported cases of NF1 and male breast cancer before ours. We present one such case of a 56-year-old male with a four generation history of NF1 and a personal history of NF1 who presented with invasive ductal carcinoma of the right breast.

Vitamin E in aging persons with Down syndrome: A randomized, placebo-controlled clinical trial.

OBJECTIVE: To determine whether vitamin E would slow the progression of cognitive deterioration and dementia in aging persons with Down syndrome (DS). METHODS: A randomized, double-blind controlled clinical trial was conducted at 21 clinical sites, and researchers trained in research procedures recruited adults with DS older than 50 years to participate. Participants were randomly assigned to receive 1,000 IU of vitamin E orally twice daily for 3 years or identical placebo. The primary outcome was change on the Brief Praxis Test (BPT). Secondary outcomes included incident dementia and measures of clinical global change, cognition, function, and behavior. RESULTS: A total of 337 individuals were randomized, 168 to vitamin E and 169 to placebo. Both groups demonstrated deterioration on the BPT with no difference between drug and placebo. At baseline, 26% were diagnosed with dementia and there was an overall rate of incident dementia of 11%/year with no difference between groups. There was no effect on the secondary outcome measures. Though numerically higher in the treatment group, there was no difference in the number of adverse events (p = 0.079) and deaths (p = 0.086) between groups. CONCLUSIONS: Vitamin E did not slow the progression of cognitive deterioration in older individuals with DS. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that vitamin E does not significantly slow the progression of cognitive deterioration in aging persons with DS.

The mTORC1/4E-BP pathway coordinates hemoglobin production with L-leucine availability.

In multicellular organisms, the mechanisms by which diverse cell types acquire distinct amino acids and how cellular function adapts to their availability are fundamental questions in biology. We found that increased neutral essential amino acid (NEAA) uptake was a critical component of erythropoiesis. As red blood cells matured, expression of the amino acid transporter gene Lat3 increased, which increased NEAA import. Inadequate NEAA uptake by pharmacologic inhibition or RNAi-mediated knockdown of LAT3 triggered a specific reduction in hemoglobin production in zebrafish embryos and murine erythroid cells through the mTORC1 (mammalian target of rapamycin complex 1)/4E-BP (eukaryotic translation initiation factor 4E-binding protein) pathway. CRISPR-mediated deletion of members of the 4E-BP family in murine erythroid cells rendered them resistant to mTORC1 and LAT3 inhibition and restored hemoglobin production. These results identify a developmental role for LAT3 in red blood cells and demonstrate that mTORC1 serves as a homeostatic sensor that couples hemoglobin production at the translational level to sufficient uptake of NEAAs, particularly L-leucine.

Snx3 regulates recycling of the transferrin receptor and iron assimilation.

Sorting of endocytic ligands and receptors is critical for diverse cellular processes. The physiological significance of endosomal sorting proteins in vertebrates, however, remains largely unknown. Here we report that sorting nexin 3 (Snx3) facilitates the recycling of transferrin receptor (Tfrc) and thus is required for the proper delivery of iron to erythroid progenitors. Snx3 is highly expressed in vertebrate hematopoietic tissues. Silencing of Snx3 results in anemia and hemoglobin defects in vertebrates due to impaired transferrin (Tf)-mediated iron uptake and its accumulation in early endosomes. This impaired iron assimilation can be complemented with non-Tf iron chelates. We show that Snx3 and Vps35, a component of the retromer, interact with Tfrc to sort it to the recycling endosomes. Our findings uncover a role of Snx3 in regulating Tfrc recycling, iron homeostasis, and erythropoiesis. Thus, the identification of Snx3 provides a genetic tool for exploring erythropoiesis and disorders of iron metabolism.

Teleost growth factor independence (gfi) genes differentially regulate successive waves of hematopoiesis.

Growth Factor Independence (Gfi) transcription factors play essential roles in hematopoiesis, differentially activating and repressing transcriptional programs required for hematopoietic stem/progenitor cell (HSPC) development and lineage specification. In mammals, Gfi1a regulates hematopoietic stem cells (HSC), myeloid and lymphoid populations, while its paralog, Gfi1b, regulates HSC, megakaryocyte and erythroid development. In zebrafish, gfi1aa is essential for primitive hematopoiesis; however, little is known about the role of gfi1aa in definitive hematopoiesis or about additional gfi factors in zebrafish. Here, we report the isolation and characterization of an additional hematopoietic gfi factor, gfi1b. We show that gfi1aa and gfi1b are expressed in the primitive and definitive sites of hematopoiesis in zebrafish. Our functional analyses demonstrate that gfi1aa and gfi1b have distinct roles in regulating primitive and definitive hematopoietic progenitors, respectively. Loss of gfi1aa silences markers of early primitive progenitors, scl and gata1. Conversely, loss of gfi1b silences runx-1, c-myb, ikaros and cd41, indicating that gfi1b is required for definitive hematopoiesis. We determine the epistatic relationships between the gfi factors and key hematopoietic transcription factors, demonstrating that gfi1aa and gfi1b join lmo2, scl, runx-1 and c-myb as critical regulators of teleost HSPC. Our studies establish a comparative paradigm for the regulation of hematopoietic lineages by gfi transcription factors.

What can we learn from study of Alzheimer's disease in patients with Down syndrome for early-onset Alzheimer's disease in the general population?

The clinical and scientific study of dementia in adults with Down syndrome led to the development of the amyloid hypothesis as a fundamental concept in Alzheimer's disease pathogenesis. The journey started with the discovery of the structure and metabolic processing of ß-amyloid brain deposits associated with Alzheimer's dementia in adults with Down syndrome, and then the prediction and confirmation of the amyloid precursor protein gene on chromosome 21. The processes and genes responsible for tau hyperphosphorylation contributing to toxic brain deposits were additionally identified. With increasing sophistication in genetic experimental techniques, additional mechanisms associated with excessive amyloid deposits were postulated and tested in brains of people with Down syndrome and Alzheimer's disease and in those with early-onset Alzheimer's disease. This in turn led to the proposal and testing for particular genetic defects associated with familial early-onset Alzheimer's disease. Nearly 200 genetic causes of early-onset types of Alzheimer's disease have since been identified. Only a minority of these causes are on chromosome 21, although the aetiology of excess amyloid production remains fundamental to their pathogenesis. Knowledge of the pathogenic mechanisms of Alzheimer's disease in predisposed families and in people with Down syndrome is a step closer to prevention or cure of this devastating disease.

The incidence of deep brain stimulator hardware infection: the effect of change in antibiotic prophylaxis regimen and review of the literature.

The complication of hardware infection related to deep brain stimulator implantation (or revision) varies between 0 and 15.2% in the literature. However, no national guidelines exist at present to define an average or acceptable rate of infection associated with, nor the preferred antibiotic prophylaxis required for, this procedure. The aim of this study was to examine the effect of changing the antibiotic prophylaxis regimen used in a single neurosurgical centre on the incidence and outcome of hardware infection. A prospective cohort of 38 patients undergoing deep brain stimulation (DBS) implantation or internal pulse generator (IPG) replacement and receiving perioperative vancomycin (including intravenous gentamicin on induction) and pouch-installed gentamicin, was compared to a historical cohort of 35 patients receiving perioperative cefuroxime in the same unit. The infection rate over 2 years in the prospective group for DBS surgery was 0 compared to 1 (5.6%) in the historical cohort (p = 0.11, χ(2)); the infection rate for IPG replacements was 1(3.6%) in the prospective cohort, versus 3 (17.6%) in the historical (p = 0.44, χ(2)). In this article, we have also systematically reviewed the literature to date and derived an average infection rate of 4.7% (PI 0.9-22%, Random Effects Meta-analysis, Stata) for 35 studies comprising 3550 patients. There is no significant difference in infection rates between DBS procedures that are primarily internalised (n = 9) compared to those in which there is a period of electrode externalisation (n = 23) (p = 0.9, Meta-regression analysis, Stata).

Link between DYRK1A overexpression and several-fold enhancement of neurofibrillary degeneration with 3-repeat tau protein in Down syndrome.

Triplication of chromosome 21 in Down syndrome (DS) results in overexpression of the minibrain kinase/dual-specificity tyrosine phosphorylated and regulated kinase 1A gene (DYRK1A). DYRK1A phosphorylates cytoplasmic tau protein and appears in intraneuronal neurofibrillary tangles (NFTs). We have previously shown significantly more DYRK1A-positive NFTs in DS brains than in sporadic Alzheimer disease (AD) brains. This study demonstrates a gene dosage-proportional increase in the level of DYRK1A in DS in the cytoplasm and the cell nucleus, and enhanced cytoplasmic and nuclear immunoreactivity of DYRK1A in DS. The results suggest that overexpressed DYRK1A may alter both phosphorylation of tau and alternative splicing factor (ASF). Two-dimensional electrophoresis revealed modification of ASF phosphorylation in DS/AD and AD in comparison to controls. Altered phosphorylation of ASF by overexpressed nuclear DYRK1A may contribute to the alternative splicing of the tau gene and an increase by 2.68 × of the 3R/4R ratio in DS/AD, and a several-fold increase in the number of 3R tau-positive NFTs in DS/AD subjects compared with that in sporadic AD subjects. These data support the hypothesis that phosphorylation of ASF by overexpressed DYRK1A may contribute to alternative splicing of exon 10, increased expression of 3R tau, and early onset of neurofibrillary degeneration in DS.

The relationship of plasma Abeta levels to dementia in aging individuals with Down syndrome.

To study the relationship between plasma levels of amyloid beta (Abeta) peptides and dementia in aging individuals with Down syndrome, we investigated the relationship among plasma Abeta, apolipoprotein E genotype and cognitive and clinical factors using baseline specimens form participants in an ongoing clinical trial in individuals with Down syndrome 50 years of age and older. Because of substantial skew in the distribution of peptide levels, analyses used log transformations of the data. The ratio of Abeta42 to Abeta40 was associated with the presence of dementia (P=0.003, df=196, F=9.37); this association persisted after adjustment for age, sex level of mental retardation, and apolipoprotein E genotype. Consistent with recent reports regarding the effect of presenilin mutations on peptide generation, our finding supports the theory that the ratio of Abeta42 to Abeta40 rather than absolute levels of the peptides is important to the pathophysiology of Alzheimer's disease in genetically susceptible populations.

Acute appendicitis in the setting of Clostridium difficile colitis: case report and review of the literature.

A 72-year-old man was hospitalized for exacerbation of chronic obstructive pulmonary disease and was treated with oral prednisone and 7 days of moxifloxacin. Five days after completing the antibiotic course, he developed watery diarrhea and diffuse, crampy abdominal pain. On presentation he was afebrile, and abdominal examination revealed diffuse tenderness without peritoneal signs. Stool tested positive for Clostridium difficile toxin A by enzyme-linked immunosorbent assay. Despite starting oral metronidazole, the patient developed a fever of 101.2 degrees F 36 hours after his initial episode of diarrhea, 12 hours after admission. His abdominal pain intensified and became localized to the right and left lower quadrants. Computed tomography scan revealed both a thickened cecal wall and an edematous appendix with ileocecal stranding consistent with appendicitis. Appendectomy was performed, and the appendix was found to be suppurative in appearance and nonperforated. The cecum had mild edema and erythema, whereas the colon and rectum were grossly unaffected. Pathology examination revealed exudative material in the appendiceal lumen and a diffuse transmural inflammatory cell infiltrate. The patient had an uneventful recovery and continued to improve on oral metronidazole. Although Clostridium difficile colitis and appendicitis are each very common independently, C. difficile as an etiology of appendicitis is exceedingly rare. A review of the literature revealed 2 prior cases. We speculate that this association is underdiagnosed, because milder cases might respond to antibiotic therapy alone, and severe cases might involve the entire colon and require total colectomy. In each scenario, the involvement of the appendix might be overlooked.

Increased serum neopterin levels in adults with Down syndrome.

We quantitated serum neopterin levels in Down syndrome (DS), normal controls, Alzheimer's disease, multiple sclerosis and other neurological diseases. We then analyzed the relationships with age, sex, apolipoprotein E (Apo E) phenotype, and amyloid beta protein 1-40 (Abeta40) and 1-42 (Abeta42) levels. Neopterin levels were higher in DS than all other groups. Levels in young DS (< 40 years of age) and old DS (> 41 years) were similar. There was no significant correlation between neopterin levels and age, sex, Apo E phenotype, and Abeta40 or Abeta42 levels in DS. This lack of correlation between neopterin and Abeta levels suggests that the higher neopterin concentrations in DS group reflect inflammatory cell activation rather than AD neuropathology.

Dollars and sense: attributing value to a level I trauma center in economic terms.

BACKGROUND: Reliable, accurate, program-specific data for hospital product lines are often difficult to obtain. The purpose of this study was to determine the impact that trauma center status has on hospital net income when compared with other traditional hospital product lines and services. METHODS: Over a 3-year period, financial data were collected for 16 payor classes: 8 major payors for all injury diagnoses, in-patient and out-patient. These data were analyzed by total charges, total direct costs, contribution margin, and net income. A key assumption of this strategy was that although injury patients are treated at most hospitals, only trauma center status allows access to patients and provision of services that can contribute significantly to the bottom line. RESULTS: Over the 3-year period, the contribution margin increased for trauma patients (excluding Level I trauma), Level I trauma patients, and the combined population of trauma patients. The most significant portion of the increase resulted from patients seen as a result of trauma center status. CONCLUSION: We conclude that, for our institution, the investment in resources necessary to achieve and maintain trauma center status makes economic sense in that the trauma program contributes favorably to hospital net revenue.

Relation between apolipoprotein E genotype, hepatitis B virus status, and thyroid status in a sample of older persons with Down syndrome.

Dementia of the Alzheimer type (DAT) is common in older persons with Down syndrome (DS). There are three common alleles of the apolipoprotein E (ApoE) gene (Sigma 2, Sigma 3, and Sigma 4) resulting in three different isoforms (E2, E3, and E4) and six different genotypes (2,2; 2,3; 2,4; 3,3; 3,4; and 4,4). Sigma 4 is a risk factor for DAT whereas Sigma 2 appears prophylactic. As hepatitis B virus (HBV) infection and hypothyroidism also are common in DS, we evaluated associations between ApoE type, HBV status, and thyroid status in a sample of older persons with DS (n = 55; mean age, 44.3 +/- 10.8 years) using chi-squared analysis. Participants were classified as E2 (2,2 or 2,3), E3 (3,3), or E4 (3,4 or 4,4); positive for markers of HBV infection in the present or past (i.e., total HBcAb+ and/or HBsAg+ with or without infectivity, defined as HBV+) or negative for markers of HBV infection (defined as HBV-) and, currently receiving thyroid hormone supplement (defined as "hypothyroidism") or having normal thyroid function. The majority of the HBV+ were currently HBcAb+ and HBsAb+, but not HBsAg+. In females, there was an ApoE allele effect on thyroid status (P < or = 0.01), E2 being negatively (P < or = 0.01) and E4 being positively (P < or = 0.05) associated with "hypothyroidism". There was no evidence for an ApoE allele effect on thyroid status in males. There was no evidence for an ApoE allele effect on HBV status, or for an HBV status effect on thyroid status. As thyroid status can affect cognitive function, ApoE allele effects in DAT may, in part, be thyroid effects.

Plasma amyloid beta protein 1-42 levels are increased in old Down Syndrome but not in young Down Syndrome.

Plasma amyloid beta protein 1-40 (Abeta40) and Abeta42 levels were quantitated from 28 young Down syndrome (DS) (20-40 years old), 28 age-matched controls, 32 old DS (41-65 years old) and 32 age-matched controls in a sandwich enzyme-linked immunosorbent assay. Abeta40 levels were higher in young DS and old DS than controls. Abeta42 levels in young DS and controls were similar, however Abeta42 levels were higher in old DS than controls or young DS. The higher Abeta42 levels in old DS suggests that Abeta42 is selectively increased in plasma concurrently with the development of Alzheimer disease neuropathology.